Industry Report On Metabolic Disorders and Digestive Diseases Drug Market

Industry Report on Metabolic disorders and
Digestive diseases drug market
April 2023
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Terms and Abbreviations (1/8)
Terms and abbreviations

5-HT1A 5-Hydroxytryptamine ANGPTL-3 Angiopoietin-Like 3
6-MP 6-mercaptopurine Acute Pancreatitis, a condition where the pancreas
A1C Hemoglobin A1C Test AP
becomes inflamed over a short period of time
AASLD American Association for the Study of Liver Disease
aPBC Asymptomatic PBC
AC Alcohol-associated Cirrhosis
ACEI Angiotensin-Converting-Enzyme Inhibitors active pharmaceutical ingredients, any substance or
the active component which is responsible for a drug’s mixture of substances intended to be used in the
active moiety
physiological or pharmacological action manufacture of a drug (medicinal) product in order to
AD Alzheimer's Disease API furnish pharmacological activity or other direct effect in
ADP Adenosine Diphosphate the diagnosis, cure, mitigation, treatment, or prevention
AEs Adverse Effects of disease or to affect the structure or function of the
Alcoholic Hepatitis, a type of alcohol-associated liver body
AH
disease characterized by acute liver inflammation ApoC-III Apolipoprotein C-III
AKR1C2 Aldo-Keto Reductase family 1, member C2
Alcoholic Liver Disease, characterized by liver damage apoptosis a type of programed cell death
ALD
caused by heavy alcohol intake aspartate aminotransferase to platelet ratio index, a
Alkaline Phosphatase, an enzyme primarily found in the APRI noninvasive and readily available tool for the
liver, bones, intestine, and kidneys, and a key biomarker assessment of liver fibrosis
ALP indicating the presence of cholestatic liver diseases ARB Angiotensin Receptor Blockers
including primary sclerosing cholangitis and primary biliary
ASBT Apical Sodium-dependent Bile Acid Transporter
cholangitis
Amyotrophic Lateral Sclerosis, a paralyzing progressive ASCVD Atherosclerotic Cardiovascular Disease
ALS disease with a short life expectancy typically of only two to ASK1 Apoptosis Signal-Regulating Kinase 1
five years from diagnosis aspartate aminotransferase, an enzyme found mostly
alanine transaminase, an enzyme found in the liver that in the liver, heart, muscles and kidneys; high levels of
helps convert proteins into energy for the liver cells; the AST
which in the blood may indicate hepatitis, cirrhosis, or
ALT level of ALT increases when the liver is damaged, making it other liver diseases
a biomarker commonly associated with injury or apoptosis
of liver cells ATP Adenosine Triphosphate
AMA American Medical Association Aβ Amyloid β
AMPK AMP-activated protein kinase AMPK AMP-activated protein kinase
1

ANGPTL-3 Angiopoietin-Like 3 berberine, an isoquinoline alkaloid with a long history of
AP Acute Pancreatitis use for its wide-ranging biological effects, particularly
aPBC Asymptomatic PBC antimicrobial effects, in Chinese, Indian and
BBR
active pharmaceutical ingredients, any substance or Middle-Eastern medicine, and is an approved drug for
mixture of substances intended to be used in the the treatment of intestinal infection in mainland China,
manufacture of a drug (medicinal) product in order to Japan and Taiwan
API furnish pharmacological activity or other direct effect in BID two times a day
the diagnosis, cure, mitigation, treatment, or prevention
of disease or to affect the structure or function of the
body the fraction of an administered drug that reaches the
bioavailability
systemic circulation
ApoC-III Apolipoprotein C-III
apoptosis a type of programed cell death
aspartate aminotransferase to platelet ratio index, a

APRI noninvasive and readily available tool for the a measurable indicator of a biological state or
biomarker
assessment of liver fibrosis condition
ARB Angiotensin Receptor Blockers

ASBT Apical Sodium-dependent Bile Acid Transporter
ASCVD Atherosclerotic Cardiovascular Disease BIRC5 Baculoviral Inhibitor of Apoptosis Repeat-Containing 5
ASK1 Apoptosis Signal-Regulating Kinase 1
BP Blood Pressure
aspartate aminotransferase, an enzyme found mostly in bile salt hydrolase, an enzyme produced in the
the liver, heart, muscles and kidneys; high levels of intestinal microbiota that catalyzes the hydrolysis of
AST BSH
which in the blood may indicate hepatitis, cirrhosis, or amide bonds in conjugated bile acids, resulting in the
other liver diseases release of free amino acids
CAGR Compound Annual Growth Rate
ATP Adenosine Triphosphate CAR Chimeric Antigen Receptor
Aβ Amyloid β CBP CREB Binding Protein
2

cholangiocarcinoma, a type of cancer that forms in the Central Nervous System, the part of the nervous
CCA CNS
bile ducts system consisting primarily of the brain and spinal cord
CCR CC Chemokine Receptor CO2 carbon dioxide
Crohn's Disease, a type of inflammatory bowel disease a group of patients as part of a clinical trial who share
CD
which can affect any part of the gastrointestinal tract cohort a common characteristic or experience within a defined
CDE Center for Drug Evaluation period and who are monitored over time
ClinicalTrials.gov, a registry of clinical trials run by the
contract development and manufacturing organization, clinicaltrials United States National Library of Medicine at the
a company that serves other companies in the National Institutes of Health
CDMO pharmaceutical industry on a contract basis to provide
comprehensive services from drug development
through drug manufacturing combination treatment in which a patient is given two or more drugs
therapy (or other therapeutic agents) for a single disease
a disease characterized by a decrease or blockage in
cholestatic liver
the flow of bile, including primary sclerosing cholangitis
disease
and primary biliary cholangitis the simultaneous presence of two or more diseases or
comorbidity
medical conditions in a patient
the impaired liver function caused by the formation of also known as multifactorial disease, caused by a
cirrhosis
scar tissue due to damage caused by liver disease complex disease combination of genetic, lifestyle and environmental
factors
a research study for validating or finding the
therapeutic effects and side effects of test drugs in
clinical trial/study COMT Catechol-O-Methyltransferase
order to determine the therapeutic value and safety of
such drugs
CMC chemistry, manufacturing, and controls CPH Carboxypeptidase H
CRAC Calcium Release-Activated Calcium
contract manufacturing organization, a company that contract research organization, a company that
serves other companies in the pharmaceutical industry CRO provides support to the pharmaceutical, biotechnology,
CMO and medical device industries in the form of research
on a contract basis to provide comprehensive services
for drug manufacturing services outsourced on a contract basis
CRP C-Reactive Protein
3

CRS Cytokine Release Syndrome digestive
health conditions associated with the digestive system
CT Computed Tomography diseases
corrected T1 value, a novel MRI-based quantitative diabetic neuropathy, nerve damages caused by
DN
cT1 metric for assessing a composite of liver inflammation diabetes
and fibrosis dipeptidyl peptidase 4 inhibitors, a class of oral
DPP-4I hypoglycemics that block the enzyme dipeptidyl
peptidase-4 (DPP-4) for the treatment of T2DM
CTCAE Common Terminology Criteria for Adverse Events DR Diabetic Retinopathy
EASL European Association for the Study of the Liver
Cardiovascular Diseases, conditions affecting the heart

CVDs EBV Epstein-Barr Virus
or blood vessels
ELF Enhanced Liver Fibrosis
CVM Cardiovascular and Metabolic
EMA European Medicines Agency
end-of-phase meeting; a meeting held when the clinical

DBS Deep Brain Stimulation EOP meeting trial has reached the end of a particular phase and is
ready to move to the next
DHA Docosahexaenoic Acid EPA Eicosapentaenoic Acid

a complex, chronic metabolic disease characterized by
elevated levels of blood glucose, which leads over time
to serious damage to the heart, blood vessels, eyes, ER Extended Release
diabetes
kidneys, nerves and other organs, comprised of two
categories including type 1 diabetes mellitus and type 2
diabetes mellitus ERCP Endoscopic Retrograde Cholangiopancreatography
4

hepatic stellate cells, also known as perisinusoidal investigational new drug, an application in the drug
HSCs cells or Ito cells, that are pericytes found in the review process required by an regulatory authority to
perisinusoidal space of the liver IND decide whether a new drug is permitted to initiate
clinical trials; also known as clinical trial application, or
Hypertriglyceridemia, the presence of high amounts of CTA, in China
HTG
triglyceridemia in the blood
IP-10 Interferon-γ-induced Protein 10
hypercholesterola IPF Idiopathic Pulmonary Fibrosis
elevated amounts of cholesterol in the blood
emia IR Insulin Receptor
abnormally elevated levels of any or all lipids or ITGAV Integrin Alpha-V
hyperlipidemia
lipoproteins in the blood ITGB1/B6 Integrin Beta1/Beta 6
IBAT Ileal Bile Acid Transporter ITT intention-to-treat
ITT population the set of all randomised subjects in a randomised trial
Inflammatory Bowel Disease, a group of inflammatory JAK1 Janus Kinase 1
conditions of the colon and small intestine, comprised
IBD Janus Kinase/Signal Transducer and Activator of
of two major categories including CD and ulcerative JAK-STAT
Transcription
colitis
key opinion leader, a trusted, well-respected influencer
IBP-7 Insulin-like growth factor-Binding Protein 7 KOL with proven experience and expertise in a particular
IFG Impaired Fasting Glycemia field
IFN-γ Interferon-γ KOR Kappa Opium Receptor
Low-Density Lipoprotein Cholesterol, often referred to
IGF1R Insulinlike Growth Factor1 Receptor
LDL-C as “bad” cholesterol as it may build up in the walls of
IGFBP9 Insulin-like Growth factor-Binding Protein 9 blood vessels and cause atherosclerotic diseases
IgG4 Immunoglobulin G4 LFC liver fat content, fat accumulated in the liver
IGT Impaired Glucose Tolerance LOXL2 Lysyl Oxidase Like-2
Lipopolysaccharides, an agent commonly used to
IL-1β Interleukin-1 beta LPS
induce inflammatory responses in animal studies
IL-6 Interleukin-6 LRP-2 Low-density lipoprotein Receptor-related Protein 2
MAFLD Metabolic (dysfunction) Associated Fatty Liver Disease
Latin for “within the glass”, referring to studies that are
MAO-B Monoamine Oxidase B
in vitro performed with microorganisms, cells, or biological
molecules outside their normal biological context MAP Mild Acute Pancreatitis
Source: China Insights Consultancy 5


NASH Nonalcoholic Steatohepatitis, an advanced form of NAFLD
MAPK Mitogen-Activated Protein Kinase
ND Not Defined
MCD Multicentric Castleman Disease
new drug application, a process required by an regulatory
mechanism of the specific biochemical interaction through which a NDA
authority to approve a new drug for sale and marketing
action drug substance produces its pharmacological effect NE No Effects
MELD Model for End-stage Liver Disease NFS NAFLD Fibrosis Score
MRCP magnetic resonance cholangiopancreatography NFT Neurofibrillary Tangles
MRCT multi-regional clinical trials NF-κB Nuclear Factor Kappa-light-chain-enhancer of activated B cells
NGT Normal Glucose Tolerance
MRE Magnetic Resonance Elastography
NMDA N-Methyl D-Aspartate
Magnetic Resonance Imaging, a non-invasive imaging
technology that uses strong magnetic fields and radio Nox4 NADPH oxidase 4
MRI abnormal or excessive fat accumulation in the body;
waves to produce three dimensional detailed
anatomical images obesity defined as an individual having a body mass index over 30
kg/m2 or more
magnetic resonance imaging-derived proton density fat
MRI-PDFF fraction, a noninvasive, quantitative, and accurate Obeticholic Acid, an FDA-approved second line treatment in
measure of liver fat content OCA combination with ursodeoxycholic acid for primary biliary
cholangitis
MSAP Moderately Severe Acute Pancreatitis orphan drug designation, a designation granted by the FDA to
mTOR Mammalian Target Of Rapamycin a drug or biological product which prevents, diagnoses or
ODD
NAC N-Acetylcysteine treats a rare disease or condition, qualifying the sponsors for
NAD Nicotinamide Adenine Dinucleotide certain incentives
NADH Nicotinamide Adenine Dinucleotide Hydride related to the use of pharmaceutical drugs for an
off-label unapproved indication or in an unapproved age group,
NADP Nicotinamide Adenine Dinucleotide Phosphate
dosage or route of administration
NADPH Nicotinamide Adenine Dinucleotide Phosphate OGTT Oral Glucose Tolerance Test
NAFL Nonalcoholic Fatty Liver Over The Counter, ordinary retail purchase of drugs, with no
OTC
Non-alcoholic Fatty Liver Disease, characterized by the need for medical prescription or license
NAFLD
excessive fat accumulation in the liver pan
pan agonists acting on all three isoforms of PPAR
PPAR
NAFLD activity score, a sum of numerical score system
NAS applying to steatosis, hepatocellular ballooning, and Primary Biliary Cholangitis, an autoimmune liver disease
lobular inflammation PBC resulting from a slow, progressive destruction of the intra-
hepatic small bile ducts

proprotein convertase subtilisin/kexin type 9, an enzyme a study testing a drug on non-human subjects, to gather
PCSK9 binding to and degrading the receptor for low-density preclinical
efficacy, toxicity, pharmacokinetic and safety information
lipoprotein particles study
and to decide whether the drug is ready for clinical trials
Parkinson's Disease, a common neurodegenerative a condition characterized by elevated blood sugar levels
PD disorder that severely affects movement and decreases pre-diabetes
that fall below the threshold to diagnose diabetes
quality of life a condition characterized by elevated blood sugar levels
PEG Polyethylene Glycol pre-T2DM that fall below the threshold to diagnose type 2 diabetes
a study in which a drug is introduced into healthy human mellitus
subjects or patients with the target disease or condition and the specific key measurement upon which a clinical study is
Phase I primary
tested for safety, dosage tolerance, absorption, metabolism, designed to assess the effect of the drugs being
clinical trial endpoint
distribution, excretion, and if possible, to gain an early investigated
indication of its efficacy
Primary Sclerosing Cholangitis, a life-threatening,
a study in which a drug is administered to a limited patient PSC multifactorial and rare liver disease characterized by
population to preliminarily evaluate the efficacy of the hepatic inflammation, scarring and abnormal liver damage
Phase II
product for specific targeted diseases, to identify possible
clinical trial A repressor protein that regulates expression of the
adverse effects and safety risks, and to determine optimal QacR
Staphylococcus aureus multidrug efflux pump QacA
dosage
RCTs Randomized Controlled Trials
a study in which a drug is administered to an expanded
regenerating islet derived protein 3 alpha; a prognostic
patient population generally at geographically dispersed
Reg3α biomarker for gastrointestinal chronic graft-versus-host
Phase III clinical trial sites, in well-controlled clinical trials to generate
disease
clinical trial enough data to statistically evaluate the efficacy and safety
of the product for approval, to provide adequate information a clinical trial or study to demonstrate clinical efficacy and
registrational
for the labeling of the product safety evidence required before submission for drug
clinical trial
marketing approval
pharmacokinetics; the study of the bodily absorption,
distribution, metabolism, and excretion of drugs, which, Reactive Oxygen Species, a type of unstable molecule that
PK ROS contains oxygen and that easily reacts with other molecules
together with pharmacodynamics, influences dosing,
benefit, and adverse effects of the drug in a cell
a medical treatment or preparation with no specific serious adverse events, an event or reaction that, in the
placebo view of either the investigator or sponsor, results in severe
pharmacological activity
outcomes such as death, life-threatening adverse events,
Peroxisome Proliferator-Activated Receptor with three main SAEs
in-patient hospitalization or prolongation of existing
PPAR classes, namely α, γ and δ; a family of nuclear receptors to
hospitalization, persistent or significant disability or
regulate metabolism, inflammation and fibrosis
incapacity, a congenital anomaly or birth defect


SAH Severe Alcoholic Hepatitis Triglyceride, the main constituents of body fat in
TG
SAP Severe Acute Pancreatitis humans
SCD1 Stearoyl-CoA Desaturase-1 Therapeutic Goods Administration; Australia’s
TGA regulatory authority for therapeutic goods such as
sodium-glucose cotransporter-2 inhibitors. a class of
medicines, medical devices, and diagnostic tests
SGLT-2I prescription medicines that are FDA-approved for use with
diet and exercise to lower blood sugar in adults with T2DM thyroid hormone receptor β, one receptor for thyroid
THR-β hormone to mediate the biological activities of thyroid
Sever Hypertriglyceridemia, SHTG is the presence of hig hormone
levels of triglycerides, a type of fat, in the blood. SHTG is TIA Transient Ischemic Attack
SHTG
well known to be associated with other complex and serious
Toll - like receptor 4, a transmembrane protein in
disorders such as acute pancreatitis and CVDs
humans encoded by the TLR4 gene which plays a
TLR4
site management organization, an organization that has pivotal role in the regulation of immune responses to
adequate infrastructure and staff to meet the requirements infection
SMO of the clinical trial protocol and provides clinical trial TLR-α Toll-Like Receptors-α
related services to a CRO, a pharmaceutical company, a TMPRSS2 Transmembrane Serine Protease 2
biotechnology company, or a clinical site TNF Tumor Necrosis Factor
SNPs Single Nucleotide Polymorphisms TNF-α tumor necrosis factor alpha
thiazolidinediones, a family of drugs used in the
superoxide dismutase; an antioxidant enzyme which TZD
treatment of T2DM
SOD converts reactive oxygen species into less aggressive
forms, and reduce serum malondialdehyde Ulcerative Colitis, a type of IBD which primarily affects
UC
the colon
sPBC Symptomatic PBC Ursodeoxycholic Acid, a secondary bile acid approved
SSRI Selective Serotonin Reuptake Inhibitors UDCA by the FDA as first-line treatment for PBC, and widely
T1DM Type 1 Diabetes used off-label to treat PSC
Type 2 Diabetes, a form of diabetes characterized by high upper limit of normal, the 95th percentile of the target
T2DM ULN
blood sugar, insulin resistance and relative lack of insulin population
VAP1 Vascular Adhesion Protein-1
treatment-emergent adverse events, undesirable events not
present prior to medical treatment or already present events VCTE Vibration-Controlled Transient Elastography
TEAEs
that worsen in either intensity or frequency following the WHO The World Health Organization
treatment α1ATZ α1AT mutant Z

environmental, social and governance; a collection of
corporate performance evaluation criteria that assess the GM-CSF granulocyte-macrophage colony stimulating factor
ESG robustness of a company’s governance mechanisms and its good manufacturing practice, the practices required in
ability to effectively manage its environmental and social order to conform to the guidelines recommended by
impacts GMP
agencies that control the authorization and licensing of
fibroblast growth factor 21, a liver-secreted peptide the manufacture and sale of products
“FGF21 hormone to regulation of lipid, glucose, and energy the microorganism including bacteria, archaea and
metabolism gut microbiota fungi that live in the digestive tracts of humans and
a non-invasive scoring system based on several laboratory other animals
FIB4
tests that help to estimate the amount of scarring in the liver glycated haemoglobin, formed when haemoglobin joins
fast track designation, a designation granted by the FDA of HbA1C
with glucose in the blood and becomes glycated
a drug for expedited review to facilitate the development of
FTD
drugs which treat serious or life-threatening condition or fill
an unmet medical need HCC hepatocellular carcinoma
farnesoid X receptor, a nuclear receptor that is encoded by
FXR
the NR1H4 gene in humans high-density lipoprotein cholesterol, often referred to as
HDL-C “good” cholesterol as it is known to remove other forms
good clinical practice, an international ethical and scientific
of cholesterol from the bloodstream
GCP quality standard for the performance of a clinical trial on
Latin for “within the living”, referring to studies in which
medicinal products involving humans
the effects of various biological entities are tested on
gamma-glutamyl transferase, an enzyme found primarily in in vivo whole, living organisms or cells, usually animals,
the liver; the level of GGT increases when the liver is including humans, and plants, as opposed to a tissue
GGT extract or dead organism
damaged, making it a biomarker commonly associated with
injury or apoptosis of liver cells
glucagon-like peptide-1, a gastrointestinal peptide to
Glp-1
encourage the release of insulin from the pancreas
GLP-1R glucagon-like peptide-1 receptor
GLP-1RA glucagon-like peptide-1 receptor agonist

glycemic
the management of blood sugar levels
control
Introduction, methodology and assumptions
Introduction, methodology and assumptions
China Insights Consultancy was commissioned to conduct research and analysis of, and to produce a report on China molecular
detection market. The report commissioned has been prepared by China Insights Consultancy independent of the influence of the
Company and other interested parties.
China Insights Consultancy’s services include industry consulting, commercial due diligence, strategic consulting, etc. Its consulting
team has been tracking the latest market trends in industrial, energy, chemicals, healthcare, education, consumer goods,
transportation, agriculture, internet, finance, etc., and has the most relevant and insightful market intelligence in the above industries.
China Insights Consultancy conducted both primary and secondary research using a variety of resources. Primary research involved
interviewing key industry experts and leading industry participants. Secondary research involved analyzing data from various publicly
available data sources, such as the National Bureau of Statistics, National Medical Products Administration, Food and Drug
Association, National Health Commission of the People’s Republic of China, the International Monetary Fund, World Health
Organization, etc.
The market projections in the commissioned report are based on the following key assumptions: (i) the overall social, economic and
political environment in China is expected to remain stable during the forecast period; (ii) China’s economic and industrial
development is likely to maintain a steady growth trend over the next decade; (iii) related key industry drivers are likely to continue
driving the growth of the market during the forecast period, such as the increasing number of eye disease incidences mainly owing to
aging population, strengthened public awareness of eye care, enhanced patient affordability, enriched drugs and therapies, etc.; and
(iv) there is no extreme force majeure or industry regulation in which the market may be affected dramatically or fundamentally.
All statistics are reliable and based on information available as of the date of this report. Other sources of information, including from
the government, industry associations, or market participants, may have provided some of the information on which the analysis or
data is based.
All the information about the Company is sourced from the Company’s audited report or management interviews. The information
obtained from of the Company has not been independently verified by China Insights Consultancy.

Table of Contents
I. Industry overview of metabolic disorders and digestive diseases

II. Industry overview of metabolic syndrome (MetS) drug market
• T2DM + NAFLD
• NASH
• Hypertriglyceridemia
• Obesity
III. Industry overview of Chronic cholestatic liver disease drug market
• Primary sclerosing cholangitis
• Primary biliary cholangitis
IV. Industry overview of inflammatory disease drug market
• Cytokine release syndrome
• Central nervous system
• Inflammatory bowel disease
Metabolic disorders and Digestive diseases Overview
Overview of Metabolic disorders and Digestive diseases

- Digestive diseases include a wide spectrum of disorders, these disorders have diverse
causes; Metabolic disorders recently has been highlighted as a risk factor for digestive and
other chronic diseases
Overview of Metabolic disorders and Digestive diseases
Metabolic Diseases/Digestive Diseases occurs when a series of organs do not function normally due to a hormone or enzyme deficiency.
Multiple organs and factors are involved in the pathology of the two types of diseases, and the synergic effect between the organs or
factors makes the diseases incline to deteriorate. Besides, a series of complications could be induced, and even in some cases, the
management of the complications become the primary goal of the treatment currently.
Metabolic disorders Digestive diseases
• Metabolic disorders is a complex, pathophysiological state • The digestive system made up of gastrointestinal tract (GI), liver,
composed of a cluster of clinically measured and typically pancreas, and gallbladder helps the body digest food.
unmeasured risk factor, is progressive in its course, and is • Digestive diseases have become prevalent in a large part of the
associated with serious and extensive comorbidity, but tends to world population. Some digestive diseases and conditions are
be clinically under-recognized. acute, lasting a short time, while others are chronic, or long-lasting.
Liver disease Pancreatitis
Adiposity Dominant Insulin Resistance
There are many kinds of Digestive Inflammation of the
• Fatty liver disease such Dominant liver diseases, including pancreas: including acute
diseases
as NASH • T2DM Liver cirrhosis and chronic
• Sleep disordered • Gestational diabetes
breathing Viral hepatitis Inflammatory Bowel
• Polycystic ovary
Caused by virus, major Disease
disorders
type Hepatitis B and Including Crohn’s Disease
Vascular Dominant Lipid Dominant Hepatitis C and Ulcerative Colitis
• ASCVD • Atherogenic
Gastrointestinal Gallstones
• Prothrombotic and Metabolic dyslipidemia
proinflammatory states infection Hard, pebble-like pieces of
disorders
Viral, bacterial or parasitic material that develop in
• Hypertension
Other Risk Factors infections gallbladder
• Hormonal dysfunction Peptic ulcer Gastroesophageal
• Chronic kidney disease A sore on the lining of Reflux Disease
• Hyperuricemia your stomach or Stomach contents come
duodenum back up into esophagus
Source: National Institute of Diabetes and Digestive and Kidney Diseases; The CardioMetabolic Health Alliance: Working
Toward a New Care Model for the Metabolic disorders.; China Insights Consultancy 12
Metabolic disorders and Digestive diseases Epidemiology
Prevalent Cases of Metabolic disorders and Digestive diseases
Prevalent Cases of Major Metabolic disorders and Digestive diseases, the World
CAGR 2018-22 2022-32E Million cases

Metabolic disorders 2.1% 1.9%
Digestive diseases 1.4% 1.4%
Total 1.7% 1.7%
5,539 5,628 5,717

5,275 5,362 5,450
5,189
4,851
4,527
2,883 2,936 2,991
2,673 2,724 2,777 2,829
2,473
2,280
2,378 2,516 2,551 2,586 2,621 2,656 2,691 2,727

2,248
2018 2022 2026E 2027E 2028E 2029E 2030E 2031E 2032E

Note:
• Metabolic disorders include: Diabetes, hypertriglyceridemia, obesity, diabetic neuropathy, etc.
• Digestive diseases include: NAFLD and other chronic liver diseases, gallbladder and biliary diseases, inflammatory bowel disease,
pancreatitis, upper digestive system diseases, etc.

Metabolic disorders and Digestive diseases Market size
Updated for 1st
comment 7/6
Global market size of major metabolic disorders and digestive diseases
Global market size of major metabolic disorders and digestive diseases
CAGR 2018-22 2022-32E Billion USD

Metabolic disorders 10.9% 11.1%
Digestive diseases 2.6% 3.0% 687
Total 6.2% 7.6% 641
597
556
518
481
447 458
415 418
385 381
356 347
330 314
305 284
255
268 282 229
259 204
181
160
122 140
105 113
204 210 216 223 229

170 175 180 186 192 198
153 155 160 165
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note:
• Metabolic disorders include Diabetes, NAFLD, hypertriglyceridemia, obesity, diabetic neuropathy, etc.
• Digestive diseases include liver cirrhosis, gallbladder and biliary diseases, inflammatory bowel disease, pancreatitis, upper digestive system
diseases, etc.
Metabolic disorders and Digestive diseases Multi-target drug approach
Potential impact of the multi-target drug approach

- The multi-target approach has recently attracted much attention as a promising tool to
fights against most challenging complex diseases, and thus as a new research focus area
Potential impact of the multi-target drug approach
The transition from the single-target to the multi-target approach Multi-target drug
for drug design
• Traditionally, the discovery of therapeutic drugs has been exploited
based on the design of highly selective chemical entities to target a Multiple
single biological entity, considered as a dominant player in a certain targets
pathology. Using this strategy, researchers have expected to avoid One drug
any undesired side effects and guarantee a more drug-like property
of drug candidates. Although single-target drugs are useful to
approach single gene disorders such as hepatitis B and hepatitis C.
Advantage of multi-target drug
However, highly selective or specific therapeutic agents directed to
single molecular targets have proven to lack in efficacy, especially 1• Disease often results from the breakdown of robust
for complex diseases. The highly selective therapeutic agents have physiological systems due to multiple genetic and/or
also been associated with the increasing incidences of drug environmental factors. Thus, complex disorders are more
resistance. likely to be healed or alleviated though simultaneous
Selectivity modulation of multiple targets. And they can better treat
• Lack in efficacy, especially health conditions linked to drug resistance issues.
for complex diseases 2• The multifunctional agents capable of modulating multiple
• Increasing incidence of biological targets simultaneously display great advantages
One drug One target drug resistance of higher efficacy, improved safety profile, and simpler
administration compared to single-targeted agents.
• The complexity of the current incurable pathologies has clearly
demonstrated that such single-target drugs are inadequate to
achieve a therapeutic effect. Therefore, multi-target agents would certainly open novel
• Multi-target drugs have attracted considerable attention in the last avenues to rationally design more effective but less toxic
decade, as a potential therapeutic solutions to diseases of complex therapeutic agents.
etiology and health conditions linked to drug resistance issues.
Source: Bizzarri, Mariano (2020). [Human Perspectives in Health Sciences and Technology] Approaching Complex
Diseases Volume 2; China Insights Consultancy 15
Metabolic disorders and Digestive diseases Multi-functional approach
From single-target to multi-functional drug approach

- Recognizing the multifactorial nature of complex diseases, multi-functional drugs can
overcome the shortcomings of the traditional approaches
From single-target to multi-functional drug approach

Focus Reasons for the evolution of therapy
• Multifactorial diseases are
• Useful to approach single • Drug resistance
disorders that involve
gene disorders such as • Limited efficacy of single-target multiple disease-causing
Single-target drugs hepatitis B and hepatitis C, drugs against multifactorial mechanisms, such as
which are caused by a diseases genes acting in concert with
single gene mutation and
environmental factors. They
with single mechanism
represent one of the most
• Affect different targets to • Poor patient compliance significant challenges that
help overcome the problem • The inefficiency, deleterious medical research faces
of drug resistance. effects from drug–drug today.
Drug combination
• Or to reduce toxicity/ interactions, distinct • Disease-causing
improve the efficacy on pharmacokinetics, solubility and mechanisms may be (and
single pathway costs of combination therapy typically are) involved in
more than one disorder. If
• Improve patient compliance • Synergistic effect of different two diseases are related to
• Treat complex multifactorial organs is often ignored the same mechanism (say,
Single drug with diseases • Various comorbidities associated a single point mutation,
multiple targets with multifactorial diseases are SNP, or an altered
• Lower risk of drug-drug
ignored metabolic pathway), they
interactions
have a tendency to co-
occur in the same patients.
• Synergistic effect: • / • Therefore, a multiplex
1. Between effective active comorbidity network should
Multi-functional molecules be well considered, which
drugs 2. Treating multi-organ pushes the development of
disorders with multiple multi-functional drugs.
comorbidities
Source: Makhoba, X. H., Viegas Jr, C., Mosa, R. A., Viegas, F. P., & Pooe, O. J. (2020). Potential impact of the multi-
target drug approach in the treatment of some complex diseases. Drug Design, Development and Therapy, 14, 3235. ; 16
Metabolic disorders and Digestive diseases Multi-target drug approach
Multi-target drug approaches

- There are three different multi-target drug approaches: drug combination, fixed dose
combination, and multiple ligand
Multi-target drug approaches

• There are three different multi-target drug approaches
Scenario Description Benefit Limitation Representative drugs*
• Suffers from distinct pharmacokinetic
• Also known as
• Reduce the likelihood of profiles of partner therapeutics, • T2DM and NASH:
cock tail, most
drug resistance leading to an inconsistent in vivo MET409 +
frequently is
Drug • Greater dose flexibility and pharmacokinetics and biodistribution Empagliflozin (Metacrine,
administrated in
combination lower cost treatment in the and therefore an inefficient therapy Inc.)
2 tablets the form of two (or
case of generic drugs than • Poor patient compliance, particularly • T2DM: Acarbose +
2 agents more) individual
FDCs for treating asymptomatic diseases Metformin (Bayer)
tablets
such as hypertension
• Two (or more) • Simple dosage schedule

agents are co- improves patient compliance
formulated in a and treatment outcomes • T2DM: FDC of
• In case of FDCs, dosing is inflexible
Fixed dose single tablet to • Complementary mechanism Remogliflozin
combination make dosing • Increased risk of drug-drug Etabonate +Vildagliptin
of action, better tolerability
(FDCs) regimes simpler interactions compared to multiple (Glenmark
1 tablets and elongated product life-
and thereby ligand approach Pharmaceuticals)
cycle management
2 agents improve patient • More economic than single
compliance ingredient drugs
• HCC & RCC** & Thyroid

• Compared to combination • Significantly more difficult to adjust Carcinoma: Sorafenib
• A single-chemical therapies, more predictable the ratio of activities at the different (Nexavar)
entity that is able pharmacokinetics and higher targets • NASH: Efruxifermin
Multiple
to modulate patient compliance • Targets engineered into simplified (Akero)
ligand
1 tablets multiple targets • A lower risk of drug-drug cell-based assays do not always • NASH:
simultaneously interactions compared to behave the same as in the complex Elafibranor (Genfit)
1 agents cocktails or FDCs. environment of intact organisms • NASH: Aldafermin(NGM
& MSD)
Note: * include drugs under development and commercialized drugs ** HCC: Hepatocellular Carcinoma RCC: Renal Cell Carcinoma
Source: Multitarget Drugs: Strategies and Challenges for Medicinal Chemists; China Insights Consultancy 17
Metabolic disorders and Digestive diseases Treatment options comparison
Treatment options comparison

- Compared to traditional treatment options, multi-functional drugs have better efficacy,
synergistic effect and patient compliance with less side effects
Treatment options comparison
Fixed Dose Multi-

Single-target Drug
Combination functional
drugs combination
(FDCs) drugs
• Traditional treatments are symptom-by-symptom, organ-

by-organ basis, which did not consider the multi-organ
Efficacy physiological effects of this complex disease, while multi-
functional drug tackles through multiple pathways, which
would have much improved potency.
• Though drug combination therapies tend to have better

Synergistic efficacy comparing to single-target drugs, its synergistic
effect effect is limited. Multi-functional drugs could work
synergistically in distinct disease pathways.
• Single-target drug usually have multiple side effects such

as increased blood sugar, kidneys affection. Drug
combination and FDCs on the other hand have a higher
Safety
risk of drug-drug interactions. Yet great synergistic effect
of multi-functional drugs results in a lower side effect and
lower toxicity.
Patient • With multi-functional drugs, patients trade a handful of

compliance pills for a single pill, which improve patients’ compliance.
Source: Multitarget Drugs: Strategies and Challenges for Medicinal Chemists; China Insights Consultancy 18
Metabolic disorders and Digestive diseases Multi-target drug design
Rational design of multi-target drugs

- Multi-target drugs routinely result from the integration of pharmacophores of selective
molecules, either already known drugs or drug candidate
Rational design of multi-target drugs
Current challenges of rational design of multi-target drugs

• Target selection
It is a challenge to choose the right combination of targets for
the disease. It requires good understanding of target-disease
Target associations, path-way-target-drug-disease relationships and
Target adverse events profiling.
A
B The selection should be based on additive or synergistic effects.
Both effects can be attained at lower doses, and consequently
a better safety profile with respect to single-target drugs.
Framework Framework - Additive effects can be obtained when the targets belong to
A B the same pathway;
- Synergistic effects can be achieved only if the selected
Framework combination targets are located on functionally complementary pathways.
• Small molecule discovery

Early drugs were discovered serendipitously, multi-target drugs
are now rationally designed, typically by combining two distinct
frameworks into a single chemical entity.
Linked Linked Fused Merged
The generation of multi-target drugs is typically driven by the
(cleavable)
nature of the targets, the availability of starting frameworks and
- Pharmacophores featuring similar scaffolds can be fused or merged the chemical tractability. Beyond that, the essential requirement
depending on the overlapping degree between the starting frameworks. of the multi-target drugs is that each framework retains the
- Pharmacophores present different structural elements required for the ability to interact with its specific target. This is challenging task
interaction, they can be conjugated with cleavable or non-cleavable involves considering structure-activity relationships, especially
linkers, although this strategy often leads to molecules with poor drug- when these targes are only slightly related or unrelated.
likeness properties.
Source: Ramsay, Rona R et al. “A perspective on multi-target drug discovery and design for complex diseases.”
Clinical and translational medicine vol. 7,1 3. 17 Jan. 2018; China Insights Consultancy 19
Metabolic disorders and Digestive diseases Limitations of target-based drug design
Limitations of target-based drug design

- By some measures, target-based drug discovery has been highly successful. However,
this method also faces several limitations
Limitations of target-based drug design

Target-based drug design Disease-based drug design
Disease-based drug design introduces a better drug design
Limitations of target-based drug design approach for complex diseases.
Disease-based drug Target-based drug
•1 Complex environment of intact organisms
design design
• Recombinant systems can lead scientists astray, pursuing
projects and compounds that fail to translate into clinical • It provides
results. Targets engineered into simplified cell-based synergistically • Synergistic effect of
assays do not always behave the same as in the complex therapeutic benefits different organs is
environment of intact organisms, and even results from Synergis
to multi-factorial often ignored by
gene engineering in model species may not translate to tic effect
diseases associated target-based drug
patients. Biology is vastly complex, and a simplified with complex chronic design.
recombinant system can fail to capture the complex biology of comorbidities.
intact animals and humans.
• Better analyze and • Efficacy observed
•2 Fail to capture the whole story understand disease may not be always
• Even when a drug target is known, and the mechanism Efficacy pathogenesis to due to the
described, this can fail to capture the whole story. Drugs may achieve better mechanisms
act at more than one target, and efficacy observed may not efficacy. originally expected.
be always due to the mechanisms originally expected.
The mechanism or action of selective serotonin reuptake • Capture the whole
inhibitors (SSRIs) in the treatment of depression appears story of the diseases • Can fail to capture
Safety
more complex than elevating serotonin in synapses, for to achieve better the whole story
example. safety.
Source: Glenn E. Croston (2017) The utility of target-based discovery, Expert Opinion on Drug Discovery, 12:5, 427-429, 20
Metabolic disorders and Digestive diseases FUSIONTXTM Platform
Introduction and Advantages of FUSIONTXTM Platform

- FUSIONTXTM is a disease-based drug design platform which can lower drug
development risk and shorten development time compared to target-based drug design
platform
Introduction and Advantages of FUSIONTXTM Platform

FUSIONTXTM
Metabolic disorders and digestive diseases:
Complex
diseases • Metabolic disorders and digestive diseases are caused by a
combination of genetic, environmental, and lifestyle factors
• Single target drugs have limitation in treating complex diseases,
Discovery of lead and drugs that can synergistically regulate multiple pathways are
Clinical Drug discovery and active molecules likely to obtain greater therapeutic effect
treatment design platform for based on data FUSIONTXTM platform – Disease-based drug design
complex diseases (RWE1 and AI2)
• Design multifunctional new molecule or compound by combining
active molecules with known treatment effect and high safety
standard, and provide synergistically therapeutic benefits to
Multifunctional compound complex diseases with controlled risk
Preclinical • Hightide has designed multiple drug candidates through
designed by FUSIONTX : NME3、
development FUSIONTXTM , including HTD1801 (NME), HTD2802 (new
NCE4 or new compound compound), HTD1804 (NCE), etc.
Comparison between disease-based and target-based drug design

Disease-based drug design can lower development risk and shorten development time as compared to target-based drug design
1 Disease-based drug design
1 2 3 4 5 6 7
Analyze Identify potential
Collect and FUSIONTX drug Preclinical Clinical
pathogenic lead active Drug approval
analyze data design development development
mechanism molecules
2 Target-based drug design
1 2 3 4 5 6 7 8 9 10
Analytical
Basic Target Lead Compound Drug Preclinical Clinical Drug
method Screening
research identification compound selection candidate development development approval
development
Note: 1 Real World Evidence; 2 Artificial Intelligence; 3 New Molecular Entity; 4 New Chemical Entity
Metabolic disorders and Digestive diseases Representative drugs
Representative drugs for multi-target drugs

- Fixed dose combination drugs are one important type of multi-target drug approach, but
no synergic effects between two individual drugs
Representative FDC Drugs
Drug Name Entresto Janumet

Company Novartis Merck
Drug Type Fixed Dose Combination (FDCs) Fixed Dose Combination (FDCs)
Ingredient Sacubitril/Valsartan Metformin/Sitagliptin
• Adult Heart Failure
• Used as an adjunct to diet and exercise to improve glycemic
Indications • Pediatric Heart Failure
control in adults with type 2 diabetes mellitus
• Chronic Heart Failure
Formulation Tablet Tablet
Approval Year 07/07/2015 03/30/2007
Target/ • Neprilysin inhibitor • DPP4 inhibitor • ETF dehydrogenase inhibitor
Mechanism • Angiotensin inhibitor • AMPK activator • GPD-C inhibitor
• Serious side effect might be triggered, including serious • Serious side effects includes lactic acidosis, pancreatitis,
allergic reactions, hypotension and hyperkalemia heart failure, low blood sugar and serious allergic reactions
Limitation • Dosing is inflexible • Dosing is inflexible
• Relatively high prices • Relatively high prices
• No synergic effects between two individual drugs • No synergic effects between two individual drugs
Price USD $117 (49mg/51mg 10 tablets) $108 (50mg/500mg 10 tablets)
Average cost $618 per month (for 60 tablets) $528.16 per month (for 60 tablets)
4,644 6,014 6,109 5,896 5,914 5,524 5,276 5,288

Global Sales 3,548 4,513
2,497
(million USD) 1,726
507 1,028
21 170
2015 2016 2017 2018 2019 2020 2021 2022 2015 2016 2017 2018 2019 2020 2021 2022
Source: FDA; Official Annual Report; China Insights Consultancy 22


- Fixed dose combination drugs are one important type of multi-target drug approach, but
no synergic effects between two individual drugs
Representative FDC Drugs
Drug Name Zegerid Vytorin

Company Bayer Merck
Drug Type Fixed Dose Combination (FDCs) Fixed Dose Combination (FDCs)
Ingredient Sodium bicarbonate/Omeprazole Ezetimibe/Simvastatin
• Duodenal ulcer • Gastric ulcer
• Treatment of (GERD) • Reduction of risk of upper • Primary Hypercholesterolemia
Indications
• Maintenance of healing of gastrointestinal bleeding • Homozygous Familial Hypercholesterolemia (HoFH)
erosive esophagitis in critically III patients
Formulation Capsule Tablet
Approval Year 02/07/2006 07/23/2004
• HMGCR inhibitor • ITGAL Inhibitory • APN
Target/ • Hydrogen ions neutralizer
• AhR agonist • NPC1L1 inhibitor allosteric modulator
Mechanism • Proton pump inhibitor
• ACAT inhibitor • HDAC2 inhibitor
• Serious side effects include: cutaneous and systemic lupus • A series of serious side effects might be triggered
erythematosus, cyanocobalamin deficiency and etc. • Dosing is inflexible
Limitation
• Dosing is inflexible • Relatively high prices
• No synergic effects between two individual drugs • No synergic effects between two individual drugs
Price USD $33 (20mg/1100mg 42 capsules) $366 (10mg/10mg 30 tablets)
Average cost $18 per month (for 30 capsules) $366 per month (for 30 tablets)
3,777 3,701
Global Sales 2,095
N.A. 1,355 874
(million USD) 664
N.A. N.A.
2015 2016 2017 2018 2019 2020 2021 2022


- Multiple ligand drugs are another important type of multi-target drug approach
Representative Multiple Ligand Drugs
Drug Name Nexavar

Company Bayer
Drug Type Multiple Ligand
Ingredient Sorafenib
• Hepatocellular Carcinoma
Indications • Renal Cell Carcinoma
• Differentiated Thyroid Carcinoma
Formulation Tablet
Approval Year 12/20/2005
• RAFB1 inhibitor
• PDGFR1 antagonist
• RAF inhibitor
Target/ • SCFR antagonist
• FLT-3 antagonist
Mechanism • FGFR-1 inhibitor
• VEGFR1/2 antagonist
• RET51 inhibitor
• FLT-3 antagonist
• Side effects including decreased blood flow to the heart,
heart attack and heart failure, high blood pressure, an
Limitation
opening in the wall of stomach or intestines
• High price
Price USD $21682.9 (20mg 120 tablet)
Average cost $10841.5 per month (for 60 capsules)
892 870 834 712 706 639
Global Sales 435
(million EUR) N.A.
2015 2016 2017 2018 2019 2020 2021 2022

Metabolic disorders and Digestive diseases Market Driver
Market drivers of metabolic disorders and digestive diseases
Market Drivers for Metabolic Disease and Digestive Disease
Market Drivers Description and implications
• Metabolic disease and digestive disease may develop congenitally or from multiple factors such as stress, fatigue
Expansion of or diets. Abusing alcohol imposes the most significant risk for both diseases. Global aging results in more
1 Vulnerable vulnerable population, due to the incidence of most digestive diseases and metabolic diseases increase with age.
Population • Besides, with the accelerated pace of life and the improvement of people’s living standard, young generation are
also exposed to risk of digestive diseases and metabolic diseases than before.
• Along with the development of the economy and growth in the living standard, increasingly more attention is being
paid to healthcare, with more and more resources and money therefore expected to be spent on healthcare in the
Strengthened
2 future. Under such a condition, the improvement of government medical system and popularization of regular
Public Awareness health examination are expected to result in decreasing in the ignorance of diseases that are easily overlooked
before.
• Increased disposable income per capita and broader medical insurance coverage in China and the U.S. make it
Improved easier for patients to afforded relatively more expensive medical fees. Health expenditure per capita in China
3 Affordability of increased from 2981 RMB in 2015 to 5146 RMB in 2020 with compound annual growth rate of 11.5%. Health
Patients expenditure per capita in the U.S. increased from 9990 USD in 2015 to 12000 USD in 2020 with compound annual
growth rate of 3.7%.
• Moreover, with the development of scientific research in the field of digestive diseases and metabolic diseases, a
deep and comprehensive understanding of the diseases are surely expected. A better understanding of the
Novel Technology
diseases lays a solid foundation for new drug development.
4 & Disease
• In addition, as the new technologies are being introduced to drug discovery systems, for example high throughput
Understanding
screen (HTC) and artificial intelligence (AI), a series of more reliable and feasible strategies for new drug
development are expected to reach.

Metabolic disorders and Digestive diseases Future trends
Future trends of Metabolic disorders and Digestive diseases
Future Trends
Drug discovery in the 21st century has the disadvantage that it is difficult to get new compounds into the clinic, and most drugs on the
market today take aim at a single biologic substance which is not capable of solving the challenge in complex diseases. Despite some
combo drug has been emerging in the market to solve such problem, in contrast, multi-target drugs (or multi-functional drugs or network
therapeutics) hit several targets simultaneously, which provides a new idea to solve a number of challenges in research and medication.
The development of multi-target/function drug has been raising considerable interest in the last decades and in the future.
Challenges Solutions
• Complex disease • Targeting Multiple target/organ Simultaneously

A complex disease is caused by the interaction of multiple Multi-target/function drugs act on multiple targets involved in
genes and environmental factors. Complex diseases are also multiple organs simultaneously, which could be a potential
called multifactorial, in which multiple organ dysfunction is solution for complex diseases. Amounts of research work have
always involved. been doing on caner, inflammation and psychiatric disorders.
• Drug Resistance • Multiple Pathways Involved
Drug resistance is the reduction in effectiveness of a Simultaneously impacting different targets could be
medication such as an antimicrobial or an antineoplastic in advantageous to approach individual expressing intrinsic or
treating a disease or condition. Such traits are inherited in the induced variability in drug response due to modifications in
evolution, resulting in a more drug-resistant population. disease-relevant biological pathways and activation of
compensatory mechanism.
• Rational Discovery and Design • Prospective Drug Repositioning
The potential synergistic or antagonistic effect between the Serendipity or exploitation of the original action mechanism of
individual drug might exist in the development of fixed dose a drug for new indications were the main drug repositioning
combination drug. The target selection or topology of drug pathways. With the development of technology, for instance AI,
structure would be the challenge for multiple ligand the process of drug discovery would be shortened, and more
development. drugs would be invented.

Nature Products Introduction to Nature Products
Introduction to Nature Products(NPs) in drug discovery

- NPs are an essential, reputable source of successful drug leads which originate from
Earth’s biodiverse flora and fauna
Introduction to nature products(NPs) in drug discovery

Definition of NPs
• Natural Products (NPs), also known as secondary metabolites, are compounds derived from natural sources, e.g., plants, animals and
micro-organisms, which have biological activities.
• The wide diversity of natural chemicals is due to different factors, mostly the countless biodiversity of marine and terrestrial organisms,
which produce different chemical structures having an array of biological activities.
• Further, the chemical diversity is also the result of millions of years of evolution, that have modified the biosynthetic pathways in
response to various biotic and abiotic stresses caused by natural (e.g., viruses and environmental changes) or unnatural events (e.g.,
chemicals or radiations)
• Therefore, NPs are an essential, reputable source of successful drug leads which originate from Earth’s biodiverse flora and fauna.
Outline of traditional bioactivity-guided isolation steps in natural product drug discovery
• The process of traditional bioactivity-

guided isolation in natural product
drug discovery begins with extraction
of NPs from organisms such as Multiple
bacteria. rounds of
• Following the identification of a crude fractionation
extract with promising
pharmacological activity, the next step
is its (often multiple) consecutive
bioactivity-guided fractionation until Crude Single
Organisms Fractions
the pure bioactive compounds are extracts compounds
isolated.
• Finally, at the last stage, when
bioactive compounds are identified by
phenotypic assays, significant time
and effort are typically needed to Bioactivity
identify the affected molecular targets. evaluation
Source: Nature; China Insights Consultancy 27

Technology development in Nature
Nature Products
products-based drug discovery
Technology advancements of Nature Products(NPs) in drug discovery

- Artificial intelligence and machine learning algorithms have slowly integrated different
stages of NP drug discovery
Technology advancements of Nature Products(NPs) in drug discovery
• Natural products have originated multiple drug discovery success stories, yet the many challenges associated with their discovery or their design –
minute amounts, unfriendly extracts, unknown biological functions, missing biological targets, difficult chemical syntheses, complex SA/PR studies,
undruggable ADME/Tox properties – led to the decline of NP drug discovery programs.
• However, laboratory and computer scientists alike continue to marvel at NPs for their unique privileges to bind biological drug targets specifically for
their therapeutic potentials.
• Artificial intelligence and machine learning algorithms have slowly integrated different stages of NP drug discovery (1) to assist discovering and
elucidating bioactive structures and (2) to capture the molecular patterns of these privileged structures for molecular design and target selectivity.
Computer-assisted discovery and machine learning algorithms in natural product drug discovery process
1.Computer-assisted discovery of NPs 2. ML algorithms applied to NPs
Organisms Generating de novo

NP-inspired
compounds
Extracts
Bioactivity data
De-orphanizing
Encoding NPs into

Structure elucidation Engineering
Data-mining Single compounds molecular
and dereplication likeness Predicting
representations
scores biologic
functions
Omics data
Genome-mining
Chemical space
Source: Royal Society of Chemistry; China Insights Consultancy 28

Metabolic disorders and Digestive diseases Market Driver
Market drivers of metabolic syndrome drug
Market drivers of metabolic syndrome drug
Market Drivers Description and implications
• The increasing investments in R&D activities for the development of new drugs and therapies for metabolic
Pharmaceutical syndrome is expected to drive the growth of the market. There are more than 1,500 clinical trials about metabolic
1
R&D activities syndrome registered in FDA. It is expected that drugs for different metabolic syndromes will be launched one after
another in the future and continue to promote the growth of related drug markets.
• Due to the heavy disease burden caused by metabolic syndrome, many government built relevant institution to
Government provide funding for research projects and clinical trials.
initiative to prevent • For example, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is part of the
2
metabolic National Institutes of Health in the United States. The NIDDK supports research on many aspects of metabolic
syndrome syndrome, including diabetes and obesity. In addition to the NIDDK, the European Association for the Study of
Diabetes (EASD) is a non-profit organization that promotes research on diabetes and related conditions in Europe.
• Many studies have demonstrated that with age augments, the prevalence of metabolic syndrome increased
because the geriatric population is highly susceptible to major health concerns related to appetite loss and
3 Aging population metabolism. WHO forecasts that people aged 60 years and older will increase to 1.4 billion by 2030 and 2.1 billion
by 2050, which will lead to a significant increasing in metabolic syndrome prevalence and drive the growth of the
metabolic syndrome drugs market.
• About 67% of all disease loads are caused by non-communicable diseases (NCD) globally. However, metabolic
Increasing health syndrome feeds into other non-communicable diseases such as cardiovascular disease, cancer, chronic respiratory
4
awareness disease, and other NCDs. Along with the rising awareness of preventing NCD, the demand for metabolic syndrome
drugs will increase accordingly.

Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
• Alcoholic hepatitis
NASH Introduction
Introduction of NASH
- NASH is an advanced form of NAFLD. Risk of cirrhosis and hepatocellular carcinoma
increases with NASH.
Introduction of NASH
Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD). NAFLD is caused by buildup of
fat in the liver. When this buildup causes inflammation and damage, it is known as NASH. T2DM and insulin resistance increases the risk
of NASH, besides, obesity, high blood cholesterol and triglycerides, and metabolic syndrome increases the risk too.
Diagnosis for NASH Diabetes Inflammatory Cytokines

Liver fat triggers
No single test can diagnose NASH
harmful inflammation
Blood Tests Biopsy The only test can that creates scar tissue
in liver. About 3 of 4 Insulin Hepatic Oxidative
prove a diagnosis NASH
T2DM or prediabetes Resistance Steatosis Stress
of NASH
patients have too much
Imaging Test fat in liver, and about
half of them have Obesity Lipid Peroxidation
harmful inflammation First Step Second Step
and scaring. The two-hit theory of NASH
CT scan MRI scan Ultrasound
Complications of NASH
NASH can be silent diseases with no symptoms at all or very mild symptoms such as tiredness and fatigue in early stages of the disease.
Often the first sign occurs when cirrhosis has developed typically after many years.
Fibrosis and cirrhosis
The inflammation and liver cell damage will start to fibrosis. If left untreated, scar tissue will continue to replace healthy liver tissue leading
to cirrhosis, which is advanced, late-stage scarring. About 20% of people with NASH will progress to cirrhosis over several years.
Liver failure
If cirrhosis is not treated, the liver will not be able to work well or work at all. A liver transplant may be need at this stage.
Liver Cancer
One of the complications of cirrhosis is liver cancer. Risk of hepatocellular carcinoma(HCC) increases.
Cardiovascular disease/ Type 2 Diabetes
People with NAFLD or NASH are more likely to have cardiovascular disease/T2DM and cardiovascular disease is the most common
cause of death in people who have NAFLD/NASH.
Source: ALF, NIHR, NIDDK, Stanfordhealthcare, China Insights Consultancy 31
NASH Epidemiology
The prevalence of NASH in China, the U.S. and Europe

- The population of NASH patients is 96.1 million in 2022 and is expected to grow at 2.4%
CAGR between 2022 and 2032.
Prevalence of NASH in China, the U.S. and Europe
Prevalence of NASH in China, the U.S. and Europe (2018-2032E)

CAGR 2018-22 2022-32E Million patients
Prevalence of NASH in China 2.9% 2.3%

Prevalence of NASH in U.S. 3.2% 2.8%
Prevalence of NASH in Europe 2.6% 2.1%
Total 2.9% 2.4%
118.9 120.2 121.4

112.9 115.9
107.0 109.9
101.4 104.2
96.1 98.7
90.9 93.5 50.8
85.8 88.3 48.5 49.8 50.3
46.1 47.3
43.8 44.9
41.5 42.6
39.3 40.4
36.0 37.1 38.2
25.0 25.8 26.6 27.0 27.4

22.0 22.7 23.5 24.2
19.4 20.1 20.7 21.4
18.3 18.8
35.9 36.8 37.7 38.6 39.6 40.6 41.5 42.6 42.9 43.3
31.6 32.4 33.3 34.1 35.0
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

NASH Current Treatment
Current treatment and medication for NAFLD/NASH

- AGA recommends that management for NAFLD/NASH patients varies depending on their
risk of clinically liver fibrosis. Due to its complex pathogenesis, medication for NASH is
underdeveloped currently
Recommendation for NAFLD/NASH patient management
NAFLD/NASH Clinical Care Pathway multidisciplinary task force - Recommended management of patients with NAFLD/NASH
Risk level Low risk Intermediate risk High risk
FIB-4 < 1.3 or LSM < 8 kPa or liver FIB-4 1.3 – 2.67 and /or LSM 8 – 12 FIB-4 > 2.67 or LSM >12 kPa or liver
Patient stratification
biopsy F0-F1 kPa and liver biopsy not available biopsy F2-F4
Lifestyle intervention All patients require regular physical activity, healthy diet, and avoid excess alcohol intake
May benefit Greater need Strong need

Weight loss
recommended if • Structured weight loss programs
overweight or obese • Anti-obesity medications
• Bariatric surgery
No pharmacological agent is FDA-approved so far for NASH treatment, patients
with T2DM may benefit from some diabetes medications such as pioglitazone and
some GLP-1 RAs;
Pharmacotherapy for Vitamin E improves steatohepatitis in patients with NASH without diabetes, with
Not recommended
NASH less evidence in patients with T2DM
Pharmacotherapy for NASH cirrhosis is

Not applicable
very limited and should be avoided
CVD risk reduction Statins can be used safely in patients with steatohepatitis and liver fibrosis, but is to be avoided in decompensated cirrhosis
Diabetes care Standard of Care of diabetes Medications with efficacy in NASH (pioglitazone, GLP-1 RA) preferred
Abbreviations: FIB-4: fibrosis-4; LSM: liver stiffness measurement; CVD: cardiovascular disease; GLP-1 RA: glucagon-like peptide 1 receptor agonis
Note: F0-F4 are stages of liver fibrosis that measure the amount of fibrosis. F0: no scarring (no fibrosis); F1: minimal scarring; F2: scarring has occurred and
extends outside the liver area (significant fibrosis); F3: fibrosis spreading and forming bridges with other fibrotic liver areas (severe fibrosis); F4: cirrhosis or
advanced scarring
Source: Gastroenterology, China Insights Consultancy 33

MASH Market size
Market size of MASH Drugs with notes
Market size of MASH Drugs, 2018-2032E

CAGR Period CAGR Billion USD
China 2025E-2032E 79.6%
the U.S. 2024E-2032E 86.2% 37.8
35.9
Europe 2024E-2032E 84.8% 32.1 3.0 3.1
27.4 2.9
Total 2024E-2032E 87.6%
22.4 2.6 17.5 18.5
17.0 2.2 15.3
12.8
1.5 10.3
11.4
0.8 7.8
5.6 0.04 5.2 13.9 15.4 16.2
0.2 9.9 11.9
0.1 2.7 5.4 7.7
0.1 2.8
2018 2022 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note:
The size and significant growth of MASH drug market in China, the U.S. and Europe is estimated with the following assumptions: (i) market is estimated as
price * number of treated patients. (ii) the price assumption is based on the prices of other first-in-class drugs for chronic diseases; (iii) the MASH drugs
expected to be approved in forecast period would not be covered in national or regional volume-based procurement program in China; (iv) the price change
in U.S. and Europe is in line with the industry trend; (v) first drug for the treatment of MASH is expected to be approved in 2024 in the U.S. and Europe, and
2025 in China; (vi) a number of MASH drugs are expected to be approved and commercialized from 2025 onwards; (vii) increased academic promotion and
physician education by market players; (viii) the patient population that can be given MASH drugs continue to grow; (ix) As there have not yet been approved
medications specifically indicated for MASH, the treatment rate of drugs that are indicated for MASH is currently 0%. As the expected approval of drugs
specifically indicated for MASH address the unmet clinical needs, MASH patients will quickly adopt these MASH-indicated drugs and in turn number of
treated patients grow rapidly, leading to significant growth in market size after MASH-indicated drugs are approved.
(x) The range of diagnosis rates of advanced stage (F3~F4) of fibrosis among MASH patients are expected to be within 14%~15%, 25%~30% and 25%~30%
respectively in China, the U.S. and Europe. The initial MASH-indicated drug adoption rates in total MASH patients are expected to be 0.3%, 0.3%, and 0.3%
in 2028 respectively in China, the U.S. and Europe, and the expected range of annual treatment cost of MASH indicated drug are expected to be within
1,000~3,000, 9,000~10,000 and 5,000~6,000 USD respectively in China, the U.S. and Europe.
In 2024, MASH drug market is expected to be null, 127.8 million, 118.6 million USD in China, the U.S. and Europe respectively
HTD1801 MASH Pipeline
Competitive landscape of MASH medication treatment

- Currently, there is no approved medication for the treatment of MASH specifically on
market except for Saroglitazar in India; globally, only Resmetirom of Madrigal
pharmaceutical has been filed for NDA seeking for accelerated approval in FDA
Pipeline of MASH drugs in II~III active clinical stages registered at ClinicalTrials and CDE
Administratio Phas First Posted Trial Competen

Drug Name Target Company Indications
n e Date Number t Authority
NCT0550022
Resmetirom THR β Madrigal MASH with Liver Fibrosis Oral NDA 2022/08/15 FDA
2
Intercept NCT0254835
Ocaliva1 FXR MASH Oral III 2015/9/14 FDA
Pharmaceuticals 1
Dual GLP- Non-cirrhotic Non-alcoholic NCT0536493

Cotadutide AstraZeneca Injection III 2022/05/06 FDA
1/GCCR Steatohepatitis with Fibrosis 1
Inventiva NCT0484972
Lanifibranor (IVA337) PPAR MASH Oral III 2021/04/19 FDA
Pharma 8
Novo Nordisk NCT0482218
Semaglutide GLP-1 MASH Injection III 2021/03/30 FDA
A/S 1
NCT0436586
Belapectin Galectin-3 Galectin MASH Injection III 2020/04/28 FDA
8
NCT0410432
Aramchol2 SCD Galmed MASH Oral III 2019/09/26 FDA
1
Cirius NCT0461874
MSDC-0602K MPC T2DM, MASH, NAFLD Oral III 2019/05/31 FDA
Therapeutics 4
NCT0372325
Dapagliflozin SGLT-2 AZ/BMS MASH Oral III 2018/10/29 FDA
2
Fatty Liver
Multiple HighTide (Nonalcoholic),NAFLD, NCT0365674
HTD18013 Oral II 2018/09/04 FDA
pathways Biopharma NFLD, MASH, T2DM, 4
Digestive System Disease
Note:
1. The FDA has rejected Ocaliva’s application for approval to treat MASH with pre-cirrhotic liver fibrosis in May 2023 due to a lack clear data of its safety risks
2. Recruitment suspended as Interim analysis of data from open-label part, showed this part of the study met its objectives. Starting the double-blind part is being delayed due to Aramchol Meglumine
being formulated.
Source: ClinicalTrials ; CDE; China Insights Consultancy 35

- Currently, there is no approved medication for the treatment of MASH specifically on
market except for Saroglitazar in India; globally, only Resmetirom of Madrigal
pharmaceutical has been filed for NDA seeking for accelerated approval in FDA
Pipeline of MASH drugs in II~III active clinical stages registered at CDE
First Posted Competent

Drug Name Target Company Indications Administration Phase Trial Number
Date Authority
Semaglutide GLP-1 Novo Nordisk A/S MASH Injection III 2021/07/27 CTR20211818 NMPA
Lanifibranor (IVA337) PPAR Inventiva Pharma MASH Oral III 2023/09/11 CTR20232876 NMPA
Dual GLP- GUANGDONG HEC
HEC88473 NASH, T2DM, Obesity Injection II 2023/08/17 CTR20232481 NMPA
1/FGF21 TECHNOLOGY
Coptis glycosides capsules N/A Tipr Pharmaceutical NASH Oral II 2023/08/12 CTR20222042 NMPA
Recombinant human FGF21-Fc AMPSOURCE

FGF21 NASH Injection II 2023/08/11 CTR20232280 NMPA
fusion protein (AP025) BIOPHARMA
AZD2693 N/A AstraZeneca NASH Injection II 2023/07/11 CTR20232127 NMPA
Guangdong Zhongsheng
ZSP1601 Capsule PDE NASH Oral II 2022/12/30 CTR20223378 NMPA
Pharmaceutical
ASC41 Capsule N/A Ascletis Pharma NASH Oral II 2022/06/21 CTR20221529 NMPA
Chiglitazar Sodium PPAR Chipscreen MASH Oral II 2021/12/07 CTR20213202 NMPA
BI 456906 GLP-1 Boehringer Ingelheim MASH Injection II 2021/09/01 CTR20212081 NMPA
HEC96719 FXR HEC pharmaceutical MASH Oral II 2021/07/27 CTR20211428 NMPA
CZ130 Capsule N/A Hongjing NASH Oral II 2021/05/13 CTR20210871 NMPA
PF-06865571 ACC, DGAT2 Pfizer MASH Oral II 2021/03/15 CTR20210412 NMPA
MK-3655 KLB, FGFR1 Merck & Co. MASH Injection II 2021/01/21 CTR20210074 NMPA
HSK-31679 THRB Haisco MASH Oral II 2023/11/09 CTR20233629 NMPA
Efinopegdutide (MK-6024) GLP1R;GCGR Merck & Co. MASH Injection II 2023/10/19 CTR20233311 NMPA
Note:
1. The FDA has rejected Ocaliva’s application for approval to treat MASH with pre-cirrhotic liver fibrosis in May 2023 due to a lack clear data of its safety risks
2. Recruitment suspended as Interim analysis of data from open-label part, showed this part of the study met its objectives. Starting the double-blind part is being delayed due to Aramchol Meglumine
being formulated.
Source: ClinicalTrials ; CDE; China Insights Consultancy 36
nistration Endpoints in Phase II clinical trails Results by stu
Groups • Time frame: 18 week 500mg
• Absolute change in LFC as measured by MRI-PDFF from Baseline to Week 18 [Absolute Change from
Primary endpoints -3.198
Baseline to Week 18/Early Termination, LS mean]
Additional LFC
• Relative change in LFC as measured by MRD-PDFF from Baseline to Week 18 -15.942%
secondary endpoints
Oral • Changes in HbA1c from Baseline to Week 18 [Percent Change from Baseline to Week 18, mean] -4.4%
• Changes in ALT from Baseline to Week 18 [Percent Change from Baseline to Week 18, mean] -6%
Secondary endpoints • Changes in AST from Baseline to Week 18 [Percent Change from Baseline to Week 18, mean] 3%
• Changes in GGT from Baseline to Week 18 [Percent Change from Baseline to Week 18, mean] -23%
• Number (%) of Serious TEAE (Treatment-Emergent Adverse Events) in TEAE 1 (5%)
Groups • Time frame: 24 week
• Change in intrahepatic triglycerides (IHTG) quantified by proton magnetic resonance and spectroscopy
Primary endpoints
(1H-MRS) [LS Means Relative Percent change from Baseline in Liver Fat at Week 24], FAS 1, 3
• Proportion of patients with a decrease from baseline in IHTG (quantified by 1H-MRS) to week 24 of ≥ 30%
[Percentage of patients achieving liver fat reduction ≥30% at week 24], FAS
Oral • Proportion of patients with NAFLD resolution, defined as having ≤ 5.5% IHTG (quantified by 1H- MRS)
[Percentage of patients achieving NAFLD resolution at week 24], FAS
Secondary endpoints
• Change in glycemic control (HbA1c) [LS Mean absolute Change from Baseline to week 24], Completers
• Improvement in muscle insulin sensitivity (Rd) [LS Mean absolute change from Baseline to week 24],
Completers
• Number (%) of SAE in TEAE
Groups • Time frame: 12 and 36 week 80mg Week 12 Placebo Week 12
Primary endpoint • Relative change from baseline in hepatic fat fraction assessed by MRI-PDFF [LS mean] 3
-22.5% -10.4%
• Proportions of patients with 30% or more relative hepatic fat reduction assessed by MRI-PDFF 60.3% 18.4%
Oral
• Alanine Aminotransferase (ALT), (IU/L) [LS mean differences of change from baseline compared to
-3.0 n/a
placebo]
Secondary endpoints
• Aspartate Aminotransferase (AST), (IU/L) [LS mean differences of change from baseline compared to
-4.8 n/a
placebo]
• Number (%) of SAE in TEAE
37

- comparing the HTD1801 phase IIa results of MASH with other typical trials entered phase
III stage and posted the phase II results
Comparing the phase II results1 of MASH with typical trials registered at ClinicalTrials
Note:
1. FAS, Full Analysis Set. The FAS population consists of all subjects randomly assigned to treatment who received at least one dose of trial medication
2. The numbers shown represent total number of severe adverse events in treatment-emergent adverse events during treatment period
3. MRI and MRS, both leveraging the same MR physics concepts, quantitatively assess liver fat accumulation by measuring signal fat-fraction and/or proton
density fat-fraction. These techniques are employed for detecting liver fat (hepatic fat), including quantitative measurement of intrahepatic triglycerides and
other lipid metabolites
Source: ClinicalTrials, Corporate presentation of Inventiva (June, 2023), Nature, China Insights Consultancy 38
HTD1801 MASH Correlation with CVD
Pathophysiologic mechanisms linking hepatic steatosis to CVD
Hepatic TG burden
Hepatic lipo-toxicity
Prothrombotic state
Congestive
hepatopathy
Diet
Serum FFA
Genetics NAFLD/NASH CVD
availability
Obesity
Adipose tissue
expansion
Ischemic hepatitis
Hepatic Endothelial
Insulin resistance
lipogenesis dysfunction
Cardiac structural
changes
Notes:
FFA: free fatty acid; TG: triglyceride;
Source: HHS Public Access; Journal of Clinical Medicine; China Insights Consultancy 39
HTD1801 MASH Correlation with CVD
Pathophysiologic mechanisms linking hepatic steatosis to CVD
• NAFLD and CVD exhibit an intricate bidirectional relationship. Shared risk factors, notably T2DM, dyslipidemia, and obesity, suggest a
common etiology for both MASLD/MASH and CVD. In addition, substantial evidence supports the existence of a direct mechanistic link
between MAFLD/MASH and CVD, with the former identified as an independent risk factor for the latter.
• On the other hand, this relationship can be reversed: the impact of cardiac pathologies, particularly acute and chronic heart failure, on
hepatic diseases. Liver ailments induced by heart failure encompass congestive hepatopathy or chronic hepatic passive congestion, as
well as cardiogenic ischemic hepatitis, a swift and acute cardiogenic liver injury.
• In patients with NAFLD, clinical CVD, notably IHD (ischemic heart disease), stands as the primary cause of mortality. NAFLD patients
appear to face an elevated risk of developing IHD, with the severity of NAFLD directly correlating with an increased risk of CVD. A study
examining the correlation between NAFLD and the risk of coronary heart disease in 2015 and 2016 classified NAFLD into absent, mild,
moderate, or severe categories based on liver-to-kidney echogenicity, visibility of intrahepatic vessel walls, and diaphragm
characteristics. Also, the Framingham Risk Score (FRS) and NFS were employed to forecast CHD risk and hepatic fibrosis severity.
• The findings revealed a significantly positive correlation between US-detected NAFLD and FRS. Among patients without NAFLD, only
13.2% exhibited intermediate/high CHD risk. In contrast, those with mild NAFLD, moderate NAFLD, and severe NAFLD demonstrated
higher proportions of 27.3%, 36.2%, and 78.7%, respectively, with intermediate/high CHD risk.
• MASLD and cardiovascular disease (“CVD”) exhibit an intricate bidirectional relationship, with shared risk factors, notably T2DM,
dyslipidemia, and obesity, suggesting a common etiology for both MASLD/MASH and CVD. MASLD/MASH may further cause
CVD/T2DM, and CVD is the most common cause of death in MASLD/MASH patients. Many patients with MASLD/MASH have a high
prevalence of cardiac risk factors, which further contributes to both MASLD/MASH and CVD. Among patients with MASLD, clinical CVD,
notably ischemic heart disease, stands as the primary cause of mortality. MASLD patients appear to face an elevated risk of developing
ischemic heart disease, with the severity of MASLD directly correlating with an increased risk of CVD. On the other hand, the presence
of CVD contributes to risk factors such as congestive hepatopathy that may elevate the severity of MASLD. The mortality rate of these
interrelated diseases, including cardiovascular disease, may potentially limit the market potential of the Core Product.
Source: Journal of Clinical Ultrasound; Journal of Clinical Medicine; China Insights Consultancy 40
Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
T2DM and NAFLD Introduction
Overview of diabetes mellitus

- Type 2 diabetes mellitus is an impairment in the way the body regulates and uses glucose
as a fuel. It is a chronic condition results in too much sugar circulating in the bloodstream
Introduction to Diabetes Mellitus
Diabetes is a disease in which blood glucose, or blood sugar, levels are too high. Glucose comes from the food, and insulin is a hormone
produced by pancreas that helps the glucose get into cells to give them energy to maintain normal physiological function. With type 1
diabetes, body does not make insulin. With type 2 diabetes, body does not make or use insulin well.
T1DM and T2DM Diagnosis of Diabetes and Prediabetes Symptoms of T2DM

• Frequent urination, excessive thirst
There are several way to diagnose diabetes. Each
No Insulin and fluid intake
T1DM way usually need to be repeated on a second day；
Produced • Fatigue, blurred vision, abnormal
• Hemoglobin A1C Test (A1C) measures average weight loss and increased hunger
blood sugar for the past two to three months; • Sores that do not heal
• Fasting Plasma Glucose Test (FPG) checks
No Response fasting blood sugar levels. 8-hours fasting before Comorbidities of T2DM
T2DM
to Insulin the test is required;
Nearly 97.5% of American adults
• Oral Glucose Tolerance Test (OGTT) is a two- with T2DM have at least one
hour test that checks blood sugar levels before comorbid condition and nearly 88.5%
Causes of Diabetes
and two hours after drinking a special sweet drink; have two comorbidities.
Increased • Random Plasma Glucose Test is a blood check
Hepatic Glucose 82.1%
at any time of the day when patients have severe
Production
diabetes symptoms. 78.2%
Increased 77.2%
Carbohydrate 24.1%
A1C Test FPG Test OGTT Test
Intake Blood (%) (mg/dL) (mg/dL) 21.6%
Glucose
Decreased Comorbidities of T2DM: from top to
Diabetes ≥ 6.5 ≥ 126 ≥ 200
Insulin Secretion bottom: Hypertension,
Prediabetes 5.7 – 6.4 100 – 125 140 - 199 overweight/obesity, hyperlipidemia,
Decreased
chronic kidney disease and
Peripheral Normal ≈5 ≤ 99 ≤ 139
Glucose Uptake cardiovascular disease.
Source: Medscape, American Diabetes Association, China Insights Consultancy 42

Overview of diabetes mellitus

- Type 2 diabetes mellitus is an impairment in the way the body regulates and uses glucose
as a fuel. It is a chronic condition results in too much sugar circulating in the bloodstream
Introduction to Diabetes Mellitus
T1DM and T2DM Diagnosis of Diabetes and Prediabetes Symptoms of T2DM

No Glucose • Frequent urination, excessive
There are several way to diagnose diabetes.
Insulin Each way usually need to be repeated on a thirst and fluid intake
second day； • Fatigue, blurred vision, abnormal
T1DM T2DM • Hemoglobin A1C Test (A1C) measures
weight loss and increased
hunger
average blood sugar for the past two to
• Sores that do not heal
three months;
• Fasting Plasma Glucose Test (FPG)
Comorbidities of T2DM
checks fasting blood sugar levels. 8-hours
fasting before the test is required;
Nearly 97.5% of American adults
• Oral Glucose Tolerance Test (OGTT) is a
with T2DM have at least one
two-hour test that checks blood sugar levels
comorbid condition and nearly
No Insulin Produced No Response to Insulin before and two hours after drinking a special
88.5% have two comorbidities.
sweet drink;
Causes of Diabetes • Random Plasma Glucose Test is a blood
check at any time of the day when patients 82.1%
have severe diabetes symptoms.
78.2%
Increased Hepatic Glucose
Production 77.2%
24.1%
A1C FPG OGTT
Increased Carbohydrate Intake Test Test Test 21.6%
Blood (%) (mg/dL) (mg/dL)
Glucose Diabetes ≥ 6.5 ≥ 126 ≥ 200 Comorbidities of T2DM: from top to
Decreased Insulin Secretion bottom: Hypertension,
Prediabet 5.7 – 100 – overweight/obesity, hyperlipidemia,
140 - 199
es 6.4 125 chronic kidney disease and
Decreased Peripheral Glucose cardiovascular disease.
Normal ≈5 ≤ 99 ≤ 139
Uptake
Source: Medscape, American Diabetes Association, China Insights Consultancy 43

T2DM and NAFLD Epidemiology
Epidemiology of T2DM
Prevalence of T2DM
Prevalence of T2DM in China, US and Europe 2018-2032E
CAGR 2018-22 2022-32E million patients
Prevalence of T2DM in China 1.7% 1.4%

Prevalence of T2DM in U.S. 1.3% 0.8%
Prevalence of T2DM in Europe 0.7% 0.6%
Total 1.4% 1.1%
225.3 228.1 228.9 229.7

219.8 222.6
214.3 217.0
208.4 211.3
202.6 205.5
194.3 196.7 199.7
136.3 138.4 140.5 141.2 141.8

127.6 129.8 132.0 134.1
118.9 121.0 123.2 125.4
115.1 116.6
31.5 31.8 32.1 32.4 32.7 33.1 33.3 33.6 33.9 34.1 34.4 34.5 34.7
30.5 31.1
48.7 49.0 49.4 49.7 50.1 50.5 50.9 51.4 51.7 52.1 52.4 52.8 53.2 53.2 53.3
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

Epidemiology of NAFLD in T2DM
Prevalence of T2DM with NAFLD

Prevalence of NAFLD in T2DM in China, US and Europe , 2018-2032E
CAGR 2018-22 2022-32E million patients
Prevalence of NAFLD in T2DM in China 1.7% 1.4%

Prevalence of NAFLD in T2DM in U.S. 1.3% 0.8%
Prevalence of NAFLD in T2DM in Europe 0.7% 0.6%
Total 1.3% 1.1%
133.0 134.6 135.0 135.5

128.3 129.9 131.4
125.1 126.8
121.8 123.4
118.6 120.2
115.4 116.8
70.9 72.0 73.1 73.5 73.8

66.4 67.6 68.7 69.8
61.9 63.0 64.1 65.3
59.9 60.7
23.6 23.8 24.1 24.3 24.5 24.7 24.9 25.1 25.3 25.4 25.5
22.4 22.9 23.1 23.4
33.1 33.3 33.6 33.8 34.1 34.3 34.6 34.9 35.1 35.4 35.6 35.9 36.2 36.2 36.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

T2DM and NAFLD Current treatment
Current treatment and medication for T2DM

- A range of therapies is available for the management of T2DM, and each class has
advantages and disadvantages based on their mechanism of action and clinical evidence
Glucose-lowing therapy in T2DM: general recommendation from ADA
Start with Monotherapy unless
HbA1c ≥ 9%, consider dual therapy.
HbA1c ≥10%, blood glucose ≥ 300mg/dL, or patients is markedly symptomatic, consider Combination Injectable Therapy.
Monotherapy Metformin Lifestyle Management
If HbA1c target not achieved after approximately 3 months of monotherapy, proceed to 2-drug combination.
Dual Therapy Metformin + Lifestyle Management

Sulfonylurea Thiazolidinedione DPP-4 Inhibitor SGLT2 Inhibitor GLP-1 Receptor Agonist Insulin (basal)
If HbA1c target not achieved after approximately 3 months of dual therapy, proceed to 3-drug combination.
Triple Therapy Metformin + Lifestyle Management

Sulfonylurea+ Thiazolidinedione+ DPP-4 Inhibitor+ SGLT2 Inhibitor+ GLP-1 Receptor Agonist+ Insulin (basal)+
TZD SU SU SU SU TZD
or DPP-4i or DPP-4i or TZD or TZD or TZD or DPP-4i
or SGLT2i or SGLT2i or SGLT2i or DPP-4i or SGLT2i or SGLT2i
or GLP-1 RA or GLP-1 RA or Insulin or GLP-1 RA or Insulin or GLP-1 RA
or Insulin or Insulin or Insulin
If HbA1c target not achieved after approximately 3 months of triple therapy and patients: (1) on oral combination, move to basal insulin or GLP-1 RA, (2)
on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1 RA or mealtime insulin to avoid unnecessarily complex or costly
regimens.
Combination Injectable Therapy
Source: American Diabetes Association, China Insights Consultancy 46

T2DM and NAFLD Market size
The market size of T2DM in China, U.S. and Europe
Market size of T2DM medication in China, U.S. and Europe (2018-2032E)
China -0.2% 7.5%

U.S. 2.3% 0.9%
Europe 1.4% 1.3%
Total 1.7% 2.2% 70.4
68.3 69.5 70.0
65.9 67.1
63.1 64.5
61.6 16.1
59.9 14.3 15.1 15.6
56.5 56.9 12.7 13.5
54.9 55.1 11.2 12.0
53.2 9.8 10.5
8.7 7.9
7.9 8.8 8.6
33.6 33.9 34.2 34.4 34.6 34.6 34.5

32.2 32.8 33.2
31.0 31.6
28.8 29.7 30.2
16.5 16.4 16.9 17.4 17.9 18.3 18.7 19.0 19.2 19.5 19.6 19.8 19.8 19.7
16.3
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
47
Overview of NAFLD
- NAFLD is a condition in which excess fat is stored in liver. Two types of NAFLD are NAFL
and NASH. People with NAFLD may develop liver complications or other health problems
Introduction of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive
fat build-up in the liver without another clear cause such as alcohol use. Two types of NAFLD are nonalcoholic fatty liver (NAFL) and
nonalcoholic steatohepatitis (NASH).
Development and Classification of NAFLD Symptoms of NAFLD

Stage Image Biopsy Pathogenicity NAFL NASH/Cirrhosis
Healthy Healthy liver controls the levels of • Abdominal swelling

Liver glucose, fat and protein in the blood. Most NAFL patients are Enlarged blood
asymptomatic. vessels just beneath
• Fatigue the skins’ surface
Reversible
Hepatocytes accumulate excess fat, • Pain or discomfort in • Enlarged spleen

NAFL
a process called steatosis. the upper right • Red palms
abdomen • Yellowing of the skin
and eyes
Accumulated fat causes stress and
NASH injury to hepatocytes which leads to
fibrosis Risk Factors of NAFLD
Hardly Reversible
• Type 2 diabetes • Hypopituitarism

Dead hepatocytes are broken down • High cholesterol • Obesity
Cirrhosis and scar tissue accumulates, which
• High triglycerides level • Obesity, particularly
stiffens the liver.
• Metabolic syndrome when fat is concentrated
in the abdomen
Cancer and liver failure might be • Polycystic ovary
caused as complications by long- syndrome
HCC
standing cirrhosis. • Hypothyroidism
Source: Nature, China Insights Consultancy 48

T2DM and NAFLD Relationship between T2DM and NAFLD
Two-way Pathophysiologic Relationship between T2DM and NAFLD/NASH

- T2DM and NAFLD/NASH are not the two sides of the same coin. Multiple pathways are
involved in the two-way pathophysiologic relationship of NAFLD/NASH and T2DM
The Two-way Pathophysiologic Relationship between T2DM and NAFLD/NASH
The relationship between NAFLD/NASH and T2DM is not a simple one-to-one complement to each other. The two-way pathophysiologic
relationship has been discussed in academia, though the explicit mechanism involved is still presently under investigation. One certainty
has arisen in previous research, however, which points to the fact that there are multiple pathways involved in this relationship.
Prevalence about NAFLD/NASH Multiple Pathway Involved in NAFLD/NASH and T2DM
& T2DM
General Population People with T2DM Obesity
(Metabolic Syndrome)
Intestinal Dysbiosis ↓ Adiponectin

↑ Leptin, ↑ FFAs
↑ Circulating LPS ↑ TLR-α, IL-6 ↑ Inflammation
↑ Glucose Uptake
↓ Gluconeogenesis
Insulin Resistance
Unaffected NAFLD ↑ De nono lipogenesis
NASH or Fibrosis ↓ FFAs B-oxidation
Persistent
Hyperinsulinemia De nono lipogenesis
Systemic IR
Type 2
10% 23% 44% Diabetes Insulin ↑ CRP, TNF-α, IL-6 ↑ Inflammation NAFLD
Mellitus Resistance ↑ ROS ↑ Oxidative Stress
Relative Insulin
B-cell dysfunction Hepatic IR
T2DM in T2DM in T2DM in Resistance
general NAFLD NASH
Population Population Population Adipose tissue lipolysis ↑ FFAs
Source: Open Exploration, China Insights Consultancy 49

Two-way Pathophysiologic Relationship between T2DM and NAFLD/NASH

- T2DM and NAFLD/NASH are not the two sides of the same coin. Multiple pathways are
involved in the two-way pathophysiologic relationship of NAFLD/NASH and T2DM
The Two-way Pathophysiologic Relationship between T2DM and NAFLD/NASH
Prevalence about NAFLD/NASH Multiple Pathway Involved in NAFLD/NASH and T2DM

& T2DM
General Population People with T2DM Obesity
(Metabolic Syndrome)
Intestinal
Dysbiosis ↓ Adiponectin
↑ Leptin, ↑ FFAs
↑ Circulating LPS ↑ TLR-α, IL-6 ↑ Inflammation
↑ Glucose Uptake
↓ Gluconeogenesis
Insulin Resistance
Unaffected NAFLD ↑ De nono lipogenesis
NASH or Fibrosis ↓ FFAs B-oxidation
Persistent
Hyperinsulinemia De nono lipogenesis
Systemic IR
Type 2
10% 23% 44% Diabetes Insulin ↑ CRP, TNF-α, IL-6 ↑ Inflammation NAFLD
Mellitus Resistance ↑ ROS ↑ Oxidative Stress
Relative Insulin
B-cell dysfunction Hepatic IR
T2DM in T2DM in T2DM in Resistance
general NAFLD NASH
Population Population Population Adipose tissue lipolysis ↑ FFAs

Two-way Pathophysiologic Relationship between T2DM and NAFLD

- Multiple factors are involved in the bidirectional interaction of T2DM and NAFLD, including
glycometabolism, liver and cardiovascular system.
The Two-way Pathophysiologic Relationship between T2DM and NAFLD
T2DM + NAFLD patients are under higher risk of metabolic disorders and cardiovascular diseases, besides, they are more vulnerable to
lose the control of blood glucose levels and blood pressure levels, which lead to a higher incidence of complications, such as severe livers
diseases and vascular diseases. Thus, a systematic control of glucose level and fatty degeneration in livers are required.
T2DM patients are exposed to higher risk of liver fatty degeneration and
hepatic insufficiency
The insulin resistance in tissues or organs, such as liver, muscle and etc.,
always causes NAFLD, which is followed by a higher risk of T2DM
T2DM patients with NAFLD are exposed to higher risk of complications,

NAFLD including cardiovascular diseases, kidney disease and retinopathy, and a
higher mortality was observed
ATL increase and/or GGT increases caused by NAFLD are independent

Insulin risk factors of T2DM
Resistance • The incidence rate of T2DM in NAFLD and NASH patients are 22.51%
and 43.63% respectively, which are higher than general population
NAFLD in patients with T2DM or impaired glucose tolerance are more

T2DM inclined to exacerbate and develop into NASH and cirrhosis
• The risk of NASH in NAFLD patients with T2DM increases 2-3 fold
More severe inflammation in hepatic lobule, hepatocellular ballooning and

fibrosis were observed in T2DM patients
T2DM patients with NAFLD are more difficult to reach the gold of blood
glucose control

Epidemiology of T2DM + NAFLD

- NAFLD and T2DM often coexist. Patients with T2DM take a much higher risk of NAFLD.
This results in adverse outcomes such as higher rates of mortality due to cirrhosis
Epidemiology of T2DM + NAFLD
Research has revealed that the prevalence of NAFLD among T2DM patients is 2-fold compared with its prevalence in the general
population. Besides, T2DM increases the risk of serious NASH and advanced fibrosis in patients with NAFLD. The NAFLD patients with
T2DM undertake 4-fold risk to deteriorate into NASH compared patients without T2DM. Although an explicit relationship between T2DM
and NAFLD has not yet been fully discovered, it is certain that multiple pathways are involved in generating this intricate relationship.
The epidemiology of NAFLD and T2DM Worldwide
25.0% Europe Asia

23.7% 17.4%
In T2DM In T2DM
North America
68.0% 52.0-57.9%
Worldwide 24.1%
prevalence of In T2DM (US)
NAFLD IS 25% Middle East
51.8%
31.8%
In T2DM
30.4%
55.5%
Africa
South America 13.5%
Worldwide In T2DM
prevalence of 30.5% 30.4%
In T2DM
NAFLD among
people with 56.8%
T2DM is 55.5%
Source: Journal of Hepatology, AACE, AASLD, China Insights Consultancy 52

Current treatment and medication for T2DM/Pre-T2DM + NAFLD

- Lifestyle modification is recommended for treatment of NAFLD. The main goal for
T2DM/Pre-T2DM and NAFLD medicine intervention is to control of other CV risk factors
Current Management Paths and Paradigm of T2DM/Pre-T2DM + NAFLD
Current therapy for T2DM patients with NAFLD mainly aims at decreasing disease activity, delaying the progression of fibrosis and
reducing the risk factors associated with high cardiovascular risk. Currently, there are no pharmacological treatments approved by
regulatory agencies for this condition. Because T2DM and NAFLD share some common pathophysiologic features, it is not surprise that
most medication evaluated for the treatment of NAFLD are commonly used for T2DM. However, more factors need to be taken into
consideration while prescribing for T2DM+NAFLD patients, due to their damaged liver function.
Management of T2DM/Pre-T2DM
Lifestyle Intervention Not achieved Pharmacological treatment or

Weight reduction of 8-10% metabolic surgery
Proposed Algorithm for
Treatment of
NAFLD Pharmacological Treatment No response FXR agonists, PPAR agonists and
Patients with Pioglitazone as first-line therapy other drugs under development
and NASH
prediabetes/ Glucose Control Elevated HbA1c Add pioglitazone

T2DM and Metformin as first-line therapy Add GLP-1 RA or SGLT-2 inhibitor
NAFLD
Control of other
Blood Pressure(BP) Control Elevated BP
cardiovascular Second-line therapy
ARB or ACEI as first-line therapy
risk factors Elevated TG
Lipid-lowering Therapy & low HDL1 Add fibrates to statins
Statins as first-line therapy
Lifestyle Modification Medicine Intervention Surgical Approach

• Dietary modification are recommended • Currently, the medicine used for the treatment of • Bariatric surgery, a surgery to
in over-weight or obese patients; T2DM and NAFLD could be mainly classified as: reduce weight by reducing the
• Physical activity is advised to assist in metformin, glitazones, insulin, statins and other capacity of food intake;
weight loss and to improve metabolic cholesterol-lowering agents, ursodeoxycholic • Liver transplantation is done only
disorders; acid and antioxidants, ARBs2, probiotics, FXR in NASH patients with cirrhosis
• Medicines are preserved only for NAFLD agonists and GLP-1 agonists. and end stage of liver failure.
Note: 1 High-density liporprotein; 2 Angiotensin receptor blockers
Source: ADA, NIH, China Insights Consultancy 53
Current treatment and medication for T2DM/Pre-T2DM + NAFLD/NASH
Current Management Paths and Paradigm of T2DM/Pre-T2DM + NAFLD/NASH
Patients with T2DM/Pre-T2DM + NAFLD/NASH
• Control the progression of T2DM/Pre-T2DM, NAFLD/NASH and other CV risk factors at the same time
Treatment of T2DM/Pre-T2DM Treatment of NAFLD/NASH Control of other CV risk factors
Blood pressure Lipid-lowing

Lifestyle Intervention
Glucose Control Liver disease control

control therapy
• First-line：Metformin • Currently no specific approved • First- line: Mono • First-line: Statins

Drug or Combo use of
• Second-line: Add pioglitazone, drug , other than Saroglitazar • Second-line: Add
therapy ARBs, ACEIs,
GLP-1RA, SGLT-2 inhibitor, etc. Magnesium approved by DCGI* fibrates
diuretics,
Calcium channel
blockers
• Insulin Pump • Liver transplant, when develop • Second-line: α
Other • Low fat, low
severe cirrhosis and the liver blocker, β
therapy • Metabolic surgery stops working properly
cholesterol diet
blocker, etc.
Note:* DCGI, Drugs Controller General of India.

Source: American Diabetes Association; NIH; Chinese Society of Endocrinology; Chinese Diabetes Society; China
Insights Consultancy 54
T2DM and NAFLD Medication
Current Medication for T2DM/Pre-T2DM + NAFLD/NASH

- As NAFLD/NASH and T2DM share a series of common pathophysiologic features, the
therapies used for T2DM also demonstrated efficacy in treating NAFLD/NASH
Medication for T2DM/Pre-T2DM + NAFLD/NASH
SGLT2 DPP4
Intervention Metformin GLP-1 Thiazolidinediones Sulphonylurea Insulin
inhibitors inhibitors
Glucose lowering efficacy ++ ++ + or ++ + or ++ + +++ +++
Hypoglycaemia risk Low Low Low Low Low High High
Effect on body weight Loss Loss Gain Loss Neutral Gain Gain
Liver-specific effects
Steatosis NE ↓ ↓ ? ? NE ↑
Inflammation NE ↓ ↓ ? ? ? ?
Hepatocyte ballooning NE ↓ ↓ ? ? ? ?
Fibrosis NE NE ？ ? ? ? ?
RCTs showing effectiveness Pioglitazone
NE Liraglutide ND ND ND ND
in NAFLD (Rosiglitazone)
ND: not done; NE: no effect

Metformin is associated with lactic acidosis in patients with conditions that can themselves cause lactic acidosis (heart failure, hypoxia,
sepsis, etc.). besides, metformin can cause serum vitamin B12 deficiency, but studies on the influence of its duration and dose are
lacking; GLP-1 has a half-life only 2-min because of rapid degradation by DPP-4 enzyme. To overcome the shot half-life of GLP-1, two
approaches are being practiced: the first is to use DPP-4 inhibitor, the other approach is the synthesis of DPP-4 resistant GLP-1 analogs
(exenatide, liraglutide and etc.). Besides, it is not recommended as the first-line therapy due to its expensiveness; Thiazolidinediones
can trigger heart failure via fluid retention; SGLT2 inhibitors are giving promising results in the treatment of diabetes mellitus, but
emerging data from post-marketing studies indicates their adverse effects such as diabetic ketoacidosis, genital and urinary tract
infection and even cancer; DPP4 inhibitors might trigger neurogenic inflammation, elevated blood pressure and promoting immune
response and other adverse events; Sulphonylurea may cause hypoglycemia and weigh gain, and skin allergy and leucopenia were
also observed in some patients; Insulin increases the risk of hypoglycemia and weight gain, besides, skin allergy and lipoatrophy might
happed in the injection site. Diet and exercise should be advised for all patients, and continued throughout medical treatments
Source: Nature, China Insights Consultancy 55

T2DM and NAFLD Market size
The market size of T2DM with NAFLD drugs in China
Market size of T2DM + NAFLD in China (2018-2032E)
CAGR 2026E-32E Billion USD

T2DM + NAFLD 89.8%
11.4
10.3
8.9
7.2
5.1
2.3
0.0 0.0 0.2
2018 2022 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note: the size of T2DM with NAFLD drug market in China is estimated with the following assumptions: (i) the first drug for the treatment of T2DM with NAFLD
is expected to be approved in the fourth quarter 2026 in China; (ii) a number of T2DM with NAFLD drugs are expected to be approved and commercialized
from 2027 onwards; (iii) increased academic promotion and physician education by market players; (iv) the patient population that can be given T2DM with
NAFLD drugs continue to grow.
56
HTD1801 T2DM Pipeline
Pipeline of active phase II T2DM drugs registered at FDA (1/3)
Pipeline of active phase II T2DM Drugs registered at FDA

Drug Name Target Company Indications Admin. Phase Trial Number
Date Authority
ketohexokinase, Alnylam
ALN-KHK T2DM Injection II 2023/03/09 NCT05761301 FDA
KHK Pharmaceuticals
Obesity, Overweight,
GSBR-1290 GLP-1R Gasherbrum Bio Oral II 2023/03/09 NCT05762471 FDA
T2DM
BMF-219 Menin Biomea Fusion T2DM Oral II 2023/02/16 NCT05731544 FDA
PF-07081532 GLP-1R Pfizer T2DM Oral II 2022/10/14 NCT05579977 FDA
Tofogliflozin SGLT-2 Kowa Company T2DM Oral II 2022/06/22 NCT05469659 FDA
SY-009
SGLT-1 Suzhou Yabao T2DM Oral II 2022/06/21 NCT05426018 FDA
T2DM
Inventiva
IVA337 PPAR (Combined with Oral II 2022/02/09 NCT05232071 FDA
Pharma
Empagliflozin)
Regor
RGT001-075 GLP-1R T2DM Oral II 2022/03/25 NCT05297045 FDA
Pharmaceuticals
Liraglutide GLP-1R BioLingus T2DM Oral II 2022/03/07 NCT05268237 FDA
Imbria
IMB-1018972 N/A T2DM, DCM, HFpE Oral II 2021/04/01 NCT04826159 FDA
Pharmaceuticals
Shanghai HEP
Hepalatide NTCP T2DM Injection II 2020/12/10 NCT04662164 FDA
Pharmaceutical
Inventiva
Lanifibranor PPAR T2DM, NAFLD Oral II 2018/03/08 NCT03459079 FDA
Pharma
Source: ClinicalTrials; CDE; China Insights Consultancy 57


Date Authority
NPM-119 GLP-1R Vivani Medical, Medpace T2DM Injection II 2023/01/04 NCT05670379 FDA
HD-6277 GPR40 Hyundai Pharm T2DM Oral II 2022/12/27 NCT05666128 FDA
CSPC Baike
TG103 GLP-1R (Shandong) T2DM Injection II 2021/10/01 NCT05063253 FDA
Biopharmaceutica
Shandong
HRS-7535 GLP-1R Suncadia T2DM Oral II 2023/03/08 NCT05759897 FDA
Medicine
Carmot
CT-868 Dual GIPR/GLP-1R Obesity,T2DM Injection II 2021/11/08 NCT05110846 FDA
Therapeutics
Jiangsu
HR17031 GLP-1R/Insulin HengRui T2DM Injection II 2022/04/19 NCT05333835 FDA
Medicine
AMG133 Dual GIPR/GLP-1R Amgen Obesity, Overweight, T2DM Injection II 2023/01/03 NCT05669599 FDA
HRS9531 Dual GIPR/GLP-1R Fujian Shengdi Pharmaceutical T2DM Injection II 2023/07/28 NCT05966272 FDA
Dual GCGR/GLP-
IBI362 Innovent Biologics (Suzhou) T2DM Injection II 2021/07/16 NCT04965506 FDA
1R
Semaglutide GLP-1R Novo Nordisk A/S T2DM Injection II 2022/08/03 NCT05486065 FDA


Date Authority
Tirzepatide Obesity, Overweight, CKD,

Dual GIPR/GLP-1R Eli Lilly and Company Injection II 2022/09/13 NCT05536804 FDA
(LY3298176) T2DM
Triple GLP- Obesity, Overweight, CKD,
LY3437943 Eli Lilly and Company Injection II 2023/07/07 NCT05936151 FDA
1R/GIPR/GCGR T2DM
CPL207280 GPR40 Celon Pharma SA T2DM Oral II 2022/02/21 NCT05248776 FDA
aflibercept Multiple pathways Regeneron Pharmaceuticals DME, T1DM, T2DM Injection II 2020/06/12 NCT04429503 FDA
Finerenone
(Kerendia, N/A Bayer CKD, T2DM Oral II 2020/02/24 NCT05254002 FDA
BAY94-8862 )
Hypertriglyceridemia, NAFLD,
MN-001 Multiple pathways MediciNova Oral II 2022/07/19 NCT05464784 FDA
T2DM
Obesity, NAFLD, MASH,

HU6 N/A Rivus Pharmaceuticals Oral II 2023/08/07 NCT05979779 FDA
T2DM

Pipeline of active phase II T2DM drugs registered at CDE
Pipeline of phase II T2DM Drugs registered at CDE

First Competen
Administrati Phas
# Drug Name Target Company Indications Posted Trial Number t
on e
Date Authority
1 HRS9531 N/A Hengrui/Suncadia T2DM Injection II 2023/08/02 CTR20232258 NMPA
2 GZR18 GLP-1R Ganlee T2DM Injection II 2023/07/10 CTR20232069 NMPA
Dual GIP/GLP-
3 HS-20094 Hansoh T2DM Injection II 2023/05/06 CTR20231357 NMPA
1R
4 HRS-7535 GLP-1R Hengrui/Suncadia T2DM Oral II 2023/02/20 CTR20230393 NMPA
T2DM patients, with oral non-
GLP-1R and insulin antidiabetic drugs are
5 HR17301 Hengrui Injection II 2022/04/14 CTR20220857 NMPA
Insulin ineffective or the effect is
unsatisfactory
6 TG103 GLP-1R I-MAB Pharma T2DM Injection II 2022/04/01 CTR20220751 NMPA
Multiple
7 HTD1801 HighTide Biopharma T2DM Oral II 2022/02/23 CTR20220346 NMPA
pathways
8 SY-009 SGLT-1 Yabao T2DM Oral II 2022/01/25 CTR20220144 NMPA
Patients with T2DM and
9 TG103 GLP-1R I-MAB Pharma Injection II 2021/09/24 CTR20212332 NMPA
Overweight/Obesity
Dual
10 IBI362 GCGR/GLP- Innovent T2DM Injection II 2021/07/28 CTR20211733 NMPA
1R
Tianjin Institude of
11 Tianagliflozin SGLT2 Pharmaceutical T2DM Oral II 2020/08/10 CTR20201558 NMPA
Research
12 JY09 GLP-1R Eastern Biotech T2DM Injection II 2019/10/31 CTR20192166 NMPA
13 Lianmei Granules N/A Artepharm T2DM Oral II 2020/07/31 CTR20191646 NMPA
14 PB-119 GLP-1R Pegbio T2DM Injection II 2018/08/20 CTR20180460 NMPA

Table of Contents

• T2DM + NAFLD
• NASH
• Severe Hypertriglyceridemia
• Obesity
SHTG Introduction
Overview of Hypertriglyceridemia
- Overall, more than a third of adults in the U.S. have high triglyceride levels. And it is also
one of major dyslipidemia in China. Severe HTG occurs when serum triglycerides rise
above 500mg/dL
Introduction of Hypertriglyceridemia
Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. More specifically, it is defined as fasting serum
triglyceride (TG) levels of 150 mg per dL or higher, is associated with increased risk of cardiovascular disease.
Classification of HTG Causes of Hypertriglyceridemia (HTG)

Severity Classification
familial combined
Normal Serum TG＜150mg/dL familial chylomicronemia
hyperlipoproteinemia
Primary
Mild Serum TG 150–199mg/dL causes
familial hypertriglyceridemia primary mixed hyperlipidemia
Moderate Serum TG 200–499mg/dL
Severe Serum TG >500mg/dL
Renal Disease Medication
• According to the 2018 AHA/ACC Uremia, Glomerulonephritis Estrogen, Isotretinoin
Guideline, SHTG is defined as serum
TG>500 mg/Dl Secondary Autoimmune Disorders
Miscellaneous
causes Hypothyroidism, systemic lupus
Pregnancy, paraproteinemia
• SHTG is usually caused by a erythematosus
combination of genetic and secondary
factors. A detailed history that includes Obesity, metabolic syndrome, alcohol, unhealthy diet
family history, medications, and alcohol
consumption can often lead to the Complications of HTG
cause. Physical examination findings Cardiovascular disease
may stretch across multiple organ HTG increased risk of cardiovascular disease (CVD);
systems. Patients with SHTG should Pancreatitis
be admitted to the hospital for Extreme elevations of triglycerides may cause acute pancreatitis;
aggressive medical therapy if they Chylomicronemia Syndrome
develop symptoms such as abdominal An often unrecognized and less severe condition, usually caused by triglyceride levels
pain or pancreatitis. greater than 500 mg/dL.
AHA/ACC: American Heart Association /American College of Cardiology

Source: frontiers, China Insights Consultancy 62
SHTG Introduction
The prevalence of SHTG in China, US and EUR

- The population of SHTG patients in China is expected to increase with a higher rate than
the U.S. and EUR. The growth rate is inclined to slow down.
Prevalence of SHTG
Prevalence of SHTG in China, U.S. and Europe 2018-2032E
CAGR 2018-22 2022-32E thousand patients
Prevalence of SHTG in China 1.9% 1.6%

Prevalence of SHTG in U.S. 1.3% 1.2%
Prevalence of SHTG in Europe 0.5% 0.5%
Total 1.4% 1.2%
3,019.4 3,053.5 3,087.7

2,913.7 2,948.8 2,984.0
2,808.8 2,844.0 2,878.8
2,704.0 2,739.2 2,774.0
2,593.4 2,631.1 2,668.1
1,775.4 1,802.4 1,828.6 1,855.0

1,667.9 1,695.0 1,721.8 1,748.5
1,558.9 1,586.4 1,613.7 1,640.8
1,473.4 1,502.4 1,530.9
327.1 331.6 335.6 339.8 343.9 348.1 352.4 356.4 360.5 364.7 369.0 373.1 377.0 380.9
322.7
797.3 801.6 805.6 809.5 813.0 816.4 819.9 823.7 827.4 831.4 835.5 839.7 843.9 847.9 851.8
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

SHTG Diagnosis and Management
Current diagnosis and management of SHTG
Management of SHTG
Severe hypertriglyceridemia
No active acute pancreatitis
TG plateau>500mg/dl
• Identify and treat, or eliminate (if possible),
TG plateau<500mg/dl secondary contributors
• Prescribed diet <10% fat
• Fibrates reductase inhibitors
Recheck 3-5 days
TG plateau>500mg/dl TG falling
• Control diet: 0% fat Recheck every 5-10 days
or uncontrolled diabetes
• Intensive insulin therapy (if indicated) until plateau control
• Discharge when TG <500mg/dl
TG plateau > 400mg/dl
• Readdress diet adherence

• Omega-3 fatty acids Control
• Recheck 2–4 weeks
• Consider measuring LPL
TG <400mg/dl
Recalcitrant hypertriglyceridemia • Assess LDL and non-HDL cholesterol
• Plasmapheresis TG plateau>400mg/dl
• LDL-lowering if indicated
• High-dose antioxidants • Maintenance diet: <10% saturated fat,
• Readdress diet adherence
• Nicotinic acid restriction of simple sugars
• Recheck 6–8 weeks Control • Follow-up 2–4 months
LPL: Lipoprotein lipase
Source: Nature Reviews Endocrinology, Clin Res Cardiol Suppl, China Insights Consultancy 64
SHTG Treatment options
Pharmacologic treatment of SHTG

- There are three major types of drugs are mainly used in SHTG treatment
Current pharmacological Treatment options of SHTG

Treatment modality Mechanism of action Comments Limitations Annual cost
Increase of LPL level, decrease
in hepatic TG synthesis by
Considered drugs of first Slow onset of TG
Fibrates induction of hepatic FFA ~1,300 RMB1
choice lowering
oxidation, and stimulation of
reverse cholesterol transport
Prominent side effects
Reducing VLDL secretion via Reliable long-term effect
Nicotinic acid such as facial flushing, ~1,500 RMB2
receptor on TG level
slow onset of TG lowering
Reduced hepatic TG synthesis,
enhanced peroxisomal b- Potent drug with no side
Omega-3-FA oxidation, increased LPL activity effects, immediate onset of No limitations 11,000~20,000 RMB3
and adipose tissue LPL action
expression
Note:
1 200 mg once daily dosage based on drug label of Fenofibrates to treat SHTG, expected annual treatment duration is 360 days
2 250 mg twice daily based on drug label of Acipimox to treat SHTG, expected annual treatment duration is 360 days
3 4g daily based on drug label of Omega-3-acid Ethyl Ester 90 to treat HTG, expected annual treatment duration is 360 days
Source: Nature Reviews Endocrinology, Clin Res Cardiol Suppl, China Insights Consultancy 65
SHTG Market size
Market size of SHTG drug market
Market size of SHTG drug market， 2018-2032E
CAGR 2018-22 2022-32E Million USD
China 10.5% 9.3%

the U.S. 8.8% 7.8%
Europe 8.0% 7.1% 4,802.4
Total 8.6% 7.6% 4,551.1
4,297.5 692.2
4,040.5 646.5
601.6
3,783.1
557.4
3,526.4
514.2
3,271.8
472.2
3,020.6 1,966.4
431.5 1,862.7
2,772.1 392.0 1,757.8
2,529.1 354.1 1,651.2
2,292.5 1,544.3
317.9 1,437.8
2,063.3 283.3 1,332.4
1,842.4 250.7 1,228.7
1,742.3 1,125.6
1,647.3 220.0 1,025.0
204.4
189.8 927.3
833.1
700.7 742.7
661.2 2,143.8
1,938.1 2,041.9
1,724.5 1,831.9
1,508.0 1,616.3
1,292.4 1,399.9
1,081.8 1,186.2
837.1 879.8 979.5
796.3
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Source: Annual reports published by market players, Expert interview, Literature research, China Insights Consultancy 66
HTD1801 SHTG Pipeline
Global pipeline of SHTG drugs
Pipeline of SHTG Drugs in active clinical stage registered at ClinicalTrials, as of LPD

# Drug Name Target Company Indications Administration Phase Trial Number
Date Authority
1 Pegozafermin FGF21 89Bio Severe Hypertriglyceridemia Injection III 2023/05/10 NCT05852431 FDA
APOC3 Ionis
2 Olezarsen Severe Hypertriglyceridemia Injection III 2023/01/12 NCT05681351 FDA
mRNA Pharmaceuticals
Patients with Hypertriglyceridemia and
APOC3 Ionis
3 Olezarsen Atherosclerotic Cardiovascular Disease, or Injection III 2022/11/09 NCT05610280 FDA
with Severe Hypertriglyceridemia
APOC3 Ionis
APOC3 Ionis
6 Ethyl Icosapentate N/A Mochida Severe Hypertriglyceridemia Oral III 2020/01/27 NCT04239950 FDA
7 K-877 PPARα Kowa Company Severe Hypertriglyceridemia Oral III 2017/01/05 NCT03011450 FDA
Patients With Metabolic Dysfunction
8 MAR001 N/A Marea Therapeutics Injection Ib/IIa 2023/07/22 NCT05896254 FDA
(triglyceride levels > 2.8 mmol/L)
NorthSea
9 NST-1024 N/A High Triglycerides Oral II 2023/06/05 NCT05889156 FDA
Therapeutics B.V.
Hypertriglyceridemia, Atherosclerotic
APOC3 Ionis
10 Olezarsen Cardiovascular Disease, Severe Injection II 2021/10/15 NCT05355402 FDA
Hypertriglyceridemia
11 ARO-APOC3 ApoC-III Arrowhead Severe Hypertriglyceridemia Injection II 2021/01/22 NCT04720534 FDA
FGFR1/β-
12 Pegozafermin 89Bio Severe Hypertriglyceridemia Injection II 2020/09/09 NCT04541186 FDA
Klotho
ANGPTL3 Patients with Hypertriglyceridemia, T2DM
13 ISIS 703802 Akcea Therapeutics Injection II 2017/12/03 NCT03371355 FDA
mRNA and NAFLD
Visirna Dyslipidemias, Familial
14 VSA003 N/A Therapeutics HK Hypercholesterolemia, Injection I 2023/05/09 NCT05851066 FDA
Limited Hypertriglyceridemia
15 LY3875383 N/A Eli Lily Hypertriglyceridemia Injection I 2022/11/08 NCT05609825 FDA
16 Ethyl Icosapentate N/A Mochida Severe Hypertriglyceridemia Oral III 2019/10/15 CTR20191474 NMPA
Note:* pipelines only included when inclusion criteria specify patients with triglyceride level ≥ 500 mg/dL or triglyceride levels > 2.8 mmol/L
Source: ClinicalTrials; China Insights Consultancy 67
Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
Obesity Overview
Introduction to Obesity
- Obesity is an epidemic disease that threatens to inundate health care resources by
increasing the incidence of cardiovascular diseases, diabetes, musculoskeletal disorders,
and some cancers
Introduction to obesity
• Obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. A body mass index (BMI) over 25 is
considered overweight, and over 30 is obese.
• Obesity causes or exacerbates many health problems, both independently and in association with other diseases. In particular, it is
associated with the development of cardiovascular diseases, diabetes, musculoskeletal disorders, and some cancers.
Body Mass Index(BMI) Causes

Obesity is a complex metabolic disorder with multiple causes.
Globally, significant changes in dietary and physical activity
patterns has led to the increasing prevalence of obesity.
• Increasing intake of energy-dense foods that are high in fat and

sugars
<18.5 18.5-24.9 25.0-29.9 30.0-34.9 >35.0 • Decreasing level of physical inactivity due to the increasingly
Under Normal Over- Obesity Obesity sedentary nature of many forms of work, changing modes of
weight weight weight class I class II,III transportation, and increasing urbanization.
Risk factors Complications

Body weight is determined by an interaction between genetic, Raised BMI is associated with the development of certain
environmental and psychosocial factors acting through the noncommunicable, chronic diseases including cardiovascular
physiological mediators of energy intake and expenditure. diseases, diabetes, musculoskeletal disorders and some cancers.
Obesity is associated with an
• Genetics: overweight and obesity can run in families. Obesity is a common risk
increased risk of developing
• Environmental factors: social factors such as having a low factor that can lead to the
cardiovascular disease(CVD),
socioeconomic status, built environment factors, exposure to chemicals development of prediabetes
particularly heart failure and
known as osmogenes. and type 2 diabetes.
coronary heart disease.
• Lifestyle habits: lack of physical activity, unhealthy eating patterns, not Obesity is a risk factor for
enough sleep, and high amounts of stress. Obesity is highly associated
developing endometrial,
• Age: the risk of unhealthy weight gain increases as age. with osteoarthritis, which is a
breast, ovarian, prostate,
• Race or ethnicity: overweight and obesity is highly prevalent in some disabling degenerative disease
liver, gallbladder, kidney, and
racial and ethnic minority groups. of the joints
colon cancer.
Source: WHO; National Institutes of Health; China Insights Consultancy 69

Obesity Epidemiology
Epidemiology of obesity
- The population of obesity patients in China ranks first in the world and is expected to
increase with a higher rate than the U.S. and EUR.
Epidemiology of obesity
Prevalence of obesity in China, U.S. and Europe (2016-2032E)
Prevalence of obesity in China 4.9% 2.5%
Prevalence of Obesity in U.S. 2.5% 2.1%
Prevalence of Obesity in Europe 2.1% 2.0%

Total 3.6% 2.3%
615.9 626.3
593.6 605.1
569.3 581.7
543.1 556.5
514.7 529.2
499.8
484.2
468.0
450.9 330.3
433.3 320.2 325.5
308.2 314.4
294.0 301.4
277.4 286.0
258.5 268.3
237.0 248.1
213.1 225.3
154.6 157.8 160.9 163.9

142.0 145.1 148.2 151.4
126.9 129.9 132.9 135.9 138.9
120.5 123.7
101.8 104.0 106.2 108.4 110.6 112.8 115.1 117.4 119.7 122.2 124.6 127.1 129.5 132.0
99.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
70
Obesity Treatment pathway
Treatment pathway of obesity

- The AACE/ACE treatment framework of obesity may include lifestyle therapy, anti-
obesity medication and surgical intervention based on disease stage
Treatment pathway of obesity

Diagnosis Staging and treatment
BMI, kg/m2 Suggested therapy

Clinical component Disease stage
Anthropometric component (based on clinical judgement)
<25
<23 in patients of certain ethnicities; Evaluate for presence or Normal weight
• Healthy lifestyle: Healthy meal plan/physical activity
waist circumference below absence of adiposity- (no obesity)
regional/ethic cutoffs related complications and
severity of complication
25-29.9
Overweight stage 0 • Lifestyle therapy: Reduced-calorie healthy meal plan/
23-24.9 in patients of certain • Metabolic syndrome (no complications) physical activity/behavioral interventions
ethnicities • Prediabetes
• Type 2 diabetes • Lifestyle therapy: Reduced-calorie healthy meal plan/
• Dyslipidemia physical activity/behavioral interventions
≥30 • Hypertension Obesity stage 0
≥25 in patients of certain ethnicities • Cardiovascular disease (no complications)
• Anti-obesity medications: Consider if lifestyle therapy
• Nonalcoholic fatty liver fails to prevent progressive weight gain(BMI≥27)
disease
• Polycystic ovary • Lifestyle therapy: Reduced-calorie healthy meal plan/
syndrome physical activity/behavioral interventions
• Infertility (women) Obesity stage 1
≥25
• Hypogonadism (men) (1 or more mild to moderate
≥23 in patients of certain ethnicities • Anti-obesity medications: Consider if lifestyle therapy
• Obstructive sleep apnea complications)
fails to achieve therapeutic target or imitate concurrently
• Asthma/reactive airway with lifestyle therapy(BMI≥27)
disease
• Osteoarthritis
• Lifestyle therapy: Reduced-calorie healthy meal plan/
• Urinary stress
physical activity/behavioral interventions
incontinence Obesity stage 2
≥25
• Gastroesophageal (at least 2 severe
≥23 in patients of certain ethnicities • Anti-obesity medications: Initiate concurrently with
reflux disease complications)
lifestyle therapy(BMI≥27); consider bariatric
• Mental depression
surgery(BMI≥35)
Source: AACE, ACE; China Insights Consultancy 71

Obesity Approved medications
Approved medications for obesity

- Obesity is an epidemic disease that threatens to inundate health care resources by
increasing the incidence of diabetes, heart disease, hypertension, and cancer
Approved medications for obesity

FDA approved anti-obesity drugs
Current drug therapies are often limited by weight loss efficacy and side effects.
Drug name Common side effects

Phentermine
Benzphetamine • Dry mouth, constipation, difficulty sleeping, dizziness, feeling nervous /restless,
Short-term use (a few
weeks) Diethylpropion headache, raised blood pressure, increased heart rate
Phendimetrazine
Orlistat • Diarrhea, gas, leakage of oily stools, stomach pain
Phentermine-topiramate • Constipation, dizziness, taste changes, trouble sleeping
• Constipation, diarrhea, dizziness, headache, increased blood pressure, liver

Naltrexone-bupropion
damage, nausea
Long-term use
Liraglutide • Nausea, diarrhea, constipation, abdominal pain, increased heart rate
Semaglutide • Nausea, diarrhea, vomiting, constipation, headache, fatigue
Setmelanotide • Injection site reaction, skin darkening, nausea, disturbance in sexual arousal,
72
Obesity Market size
Market size of Obesity drug market
Market size of Obesity drug market， 2018-2032E
China 37.7% 38.0%

the U.S. 8.4% 14.0% 13.0
Europe 8.1% 13.9%
Total 9.2% 16.9% 11.3
3.4
9.9 2.7
8.6 2.0
7.4 1.6
6.3 1.1
6.5
5.4 0.8 5.9
0.6 5.3
4.7
4.2
3.7
2.7 3.2
1.9 0.1
0.0 1.7
2.5 2.8 3.1
1.3 2.0 2.3
1.6 1.8
0.6 0.8
2018 2022 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note:* Only medications specifically indicated for overweight/obesity are counted as obesity drug
HTD1804 Obesity Approved targeted medications
Approved targeted medications for obesity

- There are 2 innovative medications approved for indication of obesity globally, and 2
medications targeting GLP-1 are approved to treat obesity by NMPA
Approved innovative medications for obesity, FDA

Brand Approval Annual
Drug Target Company Indications Clinical data Approval
name date cost*
chronic weight management in adults with a In a randomized, double‐blind,
BMI ≥30 kg/m2, or ≥27 kg/m2 with at least placebo‐controlled trial. The
Novo
Liraglutide Saxenda GLP-1R one weight-related comorbidity, as an liraglutide group had significantly FDA 2014/12/23
Nordisk
adjunct to a reduced calorie meal plan and greater decrease in body weight
increased physical activity. than placebo.
Liraglutide was superior to placebo ~20,000
treatment of obesity in adolescents (12–17 USD
with regard to the change from
years) with a body weight above 60 kg and
baseline in the BMI standard-
Novo an initial body mass index (BMI)
Liraglutide Saxenda GLP-1R deviation score at week 56 FDA 2020/12/04
Nordisk corresponding to 30 kg/m2 or greater for
(estimated difference, -0.22; 95%
adults, as an adjunct to reduced-calorie
confidence interval [CI], -0.37 to -
meals and increased physical activity.
0.08; P = 0.002).
adjunct to a reduced calorie diet and
increased physical activity for chronic weight
From baseline to week 68, the
management in adult patients with an initial
proportion of participants with
body mass index (BMI) of 30 kg/m2 or
Novo prediabetes, defined using the ADA
Semaglutide Wegovy GLP-1R greater (obesity), or 27 kg/m 2 or greater FDA 2021/06/04
Nordisk criteria, dropped from 48% to 7% in
(overweight) in the presence of at least one
the semaglutide group and from
weight-related comorbid condition (e.g.,
53% to 26% in the placebo group.
hypertension, type 2 diabetes mellitus, or
dyslipidemia) ~140,000
USD
In a double-blind, parallel-group,
randomized, placebo-controlled
trial, a total of 95 of 131
pediatric patients aged 12 years and older
Novo participants (73%) in the
Semaglutide Wegovy GLP-1R with an initial BMI at the 95th percentile or FDA 2022/12/23
Nordisk semaglutide group had weight loss
greater for age and sex (obesity)
of 5% or more, as compared with
11 of 62 participants (18%) in the
placebo group.
Note:* Annual cost calculated based on assumptions that i) medications are used in adults according to indications and usage in drug labels and ii) individual
treatment is continued for a year of 52 weeks
Source: FDA, Drugs.com, China Insights Consultancy 74
HTD1804 Obesity Approved targeted medications
Approved targeted medications for obesity

medications targeting GLP-1 are approved to treat obesity by NMPA
Approved innovative medications for obesity, NMPA
Brand Administrati
Drug Target Company Indications Approval Approval date Annual cost*
name on
adjunct to a reduced calorie diet and increased

physical activity for chronic weight management in
adult patients with an initial body mass index (BMI) of
30 kg/m2 or greater (obesity), or 27 kg/m2 or greater
Huadong (overweight) in the presence of at least one weight-
Liraglutide Liluping GLP-1R Injection NMPA 2023/06/30 ~7,000 RMB
Medicine related comorbid condition (e.g., hypertension, type 2
diabetes mellitus, or dyslipidemia)
Indicated for weight management in adult patients

with a BMI ≥ 28kg/m2, or BMI ≥ 24kg/m2 and at least
one weight associated metabolic disorders (eg, ~110,000
Beinaglutide Feisumei GLP-1R Benamae Injection NMPA 2023/07/28
hypertension, hypertension, dyslipidemia, fatty liver, RMB
obstructive sleep apnea syndrome)
syndrome, etc.)
Note:* Annual cost calculated based on assumptions that i) medications are used in adults according to indications and usage in drug labels and ii) individual
treatment is continued for a year of 52 weeks
Source: FDA, Drugs.com, China Insights Consultancy 75
HTD1804 Obesity Pipeline
China pipelines for obesity

medications targeting GLP-1 are approved to treat obesity by NMPA, which are Liraglutide
by Huadong Medicine and Beinaglutide by Benamae
Pipeline of innovative obesity medication, CDE-registered, phase II and III, as of Aug 2023*
First Posted
Drug Name Target Company Indications Phase Trial Number
Date
Ecnoglutide GLP-1R Sciwind Overweight/obesity III 2023/03/15 CTR20230745
Mazdutide GLP-1R/GCGR Innoventbio Overweight/obesity III 2022/10/04 CTR20222567
HR170331 GLP-1R Hengrui Overweight/obesity III 2021/03/08 CTR20210439
Tirzepatide GLP-1R Eli Lilly Overweight/obesity III 2021/02/12 CTR20210227
Semaglutide GLP-1R Novo Nordisk Overweight/obesity III 2020/10/28 CTR20202040
BEM-014 GLP-1R BENAMAE Overweight/obesity III 2019/04/01 CTR20190408
TG103 GLP-1R I-Mab Biopharma Overweight/obesity II 2022/03/09 CTR20220498
BI 456906 GLP-1R Boehringer Ingelheim Overweight/obesity II 2021/06/07 CTR20210717
Note:* Excluding Liraglutide biosimilars under clinical trials registered at CDE

Source: CDE; China Insights Consultancy 76
Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
Chronic cholestatic liver disease Overview
Introduction to Chronic cholestatic liver disease

- Cholestasis describes impairment in bile formation or flow that can manifest clinically
with fatigue, pruritus, and jaundice, which is considered chronic if last longer than 6
months. PSC and PBC are two major types of chronic cholestatic liver disease
Introduction to Chronic cholestatic liver disease

Definition Classification
Cholestasis describes impairment in bile formation or flow that can Cholestatic disorders are broadly defined as intra- or extrahepatic.
manifest clinically with fatigue, pruritus, and jaundice. Although the Intrahepatic cholestasis: caused by defects in bile canaliculi,
clinical manifestations of cholestatic liver disease vary, early hepatocellular function, or intrahepatic bile ducts;
biochemical evidence of cholestasis includes increases in serum Extrahepatic cholestasis: causes affect the extrahepatic ducts,
alkaline phosphatase (ALP) and gamma-glutamyltranspeptidase common hepatic duct, or common bile duct.
(GGT), followed by onset of conjugated hyperbilirubinemia. By ➢ Some etiologies of cholestasis, such as primary sclerosing
convention, cholestasis is considered chronic if it lasts > 6 cholangitis, can affect both the intrahepatic and extrahepatic bile
months. ducts.
Causes of Cholestasis
Incidence rate of cholestasis in first-hospitalized patients with Feature PSC PBC

chronic liver disease is 10.26%, the distribution of the cholestasis
Gender > >
incidence according to the type of chronic liver disease is:
Median age at
Incidence of cholestasis of main chronic liver diseases (%) 30-40 years 52 years
diagnosis
Site of disease Bile ducts inside and Small bile ducts inside
PSC 75
involvement outside the liver the liver only
PBC 43 MRI1 of bile ducts, liver Raised ALP, AMA3,
Mode of diagnosis
biopsy, ERCP2 diagnostic liver biopsy
Hepatic tumor 36
Co-existing IBD4 ~ 70% ~ 1%
Autoimmune hepatitis 31 No effective medical
Treatment UDCA, Obeticholic acid
therapy
Drug-induced liver diseases 28
Common Itching, fatigue, Itching, fatigue,
Alcoholic hepatitis 16 symptoms in early abdominal pain, abdominal pain, dry
stages cholangitis flares eyes and mouth
Note: 1 Magnetic Resonance Imaging; 2 Endoscopic retrograde cholangiopancreatography; 3 positive disease specific antibodies; 4 inflammatory bowel disease;
Source: 《胆汁淤积性肝病诊断和治疗共识（2015）》;China Insights Consultancy 78
PSC Overview
Overview of Primary Sclerosing Cholangitis (PSC) drug market

- PSC is a long-term progressive disease and is characterized by inflammation and
scarring of the bile ducts which normally allow bile to drain from the gallbladder
Definition and classification of PSC
Overview of PSC Heterogeneous condition of PSC
A heterogeneous condition, with different subgroups conferring

Primary sclerosing cholangitis (PSC) different prognoses:
• A long-term progressive disease
• Advances very slowly • PSC and IBD: Roughly 70% of patients with PSC have
Normal bile underlying Inflammatory bowel disease (IBD), most frequently
• Characterized by inflammation and ducts ulcerative colitis (UC). Patients with PSC-associated IBD
scarring of the bile ducts which typically exhibit pancolitis with a right-to-left intestinal
inflammatory gradient associated with a greater incidence of
normally allow bile to drain from the backwash ileitis and rectal sparing.
gallbladder • PSC and UC: Patients with concomitant UC and PSC have an
increased risk of developing colorectal cancer
• Eventually leads to liver failure,
Inflammation
and scar tissue • PSC and small/large duct: Patients with PSC and small duct
repeated infections, and tumors of the
destroy ducts disease have an improved survival and lower risk of
bile duct or liver cholangiocarcinoma compared with patients with large-duct
PSC
• PSC and lgG4: Patients with PSC and a raised
PSC affects all age groups, median age at diagnosis immunoglobulin G4 (IgG4) suffer from more severe cases of
is 30-40 years. liver disease
• ALP: Patients who demonstrate a significant reduction in their
PSC is more common in men，more than 60% of serum alkaline phosphatase (ALP) in a median time of 2 years
patients are men. following diagnosis have an improved transplant-free survival
and reduced risk of cholangiocarcinoma
Source: Elizabeth C. Goode et al. 2016, United European Gastroenterol J., China Insights Consultancy 79
PSC Epidemiology
Epidemiology of PSC
Prevalence of PSC
Prevalence of PSC in China, U.S. and Europe 2018-2032E
CAGR 2018-22 2022-32E Thousand patients
Prevalence of PSC in China 1.4% 1.1%

Prevalence of PSC in U.S. 1.6% 1.4%
Prevalence of PSC in Europe 1.1% 0.8%
Total 1.3% 1.0%
305.5 308.3 311.1

296.8 299.8 302.7
287.5 290.7 293.8
277.7 281.1 284.3
267.1 270.8 274.3
184.9 186.6 188.2 189.7

177.8 179.7 181.5 183.2
169.8 171.9 173.9 175.9
163.2 165.4 167.7
49.1 49.9 50.6 51.3 52.0 52.8 53.5 54.3 55.0 55.8
45.6 46.3 47.0 47.7 48.4
58.4 59.0 59.6 60.2 60.7 61.3 61.8 62.3 62.8 63.3 63.7 64.2 64.7 65.1 65.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

PSC Treatment
Treatment pathway for PSC

- At present there are no effective medical treatment options for PSC; Ursodeoxycholic
acid is used off label to treat PSC as the current mainstay of medical treatment
Treatment pathway for PSC

Unmet need
At present there are no effective medical treatment options Over the past two decades many clinical trials of
for PSC. Hence, there are no Approved drugs. medical therapies for PSC have been conducted;
“PSC is one of the biggest unmet needs in hepatology.” however, none have demonstrated real improvements in
--European Association for the Study of the Liver annual hard clinical endpoints.
meeting, 2011, Berlin
Key focus on future treatment of PSC:
Current mainstay of medical treatment: Efforts for new diagnostic tests aiming at earlier PSC
Ursodeoxycholic acid (UDCA) (off label), although there 1 detection should be emphasized, since MRI/MRCP
is no evidence that it alters long-term outcomes; Proven (Magnetic resonance imaging/magnetic resonance
efficacy in the treatment of other cholestatic diseases such cholangiopancreatography) and ERCP still do only
as PBC detect the footprints of the disease and are therefore an
Care for primary sclerosing cholangitis focuses on imperfect gold standard.
monitoring liver function, managing symptoms and, when 2
possible, doing procedures that temporarily open blocked Combination therapy may reach a breakthrough due to
bile ducts, such as: endoscopic retrograde the still unknown cause of PSC. Theoretically, a
cholangiopancreatography (ERCP), percutaneous potential treatment regimen in PSC may include
transhepatic cholangiography synergistically acting anticholestatic norUDCA (Nor-
ursodeoxycholic acid) and fibrates. Targeting at an
The only known cure for advanced PSC: inflammatory gut-liver axis in PSC may contain novel
Liver transplant, but the disease may recur in the therapeutic antibodies, antibiotics, sulfasalazine, and
transplanted liver in a small number of patients. FMT (Fecal microbiota transplantation).
.
Now Future
Source: Literature search, China Insights Consultancy 81
PSC Treatment
Treatment pathway for PSC for Industry Overview

- At present there are no effective medical treatment options for PSC; Ursodeoxycholic
acid is used off label to treat PSC as the current mainstay of medical treatment
Treatment pathway for PSC for IO
As of May 2023, there are no effective medical treatment options for PSC and no approved drugs specifically indicated for PSC.
According to the 2011 annual meeting of EASL (European Association for the Study of the Liver), PSC is one of the biggest unmet needs
in hepatology.
The current mainstay of PSC is Ursodeoxycholic acid (UDCA). Although there is no evidence that UDCA alters long-term outcomes, it has
proven efficacy in the treatment of other cholestatic diseases such as PBC.
Care for primary sclerosing cholangitis focuses on monitoring liver function, managing symptoms and, when possible, conducting
procedures that temporarily open blocked bile ducts, such as: endoscopic retrograde cholangiopancreatography (ERCP), percutaneous
transhepatic cholangiography. The only known cure for advanced PSC, but the disease may recur in the transplanted liver in a small
number of patients.
Over the past two decades, many clinical trials of medical therapies for PSC have been conducted; however, none have demonstrated
real improvements in hard clinical endpoints.
Key focus on future treatment of PSC:
Efforts for new diagnostic tests aiming at earlier PSC detection should be emphasized, since MRI/MRCP (Magnetic resonance
imaging/magnetic resonance cholangiopancreatography) and ERCP still do only detect the footprints of the disease and are therefore an
imperfect gold standard.
Combination therapy may reach a breakthrough due to the still unknown cause of PSC. Theoretically, a potential treatment regimen in
PSC may include synergistically acting anticholestatic norUDCA (norursodeoxycholic acid) and fibrates. Targeting at an inflammatory gut-
liver axis in PSC may contain novel therapeutic antibodies, antibiotics, sulfasalazine, and FMT (Faecal microbiota transplantation).

PSC Market size
Market size of PSC drug market with notes
Market size of PSC drug market, 2018-2032E
CAGR 2028E-32E Million USD
China 126.6% 452.5

the U.S. 117.3% 79.6
Europe 127.6% 310.5
54.3 225.5
Total 121.2% 202.6
35.5 154.7
108.4
3.0 19.1 100.9
18.6 54.2 35.2 101.5 147.4
0.0 0.0 0.0 0.0 5.5 66.2
10.1
2018 2022 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note: the size and the significant growth of PSC drug market is estimated with the following assumptions:
• (i) market is estimated as price * number of treated patients.
• (ii) the price assumption is based on the prices of other first-in-class drugs for chronic diseases;
• (iii) the PSC drugs expected to be approved in forecast period would not be covered in national or regional volume-based procurement program in China;
• (iv) the price change in U.S. and Europe is in line with the industry trend;
• (v) the first drug for the treatment of PSC is expected to be approved in the second quarter 2028 in China, the U.S. and Europe;
• (vi) a number of PSC drugs are expected to be approved and commercialized from 2029 onwards;
• (vii) increased academic promotion and physician education by market players;
• (viii) the patient population that can be given PSC drugs continue to grow;
• (ix) As there have not yet been approved medications specifically indicated for PSC, the treatment rate of drugs that are indicated for PSC is currently 0%. As the
expected approval of drugs specifically indicated for PSC address the unmet clinical needs, PSC patients will quickly adopt these PSC-indicated drugs and in turn
the treatment rate will grow significantly
• (x) From 2028 to 2032, the range of diagnosis rates among PSC patients are expected to be within 40%~50%, 50%~60% and 50%~60% respectively in China, the
U.S. and Europe. The initial PSC-indicated drug adoption rates in total PSC patients are expected to be 2.1%, 1.2%, and 0.8% in 2028 respectively in China, the
U.S. and Europe, and the expected range of annual treatment cost of PSC-indicated drug are expected to be within 600~1,300, 16,000~17,000 and 11,000~12,000
USD respectively in China, the U.S. and Europe.
• The basis of HTD1801 to be approved as the first drug in China, US and Europe to treat PSC:
1. HTD1801 is the first drug candidate to finish phase II clinical trial under CDE and NMPA in China
2. in September 2018, HTD1801 has been granted the first fast track designation status by FDA in the field of PSC treatment
HTD1801 PSC Pipeline
Pipeline of PSC drugs
Pipeline of PSC drugs in active clinical phase registered at ClinicalTrials and CDE, as of LPD
Fast track/
Indication Phas Administratio First Posted Competen
# Drug Name Target Company orphan Trial Number
s e n Date t Authority
drug
GS-9674
1 FXR Gilead Sciences PSC III Oral Orphan drug 2019/03/26 NCT03890120 FDA
(Cilofexor)
Dr. Falk Pharma
2 norUDCA α1ATZ PSC III Oral / 2019/03/13 NCT03872921 FDA
GmbH
3 CS0159 FXR Cascade PSC II Oral / 2023/06/09 NCT05896124 FDA
4 A3907 ASBT Albireo PSC II Oral / 2022/12/08 NCT05642468 FDA
5 Elafibranor PPAR-α/δ Ipsen PSC II Oral / 2022/12/25 NCT05627362 FDA
Escient
6 EP547 MRGPRX4 PSC II Oral Orphan drug 2022/09/01 NCT05525520 FDA
pharmaceuticals
SHP626 Mirum
7 IBAT PSC II Oral / 2020/12/11 NCT04663308 FDA
(Volixibat) Pharmaceuticals
Intravenous
8 CM-101 Unidentified ChemomAb Ltd. PSC II and Orphan drug 2020/10/22 NCT04595825 FDA
subcutaneous
Fast track,
9 PLN-74809 αvβ6/αvβ1 Pliant Therapeutics, PSC II Oral 2020/07/21 NCT04480840 FDA
Orphan drug
MBX-8025 CymaBay
10 PPAR-δ PSC II Oral / 2019/07/18 NCT04024813 FDA
(Seladelpar) Therapeutics
Multiple Fast track,
11 HTD1801 HighTide PSC II Oral 2017/11/07 NCT03333928 FDA
pathways orphan drug
12 CS0159 FXR Cascade PSC II Oral / 2023/05/22 CTR20231403 NMPA
Multiple
13 HTD1801 HighTide PSC II Oral / 2020/02/05 CTR20200049 NMPA
pathways
Source: Clinical trials; CDE; China Insights Consultancy 84

Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
PBC Overview
Overview of Primary Biliary Cholangitis (PBC)

- PBC is a rare chronic cholestatic liver disease with unspecified causes that mostly
affects women; it is progressive and eventually leads to liver failure in some cases
Definition and classification of PBC
Overview of PBC Subgroups of PBC
PBC is classified into two groups depending on the absence or

Primary Biliary Cholangitis (PBC) presence of symptoms caused by liver damage: aPBC and sPBC.
• Primary biliary cholangitis, formerly known as primary
biliary cirrhosis, is a rare chronic liver disease that is
caused by an autoimmune reaction and affect small bile 1 Asymptomatic PBC (aPBC): Condition absent from
ducts inside the liver only. symptoms caused by liver damage
• Disproportionately affect women, with 10 women for • Median survival of asymptomatic patients is 16 years
every men. • Account for more than half of patients
• The cause(s) of PBC remains unknown, caused due to a 2 Symptomatic PBC (sPBC): Condition with symptoms caused
combination of genetic risk factors and environmental by liver damage
triggers. ➢ s1PBC: serum bilirubin level below 2.0 mg/dL
• PBC is progressive, which means that the damage gets ➢ s2PBC: serum bilirubin level equal or over 2.0 mg/dL
worse over time. Starting with inflammation, the damage • Median survival of symptomatic patients is 7.5 years
can cause fibrosis, and then cirrhosis. In some cases, • Account for 36%-89% of patients
cirrhosis can lead to liver failure.
Classical symptoms Other symptoms

• Pruritus • Bone pain
• Fatigue • Joint pain
Chronic Cirrhosis and • Jaundice • Abdominal pain
Immune
cholestasis/ Fibrosis end-stage • Dry eyes and mouth • Restless legs
response
inflammation liver disease
➢ Fatigue or pruritus affects over 50% of patients with PBC
Source: 2018 practice guidance from AASLD; EASL clinical practice guidelines; China Insights Consultancy 86
PBC Epidemiology
Epidemiology of PBC
Prevalence of PBC
Prevalence of PBC in China, U.S. and Europe 2018-2032E
CAGR 2018-22 2022-32E Thousand patients
Prevalence of PBC in China 1.7% 1.6%

Prevalence of PBC in U.S. 1.9% 1.8%
Prevalence of PBC in Europe 2.7% 2.2%
Total 1.9% 1.7%
1,292.6 1,306.7
1,255.5 1,275.9
1,208.0 1,232.5
1,161.3 1,183.8
1,119.7 1,139.7
1,082.0 1,100.8
1,042.2 1,062.6
1,021.6
909.5 919.4 926.5

880.0 896.1
845.2 862.4
801.8 814.9 829.6
765.4 777.9 789.8
738.5 752.1
150.9 153.5 156.2 158.8 161.5

137.9 140.5 143.1 145.6 148.2
125.5 128.0 130.4 132.9 135.4
166.7 171.2 175.6 180.0 184.3 188.6 193.0 197.3 201.6 205.9 210.2 214.4 218.6
157.7 162.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
PBC Treatment
Treatment pathway for PBC

- UCDA is the first-line agent for the treatment of PBC, OCA is recommended as the
second-line agent used in combination with UDCA; None of the other drugs has been
tested beneficial as single agent
Treatment pathway for PBC

Approved drugs Other therapies Unmet need
First-line Second-line OCA is the only approved drug during

the past 20 years since the approval of
Ursodeoxycholic acid (UDCA) Obeticholic acid (OCA)
UDCA. Other drugs are tested, while
Representative none of them found as single agent to be
drugs* benefit.
Approval FDA: 1987/12 FDA: 2016/5 Fibric acid derivatives
Starting at 5 mg/day for inadequate • Fibrates can be considered as off-
Dosage 13 to 15 mg/kg/day orally label alternatives for patients with
responders to UDCA
PBC and inadequate response to
Manufacturer UDCA.
• Use of OCA and fibrates is
Annual cost $5,000~$7,000 $150,000~170,000 discouraged in patients with
US sales ex-US sales 313 decompensated liver disease (Child-
250 Pugh-Turcotte B or C).
178
Annual Sales 129 188 234 Other drugs
No public information disclosure 141
(million dollars) 116
62 79 • Newer agents under consideration
13 37
2017 2018 2019 2020 include the selective PPAR- agonist
seladelpar and other FXR agonists.
• Black Box Warning
• Dosing higher than recommended Liver transplantation
in the drug label can increase the • Patients with manifestations of end-
• Up to 40% of PBC patients risk for liver decompensation, liver stage PBC should be referred for liver
Limitations do not achieve a complete failure, and sometimes death transplantation when they present with
response to UDCA
complications of cirrhosis, or their
Model for End-Stage Liver Disease
score exceeds 14.
Note: Representative drugs are genetic drugs.
PBC Market size
Market size of PBC drug market
Market size of PBC drug market， 2018-2032E
China 5.8% 10.7%

the U.S. 9.0% 12.7%
Europe 9.8% 13.2%
Total 8.2% 12.3% 2,376.3
2,197.4
1,993.6 591.7
554.6
1,756.4
507.5
1,473.0 448.8
377.5 1,020.0
1,119.2 942.4
1,015.8 853.8
946.2 297.6
878.0 750.2
811.3 270.2
746.3 256.3 625.8
682.9 242.3
621.0 228.5
543.6 581.1 214.8
200.8 473.0
179.0 186.6 398.7 430.0
171.5 368.1
309.4 338.3 764.6
254.3 281.3 632.2 700.4
219.4 236.3 557.4
469.7
267.5 291.2 315.6 348.7
165.9 180.1 200.7 222.2 244.5
152.7
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
HTD1801 PBC Pipeline
Competitive landscape of PBC drugs
Pipeline of PBC drugs in active clinical phase registered at ClinicalTrials and CDE, as of LPD
Competent
# Drug Name Target Company Indications Administration Phase First Posted Date Trial Number
Authority
1 TQA3526 FXR/Bile Acid Chia Tai Tianqing PBC Oral III 2022/07/11 NCT05450887 FDA
MBX-8025 CymaBay
2 PPAR-δ PBC Oral III 2020/11/09 NCT04620733 FDA
MBX-8025 CymaBay
3 PPAR-δ PBC Oral III 2020/11/09 NCT03602560 FDA
GFT505 dual PPAR-
4 Genfit PBC Oral III 2020/08/26 NCT04526665 FDA
(Elafibranor) α/PPAR-δ
Fudan-Zhangjiang
5 Obeticholic Acid FXR PBC Oral III 2021/08/16 CTR20211958 NMPA
Bio-Pharmaceutical
6 TQA3526 FXR/Bile Acid Chia Tai Tianqing PBC Oral III 2021/08/16 CTR20211444 NMPA
7 TQA3526 FXR/Bile Acid Chia Tai Tianqing PBC Oral III 2021/06/17 CTR20211354 NMPA
Zydus
8 Saroglitazar PPAR α/γ PBC Oral IIb/III 2021/11/24 NCT05133336 FDA
Therapeutics
Ascletis
9 ASC42 FXR PBC Oral II 2022/01/13 NCT05190523 FDA
Pharmaceuticals
HighTide
10 HTD1801 Multiple pathways PBC Oral II 2020/10/27 NCT04604652 FDA
Biopharma
Enanta
11 EDP-305 FXR PBC Oral II 2018/01/09 NCT03394924 FDA
Pharmaceuticals
12 GKT137831 Nox4 Genkyotex SA PBC Oral II 2017/07/21 NCT03226067 FDA
Zydus
13 Saroglitazar PPAR α/γ PBC Oral II 2017/04/13 NCT03112681 FDA
Therapeutics
14 CS0159 FXR Cascade PBC Oral II 2023/05/12 CTR20231402 NMPA
Ascletis
15 ASC42 FXR Pharmaceuticals/G PBC Oral II 2021/12/10 CTR20213229 NMPA
annex
16 TQA3526 FXR/Bile Acid Chia Tai Tianqing PBC Oral IIa 2020/01/10 CTR20200055 NMPA
COUR
Pharmaceutical
17 CNP-104 N/A PBC Injection I/IIa 2021/11/03 NCT05104853 FDA
Development
Company
MBX-8025 CymaBay
18 PPAR-δ PBC Oral I 2021/09/17 NCT04950764 FDA
Source: Clinical Trials; CDE; China Insights Consultancy 90

HTD1801 PSC Pipeline
Competitive landscape of PBC drugs

- Only two drugs have been approved for the treatment for PBC by the FDA
Approved PBC drugs by the FDA, as of August 2023
Drug Name Target Manufacturer Approval Indications Dosage Annual cost* Limitations
13 to Up to 40% of PBC patients

Ursodeoxycholic
/ Allergan 1987/12 Primary Biliary Cholangitis 15mg/kg/day 5,000~7,000 USD do not achieve a complete
acid (UDCA)
orally response to UDCA
Treatment of primary biliary

cholangitis, previously known
• Black Box Warning
as primary biliary cirrhosis Starting at 5
• Dosing higher than
(PBC), in combination with mg/day for
Obeticholic acid 150,000~170,000 recommended
FXR Intercept 2016/5 ursodeoxycholic acid(UDCA) in inadequate
(OCA) USD in the drug label can increase the
adults with an inadequate responders to
risk for liver decompensation, liver
response to UDCA or as UDCA
failure, and sometimes death
monotherapy in adults unable to
tolerate UDCA
Note:*Annual cost calculated based on assumptions that i) medications are used in adults according to indications and usage in drug labels and ii) individual treatment
maintains for a year of 52 weeks
Source: Clinical Trials; NMPA; China Insights Consultancy 91

PSC&PBC Drivers and barriers
Drivers and barriers for the treatment of chronic cholestatic liver diseases
Drivers and barriers for the treatment of chronic cholestatic liver diseases
Growth drivers and trend Description and implications
• An increase in support for orphan drugs implies a shift towards increased attention on rare diseases. More than
Increasing attention 3,500 potential treatments have been designated as orphan drugs, and more than 500 orphan therapies have been
1 towards rare approved by the FDA since 1983 with the passing of the Orphan Drug Act (ODA).
diseases • With awareness towards PSC/PBC increasing, and advanced diagnostic techniques being continually developed
over the years, the prevalence of PSC/PBC is also showing a steady increase in China.
Multi-targeting drugs • The new and rising global trend of research area, multi-targeting drugs, has attracted much attention as promising
2 as promising tools in tools to fight against most challenging diseases, such as PSC and PBC . Multi-targeting drugs are aimed to solve
treating complex limitations of single-target drugs that have limited efficacy against complex diseases in which the pathogenesis is
diseases dependent on a set of biochemical events and several bioreceptors operating concomitantly.
• With improvements in PBC/PSC diagnostic techniques, patients nowadays are diagnosed in earlier stages and are
Early diagnosis
less likely to be suffering from a more advanced form of fibrosis, while liver transplantation is much rarer compared
3 increases demand
with the 1980s. The trend towards earlier diagnosis has hence led to a higher demand for PSC/PBC treatment
for medication
drugs.
Increased • With awareness towards PSC and PBC increasing, and advanced diagnostic techniques being continually
prevalence and developed over the years, the prevalence of PSC and PBC is also showing a steady increase in China. Meanwhile,
4
spending power of increased disposable income per capita and broader medical insurance coverage in China make it easier for
patients in China patients to afford relatively more expensive medical fees
Entry barriers Description and implications
• The majority of patients with PSC and PBC are asymptomatic. Patients with PSC are diagnosed upon discovering
Limited medical an increase in ALP during a physical examination or during liver function screening due to IBD, while 15%~55%
treatment effect due patients with PSC are asymptomatic when diagnosed, which therefore leads to a situation wherein most patient are
1 to late diagnosis in a late stage of the disease when they present with symptoms of cholestasis. Therefore, medical treatments will be
of limited benefit when patients are already in a late stage of the disease, such as experiencing liver cirrhosis. This
set of circumstances is moreover the same in terms of cases of PBC.

Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
AH Overview
Overview of Alcoholic Hepatitis (AH)

- Alcoholic hepatitis is one of the manifestations from alcohol-associated liver disease,
liver biopsy is the gold-standard diagnostic tool
Definition and classification of AH
Alcoholic liver disease (ALD) Alcoholic Hepatitis (AH)

Definition： Definition：
Alcohol-associated liver disease (ALD) Alcoholic hepatitis is defined as a syndrome of acute liver injury in persons with known
represents a spectrum of liver injury alcoholic liver disease or heavy alcohol use for >6 months presenting with recent onset or
resulting from alcohol use, ranging from worsening jaundice (serum bilirubin >3 mg/dl) and hepatitis with <2 months of abstinence
hepatic steatosis to more advanced before the onset of jaundice in the absence of other known causes of liver disease.
forms including alcoholic hepatitis (AH),
alcohol-associated cirrhosis (AC), and Severe alcoholic hepatitis (SAH)
acute AH presenting as acute-on chronic
liver failure. SAH is commonly defined by one of the following two standards:
Standard Predicted mortality

Distribution in ALD:
1 Maddrey Discriminant Function (MDF) score ≥32 30% at 30 days
Mild ALD 11.2% 2 Model for end-stage liver disease(MELD) score ≥20 20%–40% at 90 days
Diagnosis of AH
Alcoholic Fatty Liver 22.6% Gold standard: liver biopsy is the gold standard for the diagnosis of AH.
Basic clinical diagnostic criteria for AH are:
① Within 8 weeks of the onset of jaundice;
Alcoholic hepatitis 28.8% ② Prior to onset of jaundice, consumption of alcohol exceeds 40 g/d (for women) or 60
g/d (for men) for at least 6 months continuously, abstaining from alcohol less than 60
days;
Alcoholic Cirrhosis 37.4% ③ Serum bilirubin>3 times the upper limit of normal, aspartate aminotransferase
Severe (AST)>50 IU/L and AST/alanine aminotransferase (ALT)>1.5.
Note: MELD: Model for end-stage liver disease
Source: American Association for the Study of Liver Diseases (AASLD); China Insights Consultancy 94
AH Epidemiology
Epidemiology of Alcoholic Hepatitis
Prevalence of Alcoholic Hepatitis

Prevalence of AH in China, U.S. and Europe 2018-2032E
Prevalence of AH in China 1.4% 1.0%
Prevalence of AH in U.S. 1.6% 1.5%
Prevalence of AH in Europe 1.0% 0.8%
Total 1.3% 1.0%
36.5 36.8 37.2

35.4 35.8 36.1
34.3 34.7 35.0
33.1 33.5 33.9
32.3 32.7
31.8
20.0 20.2 20.4 20.6

19.2 19.4 19.6 19.8
18.6 18.8 19.0
17.9 18.1 18.3
17.6
6.1 6.2 6.3 6.4 6.4 6.5 6.6

5.5 5.6 5.6 5.7 5.8 5.9 6.0
5.4
8.8 8.9 9.0 9.1 9.2 9.3 9.4 9.4 9.5 9.6 9.7 9.7 9.8 9.9 10.0
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

AH Treatment
Treatment pathway for AH

- There is currently no approved medical therapy for the treatment of alcoholic hepatitis,
Corticosteroids is the only recommend treatment
Treatment pathway for AH

Non-medical therapy
• Abstinence: the key to long-term survival, patients of the need to abstain from all alcohol
• Nutrition: patients with AH should have malnutrition addressed and treated, preferably with enteral nutrition
• Liver transplantation: liver transplantation may be considered in carefully selected patients with favorable psychosocial profiles in
severe AH not responding to medical therapy
Require 6 months of abstinence, >50% patients die during the first 3 months, which is an unacceptable high barrier for patients
with AH to overcome
Medical therapy
Corticosteroids:
• Chinese Society of Hepatology, American Association for the
Approved treatments for AH Study of Liver Disease (AASLD) and European Association for the
Study of the Liver (EASL) practice guidelines recommend the use
• None of corticosteroids (ie, prednisolone 40 mg daily for four weeks) for
patients with severe AH, but without long term survival benefit.
Recommended treatment for AH • The addition of intravenous NAC to prednisolone (40 mg/day) may
improve the 30-day survival of patients with severe AH.
• Corticosteroids
• However, use of corticosteroids faces several constraints:
Therapeutic Approaches With Unclear Benefits 1. Higher risk of mortality: Patients with severe AH who
experience development of infection posttreatment of steroids
• Pentoxifylline have a higher rate of mortality compared with pre-treatment,
according to a comparative study conducted with 264 severe AH
patients
Therapeutic Approaches That Require Confirmation
2. Higher rate of infection: The STOPAH (Steroids or
• N-acetylcysteine (NAC) and antioxidants Pentoxifylline for Alcoholic Hepatitis Trial) reported that the rate
• Granulocyte colony stimulating factor (GCSF) of infection doubled in the group of patients who received
Prednisolone compared with no-prednisolone group

AH Market size
Market size of AH drugs
Market size of AH drugs, 2016-2035E
CAGR 2029E-32E Million USD

China 186.1%
6,196.2
the U.S. 242.7%
Europe 239.1% 1,094.8
Total 228.2%
4,092.3
727.7 2,893.3
2,128.4 1,899.9
420.4
960.0 2,208.1
1,464.7
175.2 46.8 748.0
0.0 0.0 0.0 0.0 0.0 71.9 56.6
2018 2022 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note: the size of AH drug market is estimated with the following assumptions: (i) the first drug for the treatment of AH is expected to be approved in 2029; (ii)
a number of AH drugs are expected to be approved and commercialized from 2030 onwards; (iii) increased academic promotion and physician education by
market players; (iv) the patient population that can be given AH drugs continue to grow.
Note: Disclosed market size includes only drugs specifically approved for AH
HTD4010 AH Pipeline
Global pipeline of AH drugs

- There are 4 active trials with indication of (severe) alcoholic hepatitis registered in clinical
trials, and there is currently no registered trials in China
Pipeline of AH drugs, registered at ClinitalTrials, as of November 2023

Drug Name Target Company Indications Phase Trial Number
Date Authority
TAK-242 TLR4 Akaza Bioscience AH II 2020/11/06 NCT04620148 FDA
DUR-928 DNMTs Durect AH IIb 2020/09/24 NCT04563026 FDA
Canakinumab IL-1 Novartis AH II 2018/12/13 NCT03775109 FDA
Intercept
INT-787 FXR SAH II 2022/12/06 NCT05639543 FDA
Pharmaceuticals
Source: Clinical trials; China Insights Consultancy 98

Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
CRS Overview
Overview of Cytokine Release Syndrome

- Cytokine release syndrome is a life-threatening systemic inflammatory response that can
be triggered by a variety of factors including various therapies, pathogens, cancers,
autoimmune conditions, and monogenic disorders
Overview of Cytokine Release Syndrome (CRS)
• Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory response involving elevated levels of circulating cytokines and
immune-cell hyperactivation that can be triggered by a variety of factors including various therapies, pathogens, cancers, autoimmune conditions,
and monogenic disorders
• CRS has characteristic clinical presentations, manifested typically with high fever, hypotension, hypoxia, and respiratory distress. Organ
dysfunctions such as liver transaminitis and renal insufficiency can occur. CRS toxicities occur as frequently as 90%, half of which is severe.
• Though only incompletely understood the pathophysiology of which, it is currently commonly believed that IL-6 contributes to many of the key
symptoms of CRS
1 Trigger immune hyperactivation 2 Cytokine release syndrome 3 “collateral damage” 4
• Adaptive T cells Interleukin-18 Interleukin-1β

Driver
• Innate antigen-
cells Sepsis
presenting cells TNF
induced CRS
• Acute systematic
Potential triggers Immune hyper- inflammatory
activation Interferon-γ Interleukin-6
effects • Multiorgan
• Inappropriate • Secondary organ failure
Lactrogenic Pathogen- triggering or danger CAR-T dysfunction (e.g.: • Could
causes induced triggers sensing induced CRS Interleukin-17 hepatic, renal, eventually
• Inappropriate or pulmonary) leads to
ineffective amplitude IP-10 - Dysfunction due to death
of response inflammation without
Monogenic &
autoimmune Cancer • Failure to resolve beyond normal proper
inflammation Prolonged activation of signaling response to treatment
disorders
• and return to pathways including: pathogen
homeostasis MAPK, NF-κB, JAK-STAT3 and mTOR - Cytokine-driven
dysfunction
• Tregs, mesenchymal stem cells Pathologically sustained cytokine
Negative
• Decoy cytokine receptors production leads to excessive circulating
regulators
• Anti-inflammatory cytokines cytokine levels
Source: N Engl J Med 2020; 383:2255-2273; China Insights Consultancy 100

CRS Treatment
Overview of treatment for CRS

- General treatment strategy involves supportive care to maintain critical organ function,
underlying disease control and trigger elimination, and targeted immunomodulation or
nonspecific immunosuppression to limit the collateral damage
Overview of treatment for CRS
Types of CRS and triggers Cause Driver cell Treatment

• The general treatment strategy
for cytokine storm involves
Macrophages, CAR T Anti–IL-6 antibody,
CAR T-cell therapy Infusion of CAR T cells supportive care to maintain
cells, IL-6, IL-1β glucocorticoids
critical organ function, control of
Latrogenic the underlying disease and
Infusion of CD19- and CD3-
Activated T cells, Anti–IL-6 antibody, elimination of triggers for
Blinatumomab specific T-cell receptor-
macrophages, IL-6 glucocorticoids abnormal immune system
engaging antibody
activation, and targeted or
nonspecific immuno-
Hematogenous bacterial Heterogeneous and suppression to limit the
Bacterial sepsis Intravenous antibiotics
infection multifactorial drivers collateral damage of the
activated immune system
- Lactrogenic: Primary cause of
Pathogen- EBV-associated EBV infection in patient with IFN-γ, TNF, CD8+ T B-cell–depleting therapy,
CRS. Among which, IL-6 has
induced HLH genetic susceptibility cells glucocorticoids
been proved as the most likely
driver cell, and tocilizumab has
HHV-8 infection in patient with
HHV-8–associated been recently further approved
HIV coinfection, genetic Viral IL-6, IL-6 B-cell–depleting therapy
MCD by FDA for the treatment of
susceptibility, or both
CRS after CAR-T
- Pathogen-induced: Due to the
Germline mutation in genes T-cell inhibition or ablation,
unclear pathogenesis,
Primary HLH regulating granule-mediated CD8+ T cells, IFN-γ IFN-γ inhibitor,
antibiotics are the current
cytotoxicity glucocorticoids
mainstay treating sepsis-
Germline mutations in genes associated CRS. While other
Autoinflammatory regulating the innate immune Innate cells, TNF, IL- Anti-TNF antibody, anti–IL- pathogen-induced CRS are
Monogenic/ disorders system and inflammasome 1β 1 antibody treated through relieving the
autoimmune activation underlying primary disease
- Monogenic/ autoimmune: As
a relatively rarer cause of CRS,
Anti–IL-6 antibody,
Interleukin-6, main treatment is eliminating
sirolimus, cyclosporine,
Idiopathic MCD Unknown cause activated T cells, the underlying disease
cytotoxic chemotherapy,
mTOR
glucocorticoids

CRS CRS pipeline
Pipeline of CRS drugs, ClinicalTrials-registered
Pipeline of CRS drugs1, ClinicalTrials-registered, as of August 2023
Drug Company Classification Indications Phase First posted Trial number

Prevention of IEC therapy-induced CRS II 2019/08/28 NCT04071366
Incyte
Itacitinib JAK1 inhibitor CRS after T-cell Replete Haploidentical
Corporation
Peripheral Blood Hematopoietic Cell I 2018/11/28 NCT03755414
Transplantation, Acute-graft-versus-host Disease
IL-1 receptor
Anakinra Kite Pharma CAR-T associated CRS II 2019/11/05 NCT04150913
antagonist
Swedish Orphan IL-1 receptor
Anakinra CD19-targeted CAR-T associated CRS II 2020/04/24 NCT04359784
Biovitrum antagonist
Note: 1 Only drugs developed for the treatment of CAR-T associated CRS are included
CRS Growth drivers
Key growth drivers for the CRS drug market
Key growth drivers for the CRS drug market

Growth drivers Description and implications
Growing • There are various kinds of triggers that can induce CRS, including autoimmune diseases; pathogens, such as various
respiratory viruses; and, latrogenic factors, such as CAR-T therapies and antibodies. Despite a pre-existing burden of
population
1 infectious diseases, CRS is among the most frequent serious adverse events associated with CAR-T therapy. With the
potentially in growing use of T cell-engaging therapies, there is an urgent need for clinical trials that can improve the evidence base
danger of CRS needed for the treatment of CRS.
Establishment of • Currently, the management strategies for CRS are predominantly based on biologic reasoning, expert opinion, and
widely retrospective analyses, and no explicit treatment algorithms have been uniformly reached and widely recognized. For
example, there are three to four mainstream grading scales currently used for clinical diagnosis, each with a different
recognized
2 emphasis. While the Penn grading scale has indicated a specific set of symptoms and relevant interventions,
diagnosis and CTCAE’s grading is a little different and does not provide clear intervention recommendations. Therefore, as diagnosis
treatment and treatment algorithms become established, CRS drugs will be applied in a more appropriate way, thus promoting
algorithms the market’s continued growth.
• The term “cytokine release syndrome” was first coined in the early '90s, and only in the most recent decade has it
Pathophysiology been described in any detail and researched in depth in relation to CAR-T therapy. Therefore, our understanding of
of CRS becoming the pathophysiology of CRS is still incomplete, while full-scale knowledge of the disease remains limited, including
3 gradually more which cytokines play key roles and to what degree do they act upon the pathophysiology of the disease. It is expected
well-understood that, along with a deepening understanding of the disease and its mechanisms, the market will undergo a continued
expansion with the subsequent introduction of innovative CRS drugs.

Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
CNS Overview
Overview of Central nervous system diseases

- Central nervous system diseases refer to a group of neurological disorders that affect the
structure or function of brain or spinal cords
Overview of Central nervous system (CNS) diseases
• Central nervous system, comprised of the brain and spinal cord, is one of the two major divisions that make up of the whole nervous system, and
controls awareness, sensations, thoughts and movements of the body
• CNS diseases refer to a group of neurological disorders that affect the structure or function of brain or spinal cords, primarily include
neurodegeneration, functional disorders, structural disorders, central nervous system infections, vascular disorders and CNS tumors
• Due to the high prevalence and lack of curative therapeutics for various kinds, CNS diseases have imposed huge burden both in patients
themselves and the caregivers
Description Representative diseases

Some micro-organisms and viruses can Meningitis, encephalitis, polio, and
Infections
invade the CNS epidural abscess
Central Nervous
Cerebrovascular malformations such as Stroke, transient ischemic attack (TIA),
System Vascular
interruption of blood supply to the brain subarachnoid hemorrhage, and
disorders
extradural hemorrhage
Structural Usually caused by traumas, autoimmune Brain or spinal cord injury, Bell's palsy,
Brain disorders/ diseases and birth defects cervical spondylosis, carpal tunnel
defects syndrome
a condition in which there is problems with Headache, epilepsy, dizziness, and
Functional the functioning of the nervous system and neuralgia
disorders how the brain and body sends and/or
receives signals
Diseases caused by the gradual Parkinson’s disease, multiple sclerosis,
Degeneration degeneration and loss of nerve cells amyotrophic lateral sclerosis (ALS), and
and/or myelin sheath Alzheimer’s disease
Spinal cord
cancerous or noncancerous tumors that Brain tumors including meningioma and
Tumors
impact parts of the CNS neuroblastoma
Source: WHO; Hopkinsmedicine; China Insights Consultancy 105

CNS Epidemiology
Epidemiology of CNS disease
Prevalence of CNS disease

Prevalence of CNS disease in China, 2018-2032E
Prevalence of CNS disease in China 0.7% 0.6%
424.5 428.7 431.2 433.8 436.3 438.8 441.3 443.8 446.3 448.8 451.2 453.7 456.1 458.5 460.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Prevalence of CNS disease in the United States, 2018-2032E

Prevalence of CNS disease in US 0.6% 0.6%

146.6 147.4 148.3 149.2 150.0 150.9 151.8 152.6 153.5 154.3 155.2 156.0 156.8 157.7 158.5
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Prevalence of CNS disease in Europe, 2018-2032E
Prevalence of CNS disease in Europe 0.4% 0.4%
366.8 368.7 370.2 371.7 373.1 374.5 376.0 377.4 378.8 380.2 381.6 382.9 384.3 385.7 387.0
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
CNS Market size
Market size of CNS drugs
Market size of CNS drugs in the world, 2018-2032E

China 10.6% 8.0%
the U.S. 2.4% 2.2%
Europe 6.8% 5.5%
145.9
Total 4.1% 3.7% 141.5
137.1
132.6 21.6
128.1 20.4
123.6 19.1
119.1 17.9
114.6 16.7
110.1 15.5
105.6 14.3
101.2 13.2
96.7 12.1
92.8 11.1
10.1
86.1 88.6 9.1
7.9
6.7 7.8 83.1
80.3 81.7
77.3 78.8
74.0 75.7
70.6 72.4
67.1 68.9
64.0 65.2
60.9 61.9
36.0 37.7 39.4 41.1

29.1 30.8 32.5 34.2
22.4 24.1 25.7 27.4
18.5 18.9 20.9
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

CNS ALS Overview
Overview of Amyotrophic Lateral Sclerosis

- Amyotrophic lateral sclerosis, the most common type of motor neuron disease, is a
progressive and fatal disease, attacking neurons that control voluntary movement
Overview of Amyotrophic Lateral Sclerosis (ALS)
• ALS is a debilitating, progressive disease with degeneration of motor neurons in the brain • The disease is more common in middle-aged and
and spinal cord causing weakness, muscle atrophy, fasciculations and spasticity elderly people, and the incidence is higher in men
• Nearly all ALS cases are considered sporadic and the cause of which is unknown, while than in women
only 5-10% are familial associating with mutations in a wide range of genes • A person with ALS usually has a life expectancy of
• Voluntary muscles gradually paralyze as the disease progresses, and the muscles that 2-5 years from diagnosis, though 10-15% patients
aid in ventilation will be compromised, thus most ALS deaths result from respiratory failure will survive longer
Cognitive/ behavioral Clinical manifestations Prevalence of ALS, 2018-32E

impairment
• 70% develop limb onset, with extremity Thousand ppl
Dysphagia/ weakness and impairment in mobility
• 25% bulbar onset, with oropharyngeal 43.6 44.6 45.2 45.4
Dysarthria
muscle involvement affecting swallowing
and speech
• 50% develop cognitive or behavioral
Respiratory impairments that led by degeneration in
insufficiency the frontal and temporal lobes
16.7 17.2 17.7 18.2
Disease diagnosis
• Clinical examination: inquiry medical
history and physical examination,
determining the range of upper and lower
motor neuron involvement
Muscle cramps/ • Neurophysiological examination: 45.1 45.7 45.7 45.6
spasticity/ muscle extension of clinical physical examination,
weakness/ muscle conducting to excluding other diseases
atrophy • Neuroimaging examination: helping to
distinguish ALS from other diseases and
exclude structural damage
2018 2022 2027 2032
Source: The Lancet; ALS Association; China Insights Consultancy 108

CNS ALS treatment
Overview of treatment for ALS

- ALS is still an incurable disease, and management of ALS currently is best achieved by a
multidisciplinary approach
Overview of treatment for ALS

Treatment Mechanism Administration Clinical Efficacy Disadvantages
Disease-modifying therapies
• A kind of glutamate inhibitor • Taken orally in tablets, film, or • As the first drug approved • The therapeutic effect is modest,
• Including an inhibitory effect on suspension form by FDA for the treatment of as it only prolongs tracheostomy-
glutamate release, inactivation of • Two times a day, and 50mg or ALS, the drug is able to free survival by 2-3 months
voltage-dependent sodium channels, 10ml at a time provide a modest effect by • No inhibition of motor deterioration
Riluzole and ability to interfere with prolonging survival time • AEs of increase in liver enzymes
intracellular events that follow with an overall good and asthenia, and fatal hepatic
transmitter binding at excitatory tolerability and minor AEs failure and pancreatitis
amino acid receptors
1
• Nootropic and neuroprotective effects • IV infusion of 60 mg administered • The first drug to show • Potentially limited patients are
of the drug are mediated through over a 60-minute period effective inhibition of the expected to benefit from the drug
inhibiting lipid peroxidation and • An initial treatment cycle with daily motor function deterioration based on the clinical trials
scavenging free radicals dosing for 14 days, and experienced by ALS designed, and thus hasn’t been
Edaravone subsequent treatment cycles with patients with early-stage approved by EMA
daily dosing for 10 days out of 14- probable and definite types • Serious AEs of hypersensitivity
day periods, each followed by a and sulfite allergic reactions
14-day drug-free period
Supportive management
• Due to the worsening swallowing • Balanced diets with high-calorie • Strengthen patient care • The supportive management is
Nutritional function, nutritional management is and high-carbohydrate both physically and only palliative care adjuvant of
2
management needed to ensure nutrition intake • Adoption of PEG if serious feeding mentally to improve life drug therapy in order to improve
difficulties and choking risks exist quality and prevent ALS patients’ life quality, and
• To help with ventilation as the • Use of non-invasive ventilation complications there’s no help in delaying the
Respiratory voluntary muscles in the lung when respiratory weakness exists disease progression course
management gradually paralyze and are unable to • Adoption of ventilator as disease
moving air in and out deteriorates
• To help ease the symptoms that ALS • Adoption of certain medicine,
Comprehensive patients are faced with in different muscle relaxants, and speech
management progression stages, including pain, therapy depending on disease
fasciculation, spasticity, and insomnia progression
Note: 1 Intravenous; 2 Percutaneousendoscopic gaslrostomy

Source: China Guideline on ALS diagnosis and treatment; Neurodegener. Dis.Manag.; 109
Expert Review of Neurotherapeutics; China Insights Consultancy
CNS ALS pipeline
Pipeline of ALS drugs, ClinicalTrials-registered
Pipeline of ALS drugs, ClinicalTrials-registered, as of Aug 20231

Drug Company Administration Phase First posted Trial number
BIIB067 Biogen Intrathecal III 2021/4/23 NCT04856982
Masitinib AB Science Oral tablet III 2017/4/25 NCT03127267
Arimoclomol Orphazyme Oral III 2019/8/7 NCT04049097
Lenzumestrocel Corestem, Inc. Stem cell therapy III 2021/2/9 NCT04745299
Intrathecal bolus
ION363 Ionis Pharmaceuticals, Inc. III 2021/2/24 NCT04768972
injection
reldesemtiv Cytokinetics Oral tablet III 2021/6/30 NCT04944784
MN-166 MediciNova Oral capsule II/III 2019/8/15 NCT04057898
Collaborative Medicinal Development

Cu(II)ATSM Oral suspension II/III 2019/9/9 NCT04082832
Pty Limited
CNM-Au8 Clene Nanomedicine Bicarbonate solution II/III 2020/6/4 NCT04414345
Verdiperstat (AZD3241) Biohaven Pharmaceuticals Oral II/III 2020/6/18 NCT04436510
AMX0035 Amylyx Pharmaceuticals Inc. Oral II/III 2020/8/18 NCT04516096
Note: 1 Include only trials beyond phase II

CNS ALS pipeline
Pipeline of ALS drugs, CDE-registered
Pipeline of ALS drugs, CDE-registered, as of Aug 2023
Drug Company Administration Phase First posted Trial number
Nitrate ketone oxazine Guangzhou Magpie Pharmaceuticals Oral II 2020/10/27 CTR20202126
Edaravone Sublingual Nanjing Baixinyu Oral I 2020/10/22 CTR20202055

CNS AD Overview
Overview of Alzheimer's disease

- Alzheimer’s disease is a neurodegenerative disorder characterized by loss of memory,
cognitive impairment, behavioural changes and loss of functional abilities
Overview of Alzheimer's disease (AD)

Stages and Symptoms
• Alzheimer’s disease is the most common (60-80%)
cause of dementia and one of the great health-care Mild Cognitive Mild Moderate Severe
challenges of the 21st century Impairment Alzheimer’s Alzheimer’s Alzheimer’s
• In China, there are ~9.8 million people living with AD
now, and the number is expected to grow in the future Duration: 7 years Duration: 2 years Duration: 2 years Duration: 3 years
• Although the pathogenesis and mechanism of AD
progression remain unclear, the two principal Diseases begins in Diseases spreads Diseases spreads Diseases spreads
neuropathological hallmarks of AD are extracellular Medial Temporal to Lateral Temporal to Frontal Lobe to Occipital Lobe
deposition of amyloid β (Aβ), in the form of plaques, and Lobe and Parietal Lobes
intracellular neurofibrillary tangles (NFT)
Prevalence of AD, 2018-32E
Million ppl
15.2 Symptoms
12.3
8.2 9.8
Short-term Reading problems, Poor judgment Visual problems
memory loss poor object recognition Impulsivity
and direction sense Short attention
7.8 8.6
5.6 6.1 Alzheimer’s disease is an unavoidable neurological disorder in
which the death of brain cells causes memory loss and cognitive
decline and ultimate dementia
It causes problems with short term memory, behavioral changes,

8.8 9.6 depression and irritability, balance problems and disorientation.
7.4 8.1
Age is the single greatest risk factor. In addition, genetics and

family history also to some extent contribute
2018 2022 2027E 2032E
Source: NCBI; CDC; China Insights Consultancy 112

CNS AD treatment
Overview of treatment for AD

- AD management includes both treatments for cognitive deficits and psychotic symptoms.
New treatments that will prevent, delay, or treat the disease are urgently needed
Overview of treatment for AD

Treatment Mechanism Application Efficacy
Treatment for cognitive deficits
Donepezil • Prevents the breakdown of • Applicable to all AD stages through • Treatment with cholinesterase
acetylcholine in the brain adjustment in dosage inhibitors can provide modest
improvement of symptoms,
temporary stabilization of cognition,
or reduction in the rate of cognitive
Rivastigmine • Prevents the breakdown of • Applicable to mild to moderate AD decline in some patients with mild to
Cholinesterase acetylcholine and butyrylcholine (a patients moderate Alzheimer's disease
inhibitors brain chemical similar to • Patients tend to show side effects,
acetylcholine) in the brain such as nausea, vomiting, diarrhea,
headaches, dizziness, abdominal
• Prevents the breakdown of • Applicable to mild to moderate AD pain, and fatigue
acetylcholine and stimulates nicotinic patients
Galantamine receptors to release more
acetylcholine in the brain
• Blocks the toxic effects associated • Used as monotherapy or in combination • More well tolerated than
N-methyl D- with excess glutamate and regulates with Donepezil for the treatment of cholinesterase inhibitors
aspartate (NMDA) Memantine glutamate activation moderate to severe AD patients • The side effects shown are the
antagonist same as that of cholinesterase
inhibitors
Anti-psychotic treatment
• Control of problematic delusions, • First-line treatment for the management • Pharmacologic interventions are
Olanzapine, hallucinations, severe psychomotor of anxiety and depression necessary when nonpharmacologic
Atypical
risperidone, agitation, and combativeness strategies or with cholinesterase
antipsychotics
quetiapine inhibitor therapy alone fail to reduce
behavioral symptoms sufficiently
• Interaction with the two major 5-HT1A • Second-line treatment for the
Selective
receptor subtypes that are involved in management of anxiety and depression
serotonin
Serotonin drugs the brain's anxiety and fear circuitry to in patients who cannot tolerate or do not
receptor agonist,
enhance the serotonergic activity in respond to atypical antipsychotic agents
SSRI
these brain areas
Source: Chinese Guideline for the diagnosis and treatment of AD dementia (2020); AAFP; China Insights Consultancy 113
CNS AD pipeline
Pipeline of AD drugs, ClinicalTrials-registered (1/2)
Pipeline of AD drugs, ClinicalTrials-registered, as of Aug 20231

Drug Company Indication Administration Phase First posted Trial number
Subcutaneous
Gantenerumab Hoffmann-La Roche Early (prodromal to mild) AD III 2018/2/23 NCT03444870
injection
TRx0237 TauRx Therapeutics Ltd AD Oral tablet III 2018/2/26 NCT03446001
Mild cognitive impairment due

AGB101 AgeneBio Oral tablet III 2018/4/3 NCT03486938
to AD (prodromal AD)
Otsuka Pharmaceutical/ Agitation Associated With AD/
brexpiprazole Oral tablet III 2018/6/7 NCT03548584
Commercialization, Inc. AD
lecanemab Eisai Inc. Early AD IV III 2019/3/25 NCT03887455
AC-SD-03 Cerecin Mild to moderate AD oral III 2019/12/5 NCT04187547
Hyundai Pharmaceutical Co.,

BPDO-1603 Moderate-to-severe AD oral III 2020/1/18 NCT04229927
LTD.
donanemab Eli Lilly and Company Early AD IV III 2020/6/18 NCT04437511
AVP-786 Avanir Pharmaceuticals AD type dementia oral III 2020/7/9 NCT04464564
Lecanemab Eisai Inc. Early Preclinical AD IV III 2020/7/13 NCT04468659
Shanghai Greenvalley
GV-971 Mild to moderate AD Oral capsule III 2020/8/20 NCT04520412
Pharmaceutical Co., Ltd.
ALZ-801 Alzheon Inc. Early AD Oral tablet III 2021/2/25 NCT04770220
Semagludtide Novo Nordisk A/S Early AD Oral tablet III 2021/3/2 NCT04777396

CNS AD pipeline
Pipeline of AD drugs, ClinicalTrials-registered (2/2)
Pipeline of AD drugs, ClinicalTrials-registered, as of Aug 20231

Semaglutide Novo Nordisk A/S Early AD Oral tablet III 2021/3/2 NCT04777409
agitation associated with

AXS-05 Axsome Therapeutics, Inc. Oral tablet III 2021/7/1 NCT04947553
Alzheimer's disease (AD)
Simufilam (PTI-125) Cassava Sciences, Inc. Mild-to-moderate AD Oral tablet III 2021/8/6 NCT04994483
Biohaven Pharmaceuticals,
Troriluzole Mild to moderate AD Oral capsule II/III 2018/7/30 NCT03605667
Inc.
ANAVEX2-73 Anavex Life Sciences Corp. Early AD Oral capsule IIb/III 2019/1/2 NCT03790709
COR388 Cortexyme Inc. Mild to moderate AD Oral capsule II/III 2019/1/30 NCT03823404

CNS AD pipeline
Pipeline of AD drugs, CDE-registered
Pipeline of AD drugs, CDE-registered, as of Aug 2023

Huperzine A Luye Pharma Mild to moderate AD Oral tablet III 2014/4/28 CTR20140253
Octohydroaminoacridine Changchun Huayang/ Jiangsu

Mild to moderate AD Oral tablet III 2017/1/19 CTR20160973
Succinate Sheneryang
Eli Lilly and Company/
LY3314814 Mild AD Oral tablet III 2018/2/13 CTR20170591
AstraZeneca AB
Subcutaneous
Gantenerumab F. Hoffmann-La Roche Early (prodromal to mild) AD III 2019/7/10 CTR20182180
injection
Mild AD and the induced
BAN2401 Eisai/ Biogen IV III 2020/3/6 CTR20200005
mild cognitive impairment
GV-971 GreenValley Pharma Mild to moderate AD Oral capsule III 2021/2/2 CTR20210187
Benfotiamine Raising Biotechnology Mild to moderate AD Oral tablet II 2018/1/4 CTR20171631
AD-35 Zhejiang Hisun Mild to moderate AD Oral tablet II 2018/7/26 CTR20181184
Methicoline Simcere/ Yenepharma/

AD Oral tablet I 2017/11/23 CTR20171446
hydrochloride Simovay
HEC30654AcOH Guangdong Dongyangguang AD Oral capsule I 2018/11/22 CTR20181499
FN12 Wepon AD Oral tablet I 2020/12/15 CTR20202529
Shanghai Hengrui
SHR-1707 AD Injection I 2021/4/26 CTR20210885
pharmaceutical
50561 Beijing Joekai AD Oral tablet I 2021/7/2 CTR20211551

CNS PD Overview
Overview of Parkinson's disease

- Parkinson's disease is a common neurodegenerative disorder that affects movement and
decreases quality of life
Overview of Parkinson's disease (PD)

Prevalence of PD, 2018-32E
• Parkinson‘s disease is a progressive neurodegenerative disorder that can cause Million ppl
tremor, rigidity, bradykinesia, and asymmetric onset
• The disease typically develops between the ages of 55 and 65 years, and the
4.1 5.7
incidence and prevalence increases as ages 2.2 3.0
• The diagnosis of PD is mainly based on onset of motor symptoms, where might
be a progressive period of more than 20 years before.
• According to the Hoehn-Yahr scale, PD can be generally divided into five stages
based on the degree of severity. It is currently estimated that only 18.5% are at 0.9 1.0 1.1 1.3
early stage (stage 1/2) at the time of diagnosis
Early stage Advanced stage 1.5 1.6 1.8 2.0

5-10% 2018 2022 2027E 2032E
Early onset: • Motor complications (motor
• Patients diagnosed ≤50 years fluctuations and dyskinesia) are Motor Non-motor
• Long course of disease, distinct common in advanced PD symptoms symptoms
clinical heterogeneity, easy to be - Adjust medication type, dosage
ignored or misdiagnosed or frequency to ease symptoms Autonomic
• Levodopa + DR agonist/ MAO-B - Surgical treatments (e.g.: DBS) Bradykinesia
dysfunction
inhibitor + COMT inhibitor • Non-motor symptoms will
PD 90-95% gradually appear and aggravate
Elderly onset: as the disease progresses Psychiatric
Rest tremor
• First-line drug is levodopa, DR - Distinguish the causes of the disturbances
agonist/ MAO-B inhibitor/ COMT symptoms
inhibitor can be added if efficacy - Adjust anti-PD medications
Rigidity Sleep dysfunction
of levodopa wears off - Use of other symptom-modifying
drugs or therapies
Cognitive
Postural instability
5-10 years 10-15 years impairment
Source: Guidelines for the diagnosis and treatment of Parkinson's disease (2019); The Lancet; China Insights Consultancy 117
CNS PD treatment
Overview of treatment for PD

- Levodopa is currently the ‘gold standard’ for managing motor and some non-motor
symptoms associated with Parkinson's Disease, though there’s still no curative
therapeutics exist
Overview of treatment for PD

Treatment Application Representatives Evaluation
Pharmacological treatment
Anticholinergics • Reduce acetylcholine activity at choline receptors • Trihexyphenidyl • More used in tremor-predominant PD under 60
through oral drugs • Less tolerance in elderly patients
Dopaminergic • Exogenetic supplement of dopamine to rebalance • Levodopa/Benserazide,• Current ‘gold standard for treatment’
medications the ratio between dopamine and acetylcholine Levodopa/Carbidopa • Favored treatment for late-onset PD
• Increasing dosage requirement and withdrawal
syndrome
Dopamine- • Promote dopamine synthesis and release at • Amantadine • Effects on both motor symptoms and dyskinesia
enhancing drugs presynaptic membrane, thus reducing the reuptake in PD patients receiving levodopa
Treatment
of dopamine and increasing its concentration
for motor
Dopamine • Though not a kind of neurotransmitter, DR agonists • Piribedil, Pramipexole • Can be used as monotherapy in earlier stage
symptoms
receptor agonists are able to exhibit similar effect with levodopa with patients to delay the use of levodopa
less side effects • Withdrawal syndrome
MAO-B inhibitor • Binds to MAO-B to block microsomal metabolism • Selegiline, Rasagiline • Used more in earlier stage patients
of dopamine and enhance the dopaminergic • Can modify symptoms with nerve protection
activity in the substantial nigra • Cannot be used simultaneously with
antipsychotic medications
COMT inhibitor • The drug serves to improve the availability and • Entacapone • Only serves as adjuvant treatment with
duration of action of levodopa levodopa to help enhance clinical efficacy
• Besides motor symptoms, PD patients also exhibit • Adjustment in • Some symptoms cannot be addressed, such as
non-motor symptoms, including autonomic medications used for dysosmia
Treatment for non-motor
dysfunction, dysphrenia, sleep disorders and motor symptoms
symptoms
sensory disorders, which require treatment through • Clozapine, lorazepam
medication adjustment and antipsychotic drugs
Non-pharmacological treatment
• Implant that stimulates the basal ganglia through • Deep brain stimulation • Established treatment for advanced PD that
Surgical treatment high frequency electrical stimulation improve both motor and non-motor symptoms
• Some certain conditions are unsuitable
• Addresses motor-related and cognitive symptoms • Physical • Can help address multiple symptoms
Therapy • Help maintain work, leisure, and self-care activities • Occupational • But usually require various other forms of
• Speech treatment and involvement of specialists
Source: Guidelines for the diagnosis and treatment of Parkinson's disease (2019); China Insights Consultancy 118
CNS PD pipeline
Pipeline of PD drugs, ClinicalTrials-registered
Pipeline of PD drugs, ClinicalTrials-registered, as of Aug 20231

P2B001 Pharma Two B Ltd. Early PD/ PD Oral capsule III 2017/11/6 NCT03329508
Motor OFF Episodes Sublingual

APL-130277 Sunovion III 2018/1/5 NCT03391882
Associated With PD apomorphine film
Advanced PD with motor
IPX203 Impax Laboratories, LLC Oral capsule III 2019/3/15 NCT03877510
fluctuations
Safinamide Zambon SpA Oral III 2019/3/19 NCT03881371
fluctuations
ND0612 NeuroDerm Ltd. Subcutaneous III 2019/7/5 NCT04006210
fluctuations
Early PD III 2019/12/17 NCT04201093

tavapadon Cerevel Therapeutics, LLC Oral tablet
III 2020/9/9 NCT04542499
fluctuations
ABBV-951 AbbVie Subcutaneous III 2020/5/8 NCT04380142
fluctuations
Opicapone Bial - Portela C S.A. Early PD Oral capsule III 2021/7/27 NCT04978597
Foot dystonia-associated
Botulinum toxin type A Allergan IM injection II/III 2020/2/20 NCT04277247
pain in PD
Dipraglurant Addex Pharma S.A. PD patients with dyskinesia Oral tablet II/III 2021/4/23 NCT04857359

CNS PD pipeline
Pipeline of PD drugs, CDE-registered
Pipeline of PD drugs, CDE-registered, as of Aug 2023

Istradefylline CSPC Pharmaceutical Idiopathic PD Oral III 2019/2/8 CTR20190177
Early idiopathic PD III 2020/2/17 CTR20190042

Microspheres for
LY03003 Luye Pharma
injection
Advanced PD I 2020/3/2 CTR20200235
WD-1603 WD Pharmaceutical Early PD Oral tablet II 2021/8/6 CTR20211904
Bial - Portela & Ca, S.A./ Advanced PD and induced

Opicapone Oral capsule I 2019/1118 CTR20192230
Shanghai Fosun motor fluctuations
HEC122505MsOH Guangdong Dongyangguang PD Oral tablet I 2020/11/10 CTR20202198
VG081821AC Vimgreen Pharma PD Oral tablet I 2021/3/18 CTR20210549

Table of Contents

• T2DM + NAFLD
• NASH
• Obesity
Inflammatory bowel diseases Overview
Introduction to Inflammatory diseases

- Inflammation is an adaptive physiological response induced by deleterious
circumstances including infection and tissue injury；Inflammatory diseases include a vast
array of disorders and conditions that are characterized by inflammation.
Introduction to inflammatory disease
• Inflammation is an adaptive physiological response induced by deleterious circumstances including infection and tissue injury. In an
inflammatory disease, inflammation occurs by mistake. Inflammatory diseases include a vast array of disorders and conditions that are
characterized by inflammation.
Classification Common inflammatory diseases
• There are two main types of inflammation:

acute and chronic. • Central nervous system
(CNS) disease, such as
Acute Alzheimer’s and
Parkinson’s diseases • Cardiovascular
• Tissue damage due to trauma, microbial invasion, disease
or noxious compounds can induce acute • Cancer
inflammation. It starts rapidly, becomes severe in • Alcoholic
a short time and symptoms may last for a few Hepatitis (AH)
days for example cellulitis or acute pneumonia. • Rheumatoid
arthritis
• Renal disease
Chronic • Pancreatitis
• Inflammatory bowel
• Chronic inflammation is also referred to as slow, disease (IBD)
• Cytokine
long-term inflammation lasting for prolonged
Release
periods of several months to years. Generally,
Syndrome
the extent and effects of chronic inflammation
(CRS)
vary with the cause of the injury and the ability of
the body to repair and overcome the damage.
Source: Pahwa, R., Goyal, A., Bansal, P., & Jialal, I. (2018). Chronic inflammation.; China Insights Consultancy 122
Inflammatory bowel diseases Overview
Overview of Inflammatory bowel disease (IBD)

- IBD is a general term for a group of chronic inflammatory disorders of the bowel with two
major categories of Crohn's disease (CD) and ulcerative colitis (UC)
Definition and classification of IBD
Inflammatory bowel disease (IBD) is a general term for a group of chronic inflammatory disorders of the bowel. The two major
categories are Crohn's disease (CD) and ulcerative colitis (UC). IBD is characterized by recurrent inflammatory involvement of specific
intestinal segments, resulting in diverse clinical manifestations.
1 UC is inflammation that is restricted to the colon and that almost universally begins in the rectum, extending variable distances
proximally without any “skip” areas. Inflammation is limited to the mucosa.
2 CD is inflammation that can involve any part of the GI tract from the mouth to the anus. Inflammation can be transmural.
Features of UC and CD Causes and Symptoms
Continuous Layers Causes:

Type Location
inflammation affected The causes of both UC and Crohn's disease are not known
and both diseases have similar types of contributing factors
such as environmental, genetic and an inappropriate response
No healthy
by the body's immune system
Only the areas in Inner most
UC large between lining of the
Symptoms:
intestine inflamed colon
The symptoms of Crohn’s disease or ulcerative colitis (UC)
spots
can be similar. They include:
• Belly cramps and pain • Rectal bleeding

Anywhere • Diarrhea • Fever
in the Healthy areas • Constipation • Smaller appetite
All the
digestive in between • An urgent need to have a • Weight loss
CD layers of the
tract, from inflamed bowel movement • Fatigue
bowel walls
the mouth spots • Feeling like your bowel • Night sweats
to the anus movement wasn’t complete
Source: Animal Models for the Study of Human Disease (Second Edition), 2017; China Insights Consultancy 123
Inflammatory bowel diseases Epidemiology
Epidemiology of IBD
- IBD has increasing incidence and prevalence in most of countries and becomes a global
emerging disease. A westernized lifestyle or habits and some environmental factors have
been found to contribute to the pathogenesis of IBD.
Epidemiology of IBD
Epidemiology of IBD, China, the US, Europe, 2018-2032E

CAGR 2018-22 2022-32E Thousand Patients
China IBD prevalenve 2.4% 2.0%
US IBD Prevalence 1.0% 1.0%
Europe IBD prevalence 0.4% 0.3%
1,109.0 1,129.5 1,149.6 1,169.4 1,188.8
1,001.9 1,023.9 1,045.6 1,067.1 1,088.2
890.8 911.0 934.2 957.0 979.6
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
796.4 804.7 812.9 821.1 829.3 837.4 845.6 853.7 861.8 869.8
757.1 762.9 771.4 779.8 788.2
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
1,600.0 1,603.8 1,612.4 1,620.1 1,627.1 1,633.4 1,639.2 1,644.7 1,650.0 1,655.0 1,659.7 1,664.1 1,668.2 1,672.0 1,675.5
2018 2019 2020 2021 2022E 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Source: GHDx; China Insights Consultancy 124

Inflammatory bowel diseases Treatment
Treatment pathway for IBD

- Treatment with medication is the first therapeutic option for IBD, surgical treatment is
required when symptoms are not adequately controlled by medications
Treatment pathway for IBD

Medical treatment
Non-medical therapy
There are five main categories of medications used to treat IBD:
Categories Mechanism Main Drugs Target Indication
• Sulfasalazine
Maintain remission in inflammatory bowel disease by
Aminosalicylates • Balsalazide Leukotriene B4 • Ulcerative colitis
preventing leucocyte recruitment into the bowel wall
• Mesalamine
• Prednisone
Lower the activity of your immune system and limit the Glucocorticoid receptor, • Ulcerative colitis
Corticosteroids • Prednisolone
inflammation in the digestive tract. Annexin A1 • Crohn’s disease
• Budesonide
• Azathioprine • Ulcerative colitis
Modify the activity of the immune system so that it
Immunomodulators • 6-mercaptopurine Purine • Crohn’s disease
cannot cause ongoing inflammation
• Methotrexate
Reduce luminal and mucosa adherent bacteria
DNA topoisomerase,
concentrations, eliminate in a selective way aggressive • Ciprofloxacin
Antibiotics DNA-gyrase, nucleic • Crohn’s disease
bacterial species, and decrease bacterial tissue • metronidazole
acid
invasion and translocation
• Adalimumab
Antibodies created in the laboratory that stop certain TNF-alpha, IL-12, IL-23,• Ulcerative colitis
Biologic therapies • Golimumab
proteins in the body from causing inflammation integrins • Crohn’s disease
• Infliximab
Surgical treatment
Medication may not adequately control symptoms for everyone with IBD, and some people with these conditions develop complications that require
surgery.
Categories Percentage Procedure
The standard surgical procedure for ulcerative colitis is removal of the colon and rectum. Most patients who have
Ulcerative colitis 33%
surgery for ulcerative colitis can have a procedure called an ileal pouch anal anastomosis (IPAA).
Different types of surgical procedures may be performed for Crohn’s disease, depending on the reason for surgery,
Crohn’s disease 70%
severity of illness, and location of the disease in the intestines.
Source: ccfa.org, China Insights Consultancy 125
HTD2802 IBD Approved medications
Approved targeted medications for IBD

- There are four kinds of targeted medications in terms of mechanisms of action approved
for treatment of IBD in China
Approved targeted medications for IBD in China1
Brand
Drug Target Company Indications Approval Approval date Annual cost2 Limitations
name
Moderate-to-severe • Black box warning of risk of serious

Adalimumab Humira TNF-α Abbvie NMPA 2020/01/13 ~40,000 RMB
Crohn's Disease infections
Moderate-to-severe
Janssen 2006/5 • Black box warning of risk of serious
Infliximab Remicade TNF-α Crohn's Disease NMPA ~54,000 RMB
Biotech 2019/02/19 infections and malignancy
ulcerative colitis
• Stelara may increase the risk of

infections and reactivation of latent
2L treatment of infections
Janssen moderate-to-severe • Treatment with Stelara should not be
Ustekinumab Stelara IL-12/23 NMPA 2020/03/12 ~32,000 RMB
Biotech Crohn's Disease in initiated in patients with any clinically
adults important active infection until the
infection resolves or is adequately
treated
• Infusion-related reactions and
2L treatment of hypersensitivity reactions have been
Crohn's disease and reported
Vedolizumab Entyvio α4β7 Takeda NMPA 2020/03/13 ~43,000 RMB
ulcerative colitis • Patients treated with Entyvio are at
patients increased risk for developing
infections
• Black box warnings of serious
2L treatment for
infections, mortality, malignancy,
Upadacitinib Rinvoq JAK1 Abbvie ulcerative colitis NMPA 2023/02/20 ~35,000 RMB
major adverse cardiovascular events
patients
and thrombosis
Note:1 Information of biosimilars of the listed target medications for IBD are not presented
2 :*Annual cost calculated based on assumptions that i) medications are used in adults according to indications and usage in drug labels and ii) individual treatment is
continued for a year of 52 weeks
Source:, NMPA, FDA, China Insights Consultancy 126

HTD2802 IBD Pipeline
Global pipeline of IBD drugs

- IBD is a popular indication that a lot of drugs are in the pipeline, From 2018 to August
2023, a total of 14 targeted drugs underwent clinical trials. The following lists the phase III
clinical trial registered for each product during this period
Pipeline of IBD drugs, ClinicalTrials-registered, as of August 2023
Drug Name Target Company Indications Phase First Posted Date Trial Number
Filgotinib JAK Gilead Ulcerative Colitis III 2022/7/29 NCT05479058
SHR0302 JAK Reistone Biopharma Ulcerative Colitis III 2022/1/6 NCT05181137
Cobitolimod TLR9 InDex Pharmaceuticals Ulcerative Colitis III 2021/8/2 NCT04985968

Ulcerative Colitis /
Vedolizumab α4β7 Takeda III 2021/2/4 NCT04738942
Crohn's Disease
Tofacitinib JAK Pfizer Ulcerative Colitis III 2020/8/10 NCT04505410
Inflammatory Bowel
Adalimumab TNFα Abbvie III 2020/5/27 NCT04404517
Diseases
Etrasimod S1P Arena Pharmaceuticals Ulcerative Colitis III 2019/5/10 NCT03945188
Ustekinumab IL-23 Janssen Crohn Disease III 2018/12/20 NCT03782376
Brazikumab IL-23 AstraZeneca Crohn's Disease / IBD II / III 2018/11/29 NCT03759288
Golimumab TNFα Janssen Colitis, Ulcerative III 2018/7/24 NCT03596645
Mirikizumab IL-23 Eli Lilly Ulcerative Colitis III 2018/5/8 NCT03518086
Spesolimab IL-36 Boehringer Ingelheim Colitis, Ulcerative II / III 2018/3/29 NCT03482635
Guselkumab IL-23 Janssen Crohn's Disease II / III 2018/3/15 NCT03466411
Risankizumab IL-23 AbbVie Ulcerative Colitis III 2018/1/12 NCT03398135
Source: Clinical trials; China Insights Consultancy 127

Appendix Global pharmaceutical market
Global pharmaceutical market
Global pharmaceutical market in terms of small-molecules and biologics
Small-molecule
Biologic
2,218.8 2,240.2
2,074.8
1,989.9
1,907.4
1,827.4 693.0 737.4
1,749.7
1,672.7 648.1
1,599.6 606.1
1,528.0 566.2
1,459.7 528.1
492.0
1,393.3 453.8
1,293.7 1,332.6 418.7
1,239.0 385.1
354.3
326.0
279.2 299.7
255.9
1,525.7 1,502.8
1,341.3 1,383.8 1,426.7
1,218.9 1,257.7 1,299.2
1,105.4 1,142.8 1,180.9
983.0 1,014.5 1,033.0 1,067.3
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

Appendix China pharmaceutical market
China pharmaceutical market
China pharmaceutical market in terms of small-molecules and biologics
Small-molecule
TCM
Biologic
3,319.8
3,104.5
2,903.1
2,757.6
2,615.7
2,477.7 1,543.8
2,344.1 1,365.7
2,214.9 1,277.0
2,090.2 1,154.4
1,970.0 1,036.0
1,853.7 922.6
814.9
1,740.9 713.5
1,630.8 619.0
1,551.2 531.6
1,458.4 451.8
379.7
265.2 315.3 599.3 619.4
322.1 491.2 507.9 525.0 542.5 560.4
443.5 459.0 474.9
399.1 413.5 428.3
395.0
346.5
1,012.3 1,026.4 1,037.9 1,047.2 1,054.7 1,060.8 1,065.6 1,139.6 1,156.6

891.0 916.4 947.7 973.6 994.9
789.8
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E

Appendix NDA regulatory arrangements
Overview of FDA new drug application process
- The FDA new drug application process is a formal proposal through which drug sponsors
propose that the FDA approve a new pharmaceutical for sale and marketing in the United
States, and it has been the regulation and control of new drugs in the United States for
decades
Overview of FDA new drug application process
GLP requirements GCP requirements
FDA filling & NDA, ANDA,

Discovery IND
Basic research Pre-clinicals Clinical Clinicals Post-marketing
prototype design submitted
applications risk assessments
• Mechanical parameters • Materials selection • Human & Animal studies
including In Vitro testing • Structure activity relationship • Bench & Animal models • Human effectiveness/efficacy
• Histopathology, • Laboratory & Computer • Laboratory & Animal models • Scale-up specifications
• Nonclinical stability testing models … • Clinical quality assurance
… … …
The FDA approval process
• The FDA's Center for Drug Evaluation and Research (CDER) in charge of overseeing the drug approval process before a drug is marketed. CDER
review each drug closely using an independent team of clinicians and scientists who evaluate safety, efficacy and labeling of the drug product.
After approval, FDA follow-up continues to make sure new drugs continue to be safe and effective.
• Generally, there are four phases of a drug approval process: 1.Pre-clinical, IND; 2.Clinical; 3.NDA Review; 4.Post-marketing risk assessments.
The full research, development and approval process can last from 12 to 15 years. However, In order to incentivize the development of therapies
to fill unmet needs for serious conditions, the FDA has developed various programs to expedite drug development and review. These four
programs are: fast track, breakthrough therapy, accelerated approval, and priority review.
• In addition, supporting the development and evaluation of new treatments for rare diseases is also a key priority for the FDA. The FDA has
authority to grant orphan drug designation to a drug or biological product to prevent, diagnose or treat a rare disease or condition.
The Orphan Drug Act (ODA) was passed in 1983 to encourage

The FDA’s Fast Track program is designed to facilitate the
the development of drugs for rare diseases. The FDA’s Orphan
development and expedite the review of drugs to treat serious
Drug Designation program provides orphan status to drugs and
conditions and fill an unmet medical need. The purpose is to
biologics that are intended for the safe and effective treatment,
get important new drugs to the patient earlier. The Fast Track
diagnosis or prevention of rare diseases or disorders that affect
program is intended to help patients with serious conditions
fewer than 200,000 people in the US. The program provides
receive new drugs more quickly.
incentives for sponsors to develop products for rare diseases.
Source: FDA; China Insights Consultancy

130
Overview of NMPA and CDE new drug application process

- The Center for Drug Evaluation of NMPA (CDE) is responsible for evaluating drug clinical
trial applications, drug marketing authorization applications, supplementary applications, and
registration renewal applications of drugs manufactured overseas, etc…

Screening Non-clinical Clinical trials
Screening
Compound compounds to studies like Clinical trials Phase IV, Post-
Indication for gene
screening identify drug pharmacokinetic Phase I-III marketing risk
targets
candidates study assessments
Discovery Pre-clinical Clinical studies Post marketing review

IND NDA; ANDA
Non-clinical research refers to various toxicity tests conducted in laboratory conditions using
experimental systems to evaluate drug safety, including single-dose toxicity tests, repeated- Clinical trials of biomedical
dose toxicity tests, reproductive toxicity tests, mutagenicity tests, carcinogenicity tests, interventions typically proceed through
various irritancy tests, dependence tests and other toxicity tests related to drug safety four phases1. The purpose of these
evaluation. four main phases are:
Animal experiments are widely used in medical, biomedical and veterinary research, and are • Phase 1 is the first stage of research,
essential means of drug development and preclinical testing, including toxicology and safety testing for general safety with a small
studies. They help us advance our scientific understanding, serve as models to study volunteer group.
disease, help us develop and test potential new medicines and therapies. Animal
experiments eliminate some potential drugs as either ineffective or too dangerous to use on • Phase 2 tests how well the treatment
human beings. works on a larger volunteer group.
Good clinical practice (GCP) is an international ethical and scientific quality standard for • Phase 3 evaluates how effective the
designing, recording and reporting trials that involve the participation of human subjects. The treatment is in comparison to current
GCP guidelines detail the requirements for trial documentation, protocol amendments, treatments (e.g. current standard of
requirements such as indemnity, reporting lines for adverse events and provision of medical care).
care for trial participants. Compliance with this standard provides public assurance that the
rights, safety and wellbeing of trial subjects are protected and that clinical-trial data are • Phase 4 trials are done after a drug
reliable. has been licensed2.
Source: China Insights Consultancy

131
Appendix Overview
Process of new drug application with CDE
• Applicant submit the clinical study report, sample products, relevant

changes and supplemental information, with detailed explanation and
justifications and the relevant certified documents.
• NMPA accepts the files
• CDE will issue one notification regarding submission

of all needed supplementary materials if necessary
• CDE of NMPA conducts the technical review
and the applicant shall at one time submit all the
required supplemental materials.
• CDE will complete the technical

review on supplemental information.
• NMPA completes the approval process • Unapproved or return application
• NMPA issues Drug Certificate

132
Overview of CE new drug application process
- Similar to the US requirements, there are two steps, clinical trial and market authorization
application to go through before drug is marketed in EU. Clinical trial applications are
approved at the member-state level, whereas marketing authorization applications are
approved at both member-state and centralized levels
Overview of CE new drug application process
Flow chart of Mutual Recognition
Flow chart of Centralized Procedure Flow chart of Decentralized Procedure
Procedure
Applicant submits applications to Applicant submits application to the RMS &

MMA Start of procedure
the RMS & CMS CMS
RMS & CMS validates the application

CHMP provides Assessment report from RMS validates the application
comments (co)-rapporteur
RMS distributes the preliminary assessment
report to the CMS
CHMP forwards RMS distributes assessment
Submission of response report to CMS
to applicant list RMS sends preliminary assessment report &
by applicant
of questions all comments of the CMS to the applicant
CHMP decision CMS validates the application Clock stops, applicant responds, clock runs
on need of oral Joint assessment report
explanation by from (co)-rapporteur
applicant RMS send draft assessment report to the CMS
CMS approves the assessment & applicant
report
Final draft of English SPC,
leaflet & labelling by CMS approves the assessment report
CHMP opinion applicant to (co)- Marketing authorization in each of
rapporteur, EMEA, the CMS
CHMP Marketing authorization in RMS & each of the
CMS
Note: Marketing authorization application (MMA); Committee for Medicinal Products for
Human Use (CHMP); European Medicines Evaluation Agency (EMEA); Concerned
member states (CMS); Reference member state (RMS) Source: International Journal of Drug Regulatory
Affairs; China Insights Consultancy 133
Appendix China market access
Overview of NRDL and Volume-based procurement program

- After a new drug’s NDA is approved, access to NRDL and bid for regional or centralized
VBP are two major events that could potentially impose pressure of price reduction
Overview China market access

National Drug Reimbursement list application and inclusion process
1 2 3 4 5 6
Pharma
Product launch Expert review
Preparation for companies Price negotiation NRDL inclusion
after regulatory and vote for
NRDL listing submit and tendering results
approval shortlist
application
• Experts assess clinical • Drug manufacturers present • Two drug groups in NRDL with
• Preliminary conditions and criteria for
value, budget impact and price quote and bid for NRDL different reimbursement level
eligibility of NRDL released
cost-effectiveness of inclusion • Class A: 100% reimbursed
• Pharmaceutical companies could
underlying drugs • If proposed price exceeds • Class B: partially reimbursed,
prepare required qualifications and
proposed to be included in certain threshold, drug varies across municipalities and
documents accordingly
NRDL manufacturers may lose the bid provinces
Evolution of centralized VBP program
2019.9 2021.1 2021.6

2018.11 2019.12 2020.7 2021.11 2022.7 2023.3
4+7 4th round 5th round
4+7 pilot 2nd round 3rd round 6th round 7th round 8th round
expansion
Nationwide
Scale 11 pilot cities 25 provinces nationwide nationwide nationwide nationwide nationwide nationwide
(for Insulin)
# of drugs 25 25 32 55 45 61 16 61 39
Avg price
52% 59% 53% 53% 52% 56% 48% 48% 56%
cut
• Volume-based procurement program is a series of drug procurement policies implemented in China, which aims to encourage the substitution of generic drugs
and reduce the cost of drugs that have passed their exclusivities. In the pilot run of centralized VBP, the policy only covered 11 pilot cities in 2018, but fast
rolled out to nationwide implementation.
• Centralized procurement for drugs has yielded cost savings by creating economies of scale and improving purchasing and negotiation power over pricing by
pooling procurement process for drugs across multiple buyers. Pharma companies in turn should design market access strategies to cope with expected price
cut
Source: NHSA, frontiers, China Insights Consultancy
134
Appendix TOP10 digestive & metabolic global
Top 10 drugs in terms of sales in metabolic disorders and digestive

diseases globally
Top 10 drugs in terms of sales in metabolic and digestive diseases
Annual sales, 2022

Rank Drug name Manufacturer Indication MoA/target
(USD Billions)
1 OZEMPIC Novo Nordisk Diabetes GLP-1R 8.6
2 TRULICITY Eli Lilly Diabetes GLP-1R 7.4
3 JARDIANCE Eli Lilly Diabetes SGLT2i 6.1
4 JANUVIA Merck Diabetes DPP-4i 5.7
Ulcerative colitis and

5 ENTYVIO Takeda Α4β7 5.2
Crohn's disease
6 FARXIGA AstraZeneca Diabetes SGLT2i 4.4
7 LANTUS SOLOSTAR Sanofi Diabetes Insulin 2.4
8 HUMALOG Eli Lilly Diabetes Insulin 2.1
9 RYBELSUS Novo Nordisk Diabetes GLP-1R 1.7
10 Novorapid Novo Nordisk Diabetes GLP-1R 1.4
135
Appendix TOP10 T2DM global
Top 10 drugs in terms of sales in T2DM globally
Top 10 drugs in terms of sales in T2DM
Annual sales, 2022

Rank Drug name Manufacturer Indication MoA/target
(USD Billions)
1 OZEMPIC Novo Nordisk Diabetes GLP-1R 8.6
2 TRULICITY Eli Lilly Diabetes GLP-1R 7.4
3 JARDIANCE Eli Lilly Diabetes SGLT2i 6.1
4 JANUVIA Merck Diabetes DPP-4i 5.7
5 FARXIGA AstraZeneca Diabetes SGLT2i 4.4
6 LANTUS SOLOSTAR Sanofi Diabetes Insulin 2.4
7 HUMALOG Eli Lilly Diabetes Insulin 2.1
8 RYBELSUS Novo Nordisk Diabetes GLP-1R 1.7
9 Novorapid Novo Nordisk Diabetes GLP-1R 1.4
10 Novomix Novo Nordisk Diabetes Insulin 1.0
136
Appendix TOP10 T2DM China
Top 10 drugs in terms of sales in T2DM in China
Top 10 drugs in terms of sales in T2DM in China
Annual sales, 2022

Rank Generic name Indication MoA/target
(RMB Billions)
1 Insulin Aspart 30 Injection Diabetes Insulin 4.1
2 Insulin Glargine Injection Diabetes Insulin 3.5
Isophane Protamine Human

3 Diabetes Insulin 3.2
Insulin Injection (30R)
4 Dapagliflozin Diabetes SGLT2i 3.1
5 Metformin Hydrochloride Tablets Diabetes Metformin 2.3
6 Acarbose Tablets Diabetes α-glucosidase inhibitor 2.0
7 Sitagliptin tablets Diabetes DPP-4i 2.0
8 Semaglutide Injection Diabetes GLP-1R 1.9
9 Insulin Aspart Injection Diabetes GLP-1R 1.9
Isophane Protamine
10 Recombinant Human Insulin Diabetes Insulin 1.6
Injection (Pre-mixed 30/70)
137
T2DM/NASH/SHTG Competitive landscape
Competitive landscape of approved therapies in T2DM/NASH/SHTG
Competitive landscape
# Description
8 iii • No medicines have been approved to treat MASH, so managing underlying health conditions and leading a healthy
lifestyle are the best treatment options. Such as reducing the total cholesterol level, losing weight, controlling
diabetes, avoiding alcohol, exercising regularly, supplement with vitamin E and so on. While there is no specific
medication that directly treats MASH, taking metformin and statins to treat related metabolic disorders such as
insulin resistance and high cholesterol can help with these related conditions. When combined with weight loss and
improved diet, fatty liver can be reversed. In addition, the American Association for the Study of Liver Diseases
confirms that vitamin E and pioglitazone (used to treat diabetes) are the two best drug choices for biopsy-confirmed
MASH, but questions remain about safety, efficacy, and side effects .
• Management of T2DM includes healthy eating, regular exercise, weight loss, blood sugar monitoring and diabetes
medication or insulin therapy. Diabetes medications includes Metformin, Sulfonylureas, Glinides, Thiazolidinediones,
DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and other medicines in addition to diabetes
medications include blood pressure and cholesterol-lowering medicines, as well as low-dose aspirin, to help prevent
heart and blood vessel disease. Insulin therapy can be prescribed if blood sugar targets aren’t met with lifestyle
changes and other medicines. Weight-loss surgery changes the shape and function of the digestive system and
have several surgical procedures.
• Diet remains the mainstay of treatment of any form of primary HTG, The traditional pharmacologic therapies for
HTG such as statins, fibrates, niacin and omega-3 fatty acids, may offer some extra percentages of TG-lowering
but are often insufficient to adequately reduce TG concentrations.

138
T2DM/MASH/SHTG Competitive landscape
Competitive landscape of approved therapies in T2DM/MASH/SHTG
Input
# Description
T2DM • According to ADA guidelines in T2DM, T2DM glucose-lowering agents include Metformin, Alpha-glucosidase inhibitors (AGIs), DPP-4
competitive inhibitors, SGLT2 inhibitors, glitazones, GLP-1R agonists, insulinotropic agents, insulin and so on. Among the FDA-approved T2DM drugs,
landscape as of August 18, 2023, a total of 296 drugs of Metformin have been approved and Insulin has 57 FDA approvals. GLP-1R agonists primarily
include Dulaglutide, Exenatide, and Liraglutide, with 2, 5, and 3 cases approved, respectively. The total number of T2DM drugs approved
by the NMPA is 1,236 (the same company and the same drug but with different dosages may have different approvals).
• According to the SHTG/HTG treatment guidelines, SHTG/HTG drugs primarily include fenofibrate and ethyl eicosapentaenoate. Of the
SHTG/HTG drugs approved by the FDA, as of August 18, 2023, there were 119 approvals for fenofibrate and 11 approvals for ethyl
eicosapentaenoate, and a certain number of approvals for other SHTG/HTG drugs by the FDA; and as of August 18, 2023, there were 139
approvals for SHTG/HTG drugs by the NMPA (the same company and the same drug, but different doses may have different approvals).
SHTG/HTG • According to the SHTG/HTG treatment guidelines, SHTG/HTG drugs primarily include fenofibrate, nicotine acid and ethyl
therapies eicosapentaenoate acid.
MASH • There are more than 100 active clinical trials in the field of MASH treatment registered under ClinicalTrials and regulated by the FDA,
competitive including 7 drug candidates in active Phase III clinical stage regulated by the FDA. Intercept's Ocaliva, one of the most advanced MASH
landscape drugs in clinical stage, its second application for MASH was rejected by the FDA in June 2023. The FDA reviewers flagged increased risk
of diabetes and liver injury from using the oral tablets, called obeticholic acid (OCA), for the treatment of MASH. The FDA concluded that
benefits of Ocaliva did not outweigh the risks in MASH patients with fibrosis based on current data.
• Madrigal’s Resmetirom has been filed for NDA

139
Appendix Confirmation
CSRC filing confirmation
# Section Confirmation
1 所属行业及发行人是一家专注代谢性疾病、消化系统疾病等领域的重大未满足临床需求的全球一体化生物制药公司，
确定所属行根据中国证监会发布的《上市公司行业分类指引》（2012 年修订），发行人属于医药制造业（分类代码
业的依据为 C27）。
2 行业发展趋同种药物的多靶点拓展成为创新疗法的发展模式之一。复杂疾病在人群中的发病率逐渐提高，通常是由多
势种基因或环境因素相互作用导致的，可能会同时涉及到多器官功能障碍，单靶点药物在治疗上会出现效果
较差的情况。多靶点/多器官药物可同时针对多种靶点/器官，目前已在癌症、炎症以及神经系统疾病等领
域进行了大量的研究工作，是治疗复杂疾病的潜在解决方案。
多靶点药物将有机会通过创新机制降低药物耐药性。单靶点药物忽视了人体作为一个系统所具有的复杂性
和稳定性，而长期使用单靶点药物容易导致患者产生耐药性。通过多个途径同时影响不同靶点，可以同时
调节疾病机制中的不同节点，使患者在不易产生耐药性的同时收获较好的临床效果。
新兴科技运用缩短药物发现时间。目前，药物新适应症开发的主要途径包括传统药物发现以及利用药物的
原始作用机制进行重新定位以。随着计算机、人工智能等新兴技术在药物发现中的发展和运用，药物发现
过程将有望得到缩短，发现效率得到提高，在一定程度上将降低药物研发成本，推动创新疗法的研发进度。

140
3 行业内主要在代谢和消化系统疾病领域开展创新药研发业务的国内外医药企业数量众多，其中主要企业如下：
企业
序号公司名称公司简介 2022年营收

1 诺和诺德诺和诺德成立于1923年，是一家全球范围内的医药研发公司，总部位于丹麦哥本哈根，目前在全 1,737.2 亿
球有80个办事处，在170个国家、地区销售产品，致力于为糖尿病和其他严重慢性疾病提供有效疗元
法。
2 阿斯利康阿斯利康公司成立于1999年，是一家跨国制药和生物技术公司，总部位于英国剑桥。阿斯利康专 3,074.9亿元
注的治疗领域包括肿瘤、心血管、消化系统、感染、神经科学、呼吸系统和炎症等。
3 默克公司默克公司成立于1891年，是一家总部位于美国新泽西的跨国制药企业，默克开发和生产了多种药 4,111.3亿元
物、疫苗、和动物保健产品，在心血管、内分泌、免疫疾病、神经科学、肿瘤等多个疾病领域拥有
多个重磅产品
4 辉瑞辉瑞是一家成立于1849年的美国跨国制药和生物技术公司，总部位于美国纽约市。辉瑞专注的治 6,953.8亿元
疗领域有免疫学、肿瘤学、内分泌学等
5 微芯生物微芯生物成立于2001年，目前业务集早期研究、临床开发、产品开发及GMP生产、药政事务及药 5.3亿元
物警戒、营销、商业及市场准入、产品战略及商务拓展、知识产权于一体，并开启了全球化进程
6 东阳光药东阳光药成立于2001年，2015年于香港交易所上市，是一家专注于抗病毒、内分泌及代谢性疾病、 37.4亿元
心血管疾病等治疗领域产品开发、生产及销售的中国制药企业，在中国生产、推广及销售合共33款
医药产品，并于中国建立庞大的产品分销网络。
141
行业主管部门主要管理职责
负责药品、医疗器械和化妆品安全监督管理及拟定监督管理政策规划；负责组织制定国家药典等行业标准，组织制定
国家药品监督管理局分类管理制度，并监督实施；负责制定注册管理制度，严格上市审评审批；负责制定研制、生产、经营和使用质量管理
规范并监督实施；负责药品、医疗仪器和化妆品上市后风险管理，依法承担安全应急管理工作等
负责宏观质量管理。拟订并实施质量发展的制度措施；负责产品质量安全监督管理，建立并组织实施质量分级制度、
国家市场监督管理总局
质量安全追溯制度，指导工业产品生产许可管理；管理国家药品监督管理局、国家知识产权局等
国家卫生健康委员会负责管理公共卫生与计划生育
负责管理医疗保障体系，拟订医疗保险、生育保险、医疗救助等医疗保障制度的法律法规草案、政策、规划和标准等，
国家医疗保障局
制定并监督执行药品价格政策、药品招标采购政策，调控药品价格总水平
国家发展和改革委员会负责组织拟订综合性产业政策，推动实施创新驱动发展战略
人力资源和社会保障部拟订人力资源和社会保障事业发展政策、规划，起草相关法律法规草案等
工业和信息化部组织拟订并实施高技术产业中涉及生物医药、新材料、航空航天、信息产业等的规划、政策和标准等
生态环境部负责对医药制造行业在投资、生产方面需符合的环保要求进行管理和监督
国家科技部负责组织开展我国人类遗传资源调查，制定重要遗传家系和特定地区人类遗传资源申报登记办法

142
名称发布单位发布时间主要内容

将新型化合物药物或活性成份药物的生产（包括原料药和制
剂）；新型抗癌药物、新型心脑血管药及新型神经系统用药的开
《鼓励外商投资产业目录国家发展和改革委
2022年10月26日发、生产；采用生物工程技术的新型药物生产；药品制剂生产：
（2022年版）》员会、商务部
采用缓释、控释、靶向、透皮吸收等新技术的新剂型、新产品等
列入鼓励外商投资产业目录
明确了我国“十四五”期间药品安全及促进高质量发展的指导思想，
《“十四五”国家药品安全及国家药品监督管理提出五个“坚持”总体原则和主要发展目标，并制定出10个方面主
2021年12月30日
促进高质量发展规划》局要任务，以保障“十四五”期间药品安全，促进药品高质量发展，推
进药品监管体系和监管能力现代化，保护和促进公众健康
按照生命至上、创新引领、系统推进、开放合作的基本原则，
提出了未来5年的发展目标和15年远景目标，以及加快产品创新、
《“十四五”医药工业发展规工业和信息化部等提升产业链稳定性和竞争力、增强供应保障能力、推动医药制造
2021年12月22日
划》九部门系统升级、创造国际竞争优势等5项任务。鼓励改良新药、原料药
创新工艺、复杂制剂技术、儿童药、一致性评价等领域的技术开
发和应用
“十四五”时期，我国生物技术和生物产业加快发展，生物经济成
《“十四五”生物经济发展规国家发展和改革委
12021年12月20日为推动高质量发展的强劲动力，生物安全风险防控和治理体系建
划》员会
设不断加强

143
全面推进健康中国建设。完善创新药物、疫苗、医疗器械等快
《中华人民共和国国民经济
速审评审批机制，加快临床急需和罕见病治疗药品、医疗器械审
和社会发展第十四个五年规划全国人民代表大会 2021年3月12日
评审批，促进临床急需境外已上市新药和医疗器械尽快在境内上
和2035年远景目标纲要》
市
鼓励类包括：拥有自主知识产权的新药开发和生产，天然药物
《产业结构调整指导目录国家发展和改革委开发和生产，满足我国重大、多发性疾病防治需求的通用名药物
2019年10月30日
（2019年本）》员会首次开发和生产，药物新剂型、新辅料、儿童药、短缺药的开发
和生产；防控突发公共卫生和生物事件疫苗和药品
促进药品创新和仿制药发展。完善和落实药品试验数据保护制
度。药品注册申请人在提交注册申请时，可同时提交试验数据保
《关于深化审评审批制度改护申请。对创新药、罕见病治疗药品、儿童专用药、创新治疗用
中共中央办公厅，
革鼓励药品医疗器械创新的意 2017年10月8日生物制品以及挑战专利成功药品注册申请人提交的自行取得且未
国务院办公厅
见》披露的试验数据和其他数据，给予一定的数据保护期。发挥企业
的创新主体作用。鼓励药品医疗器械企业增加研发投入，加强新
产品研发和已上市产品的继续研究，持续完善生产工艺
将治疗恶性肿瘤、自身免疫性疾病、神经系统疾病等难治性疾
《战略性新兴产业重点产品国家发展和改革委病以及用于紧急预防和治疗感染性疾病的抗体类药物，免疫原性
2017年1月25日
和服务指导目录（2016版）》员会低、稳定性好、靶向性强、长效、生物利用度高的基因工程蛋白
质药物列入战略性新兴产业重点产品和服务指导目录

144
指出重点发展化学新药，紧跟国际医药技术发展趋势，开展重
工业和信息化部等
《医药工业发展规划指南》 2016年10月26日大疾病新药的研发，重点发展针对恶性肿瘤的创新药物，特别是
六部门
采用新靶点、新作用机制的新药
就改革药品医疗器械审评审批制度提出提高药品审批标准、推
《国务院关于改革药品医疗
国务院 2015年8月9日进仿制药质量一致性评价、加快创新药审评审批、开展药品上市
器械审评审批制度的意见》
许可持有人制度试点等一系列新举措
提出进一步加快创新药物审评，对重大疾病具有更好治疗作用、
《国家食品药品监督管理局具有自主知识产权的创新药物注册申请等，给予加快审评；调整
国家食品药品监督
关于深化药品审评审批改革进 2013年2月22日创新药物临床试验申请的审评策略、优化创新药物审评流程、配
管理局
一步鼓励药物创新的意见》置优质审评资源；对实行加快审评的创新药物注册申请，采取早
期介入、分阶段指导等措施，加强指导和沟通交流

145
我国药品生产、经营等领域的法律法规逐步完善，规范了医药企业的生产、经营活动，有利于规范医药行业的行业竞争行为。为发行人的生产、经营提供了良好的发展环境和制
度保障。
1）逐步完善的行业监管体制为发行人经营发展提供了机遇
随着《药品管理法》《药品生产监督管理办法（2020）》《药品注册管理办法（2020）》等一系列法律法规的颁布及重新修订，药品行业的整体监管要求日趋严格，药品安全及
药品质量管控逐渐成为行业监管重点，这将有利于促进行业内企业的良性竞争和优胜劣汰，从而提高行业门槛。在趋严的监管体制下，不同医药企业之间呈现出一定的分化局面，
为高标准运营的医药企业的经营提供了良好的发展环境和机遇。发行人在药品研发等方面一直保持较高标准，因此，逐步完善的行业监管体制为公司的经营发展提供了机遇。
2）药品上市许可人制度有利于发行人专注于新药研发优势环节
自2015年11月，第十二届全国人民代表大会常务委员会第十七次会议审议通过《关于授权国务院在部分地方开展药品上市许可持有人制度试点和有关问题的规定》；2016年5月，
国务院办公厅发布《药品上市许可持有人制度试点方案的通知》，多个试点省（市）陆续出台具体方案，着力开展药品上市许可持有人制度相关工作，取得积极成果。2019年新版《药
品管理法》将药品上市许可持有人制度纳入，新增“药品上市许可持有人”章节。上市许可和生产许可相互独立，上市许可持有人可以将产品委托给不同的生产商生产，药品的安全性、
有效性和质量可控性均由上市许可人对公众负责。推行该制度后,没有生产许可的研发企业可委托给其他多个企业代产，使得该研发企业将技术转化为稳定且体量大的收入。药品上市
许可人制度对于以发行人为代表的药品研发机构及研发型药企都具有积极意义，有效鼓励创新药企业专注于新药研发优势环节，提高新药研发的积极性。
3）产业支持政策促进了发行人的研发创新
2016年10月，工业和信息化部等六部门联合发布《医药工业发展规划指南》，要求推进生物药、化学药新品种、优质中药等六大重点领域发展，加快各领域新技术的开发和应用，
促进产品、技术、质量升级。2017年1月，国家发改委发布《战略性新兴产业重点产品和服务指导目录》，将化学药品和原料药制造、生物技术药物、现代中药与民族药纳入其中并鼓
励其发展。2021年3月，全国人民代表大会通过了《中华人民共和国国民经济和社会发展第十四个五年规划和 2035 年远景目标纲要》，强调要集中优势资源攻关医药领域的关键核心
技术，推动医药产品的创新发展。2022年1月，工信部等9部门发布《“十四五”医药工业发展规划》，要求加快产品创新和产业化技术突破，促进医药工业发展向创新驱动转型。前述
鼓励创新药研发的相关政策，为发行人进一步的研发创新和新药创制奠定了良好的政策环境基础。
2015年8月，国务院印发《关于改革药品医疗器械审评审批制度的意见》，提出了提高审评审批质量、解决注册申请积压、提高仿制药质量、鼓励研究和创制新药、提高审评审批透明
度五大目标。2017年10月，中共中央办公厅、国务院办公厅发布《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》，对新药临床试验管理、上市审核审批做出进一步的规范。
2021年3月发布的《中华人民共和国国民经济和社会发展第十四个五年规划和2035年远景目标纲要》中进一步强调，要完善创新药物的快速审评审批机制，加快临床急需药品的审评审
批。前述创新药审批政策将倒逼药企加速创新，同时显著利好自主研发能力强、创新管线丰富、进行原发性创新而非跟随式创新的医药企业。

146
Section Confirmation
行业未来趋势 • 同时瞄准多个靶点，解决复杂疾病，将成为代谢失调及消化系统疾病治疗市场的重要发展趋势。
• 随着复杂疾病对医疗行业的不断挑战，创新疗法已由单靶点药物发展至药物组合，再到单药多靶点，最后发展至多功
能药物方法。与传统的治疗方案相比，多功能药物具有更好的疗效、协同效应，同时可以提升患者的依从性，且副作
用更小。
• 此外，代谢失调及消化系统疾病治疗市场的另一趋势是利用多种途径解决患者天生的或因后天变异产生的个体耐药性。
耐药性指在治疗中抗微生物或抗肿瘤等药物的有效性降低。因为在药物治疗过程中，与疾病相关的生物通路可能会改
变，补偿机制也有可能被激活，所以同时作用于多个途径可能对治疗有利，尤其是对先天或后天环境引发了耐药性的
病人。

147
4 与同行业可由于公司的主要产品所在治疗领域的创新产品全部处于临床阶段，此处可比公司经营情况和市场地位的对
比公司的对比分析仅与管线进度相关，选择公司主要产品的主要适应症非酒精性脂肪肝炎（NASH）进行列示。
比分析
药物名称靶点/机制企业临床阶段首次公示日期管辖机构
IVA337 PPAR Inventiva Pharma III期 2021/04/19 FDA
司美格鲁肽 GLP-1 诺和诺德 III期 2021/03/30 FDA
Belapectin Galectin-3 Galectin III期 2020/04/28 FDA
Resmetirom THR-β Madrigal 制药 III期 2019/04/03 FDA
西格列他钠 PPAR 微芯生物 II期 2021/12/07 CDE

BI456906 GLP-1 勃林格殷格翰 II期 2021/09/01 CDE
HEC96719 FXR HEC制药 II期 2021/07/27 CDE
PF-06865571 ACC DGAT2 辉瑞 II期 2021/03/15 CDE

148
IO confirmation
IO confirmation
1 IO Targeting multiple targets simultaneously to address complex diseases. As complex diseases continue to challenge the
healthcare industry, the innovation therapies have been developed from single-target drugs to drug combination, then to
single drug with multiple targets, finally developing a multi-functional drugs approach. Compared to traditional treatment
options, multi-functional drugs have better efficacy, synergistic effect and patient compliance with less side effect. The
following chart compares treatment options among single-target drugs, drug combination, fixed dose combination, and
multi-functional drugs
2 IO NASH is liver inflammation and damage caused by a buildup of fat in the liver. It is the more severe form of
nonalcoholic fatty liver disease (NAFLD), an umbrella term for a range of liver conditions affecting people who drink little
to no alcohol. If left untreated, NASH can cause scarring of the liver, which leads to permanent scarring (cirrhosis) and
liver cancer. NAFLD is characterized by steatosis of the liver, and NASH is a necro-inflammatory process whereby the
liver cells become injured under steatosis
3 IO The global and China market follows the same treatment regimen. The international and national guideline recommend
that management for NAFLD and NASH patients varies depending on their risk of clinical liver fibrosis.
4 IO Benefits of utilizing multiple pathways in drug development:
• Disease often results from the breakdown of robust physiological systems due to multiple genetic and/or
environmental factors. Thus, complex disorders are more likely to be healed or alleviated though simultaneous
modulation of multiple targets or pathways.
• The multifunctional agents capable of modulating multiple biological targets simultaneously display great advantages
of higher efficacy, improved safety profile, and simpler administration compared to single-targeted agents.
5 IO • As the intended indications of HTD1801 are NASH, T2DM, SHTG, PBC and PSC, some of these indications are
under the relationship of comorbidity. For example, T2DM is an improtant risk factor of NAFLD/NASH，and
individuals with NASH are at a higher risk of developing T2DM. Same comrbidity relationship applies to SHTG and
T2DM. This leads the overlap of disease prevalence and thus overlap of addressable population. We are of the view
that the disclosed individual prevalence and addressable population under each indication would provide sufficient
basis for investors to evaluate the market potential for HTD1801
149
IO confirmation
IO confirmation
5 IO Industry trends of metabolic and digestive diseases drug market – TCM internationalization and globalization:
• The combination of TCM with modern scientific system have contributed to its internationalization and globalization.
One of the most significant successes of TCM modernization is the discovery and development of Qinghaosu
(artemisinin), which is a product of TCM and modern scientific system and approach. As the continuous development
and progress of modern science and technology, the quality identification, extraction and separation, analysis and
detection of TCM are increasingly mature processes, which would contribute to TCM internationalization
• Favorable policies have been introduced to promote the globalization of TCM. In the 14th Five-Year Plan period
(2021-2025), TCM was given priority in reform and development of the industry. Among the ten critical tasks outlined
in the 14th Five-Year plan for Chinese Medicine, expansion of international trade of Chinese Medicine is highlighted.
In addition, internationalization of Chinese Medicine, especially in the “belt and road” countries, should be achieved
through the integration of high-quality development of Chinese Medicine with the development of “Belt and Road”
initiative
• During the 2021 China International Fair for Trade in Services (CIFTIS), The government pledged to build a global
platform and push forward constructing a series of TCM globalization projects to improve the level of TCM service
and trade.
• One of the ten critical tasks outlined in the “National 14th Five-Year Plan” for Chinese Medicine is the expansion of its
international trade. In addition, the “National 14th Five-Year Plan” for Chinese Medicine announced that the
internationalization of Chinese medicine should be achieved through integration of high-quality development of both
Chinese medicine and the “Belt and Road Initiative”. For example, during the 2021 China International Fair for Trade
in Services (CIFTIS), The government pledged to build a global platform and push forward constructing a series of
TCM globalization projects to improve the level of TCM service and trade.
• As of May 29, 2023, there are two approved innovative Chinese drugs and over 200 undergoing clinical trials globally
suggesting good trends of Chinese medicines.

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Appendix
• Patients suffering from metabolic and digestive diseases are predisposed to multiple co-existing and highly interrelated morbidities. For example, approximately
55%, 40% and 30% of patients with type 2 diabetes mellitus (“T2DM”) worldwide are also diagnosed with nonalcoholic steatohepatitis (“NASH”), severe
hypertriglyceridemia (“SHTG”) and obesity, respectively, and these comorbidities often aggravate one another through a complex network of interactions.
• For the treatment of AH, the company are advancing the early clinical development of HTD4010. AH is a type of alcohol-associated liver disease (“ALD”)
characterized by acute liver inflammation. There are currently no approved drug treatments available for AH. Although major clinical practice guidelines
recommend the use of corticosteroids in patients with severe AH, the approach has not shown any long-term survival benefit and carry the risk of serious side
effects.
• Although JAK inhibitors are approved in the United States for the treatment of IBD, they have been plagued by safety concerns and three of them, namely
tofacitinib from Pfizer, upadacitinib from Abbvie and baricitinib from Eli Lilly, have received FDA boxed warnings of risks of serious cardiac events, cancer, blood
clots and death, all of which limit the long-term use of current treatment regimens, particularly in children.
• Metabolic and digestive diseases are among the most prevalent and challenging healthcare issues worldwide. The prevalence of these diseases has increased
significantly in recent years due to changing lifestyles, rising obesity rates and aging populations.
• Our HTD4010 is a novel polypeptide drug for the treatment of complex, life-threatening diseases such as AH, which is caused by chronic heavy alcohol abuse or
a sudden, drastic increase in alcohol consumption. It is characterized by severe inflammation and, ultimately, liver failure and death.
• The current standard of care focuses on symptom management, including abstinence, treating inflammation and providing nutrition.
• NASH is a condition characterized by liver inflammation and damage caused by the buildup of fat in the liver. It is the more severe form of NAFLD, an umbrella
term for a range of liver conditions affecting people who drink little to no alcohol.
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Appendix
• Currently, the treatment of NASH is limited to lifestyle modifications and treatment of specific comorbidities. No evidence-based pharmacological therapy has
been approved for NASH other than saroglitazar magnesium, which is approved in India but has not been widely accepted internationally.
• This increase reflects a growing aging population segment as well as changing dietary and lifestyle factors.
• T2DM and NASH are intricately and bi-directionally associated, where T2DM aggravates NAFLD into more severe forms of liver disorders, such as NASH,
cirrhosis and hepatocellular carcinoma, while the presence of NAFLD increases the incidence and severity of T2DM and makes T2DM patients more susceptible
to comorbidities such as CVDs. To date, there is no effective pharmacological treatments that can address T2DM and its comorbidities as a whole. Metformin,
the first-line treatment for T2DM in China, is not recommended for use in patients with certain pre-existing liver dysfunction due to safety concerns.
• SHTG is the presence of high levels of triglycerides, a type of fat, in the blood. SHTG is well known to be associated with other complex and serious disorders
such as acute pancreatitis and CVDs. Lifestyle changes and dietary modifications are the current standard treatment for patients with SHTG.
• PSC is a rare, chronic cholestatic liver disease characterized by intrahepatic and extrahepatic bile duct injury. Inflammation and fibrosis of the bile ducts lead to
structural damage, impaired bile flow and progressive liver dysfunction. There is no approved therapy for PSC worldwide. PSC has been identified by the
European Association for the Study of the Liver as one of the largest unmet clinical needs in the category of liver disease.
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Appendix
• According to CIC, metabolic and digestive diseases are one of the most prevalent diseases both in China and worldwide.
• Corticosteroids, often used in patients with severe AH, has not shown meaningful long-term survival benefit and usually carries serious side effects.
• These complex diseases, such as NASH, T2DM, SHTG, PSC and PBC, have multiple underlying causes that often lead to comorbidities, making them difficult
to treat on a discrete basis.
• While simple steatosis is considered a relatively benign and reversible condition, up to one-third of subjects in the spectrum of steatosis develop NASH, a
chronic, life-threatening, inflammatory liver disease characterized by hepatocellular injury, inflammation, and progressive fibrosis.
• The most common comorbidities associated with NASH are reported to include obesity, T2DM, insulin resistance, hypertension, and dyslipidemia. Several
studies have reported that the most common cause of death in patients with NAFLD or NASH is cardiovascular disease, while patients specifically with NASH
have an increased rate of liver-related mortality.
• No evidence-based pharmacological therapy has been approved for NASH other than saroglitazar magnesium, which is approved in India but has not been
widely accepted internationally.
• This increase reflects a growing aging population segment as well as changing dietary and lifestyle factors.
• The therapeutically target in treating these patients is to well control the progression of T2DM and NAFLD and improve other risk factors of CVDs.
• Furthermore, while the existing therapies for SHTG offer a benefit in treating high TGs, they offer limited benefit in the treatment of the constellation of metabolic
issues in orbit around or underlying the TG levels. It is clear that there remains a medical need for safe and effective therapies for the treatment of adult patients
with SHTG, therapies that address not only TG levels but also comorbid conditions.
153
Appendix
• AH is caused by chronic heavy alcohol use or a drastic increase in alcohol consumption. It is characterized by severe inflammation and, ultimately, liver failure
and death. Currently, there is no approved treatment for AH, and few drugs are in development. The current standard of care focuses on abstinence, treating
inflammation, and providing nutrition, which is often inadequate in moderate and severe patients.
• Although Janus Kinase (“JAK”) inhibitors have been approved in the U.S. for the treatment of IBD, they have been plagued by safety concerns and three of
them, namely tofacitinib from Pfizer, upadacitinib from Abbvie, and baricitinib from Eli Lilly, have received FDA boxed warnings of risks of serious heart-related
events, cancer, blood clots and death, all of which limit the long-term use of current treatment regimens, particularly in children.
• To date, there is no NASH drug approved for commercialization in the U.S. and China. There are seven NASH drugs under Phase III clinical development
globally and 11 NASH drugs under clinical development in China.
• According to CIC, China has the largest number of T2DM patients in the world with approximately 123.2 million in 2022, and this number is expected to increase
to 141.8 million by 2032. This increase reflects a growing aging population segment as well as changing dietary and lifestyle factors. With a market size of
US$7.9 billion in 2022 in China, resulting in a low T2DM therapy penetration rate of [5]% in 2022, indicating a large market segment with high unmet medical
need, according to CIC.
• According to CIC, worldwide prevalence of NAFLD among people with T2DM is 55.5% and the prevalence of T2DM with NAFLD in China was 64.1 million in
2022. To date, there is no effective pharmacological treatments that can address T2DM and its comorbidities as a whole. Metformin, the first-line treatment for
T2DM in China, is not recommended for use in patients with certain pre-existing liver dysfunction due to safety concerns.
154
Appendix
• UDCA is the only drug which is approved in China for PBC and approximately 40% PBC patients have an inadequate response to or are unable to tolerate UDCA. Obeticholic Acid (OCA), which is
not approved in China, is the only approved medicine in the U.S. for PBC patients who have an inadequate response to or are unable to tolerate UDCA. However, there are significantly increased
pruritus rates and LDL-C levels in patients with OCA treatment, indicating unmet medical needs.
• Corticosteroids is the only recommend treatment, and the current standard of care focuses on abstinence, treating inflammation, and providing nutrition, which is often inadequate in moderate and
severe patients, indicating unmet medical needs.
• Even though the low diagnosed rate for T2DM is approximate 50% in 2022,
• NAFLD has a two-three-fold increased risk of progression to NASH and a two-fold increased risk of ultimate progression to hepatocellular carcinoma. In《 Management of Chinese adults with T2DM
and NAFLD: an expert consensus》( 《中國成人2型糖尿病合併非酒精性脂肪性肝病管理專家共識》) announced by Chinese Diabetes Society and Chinese Society of Endocrinology in 2021, it has
been pointed out that the therapeutical target in treating this patient population is to well control the progression of both T2DM and NAFLD, and to control and improve the other CVD risk factors.
Therefore, an ideal drug for T2DM and NAFLD patients should lead to comprehensive benefits with high safety. With a deeper understanding of patients’ treatment needs and disease development
mechanisms, the treatment strategy for T2DM has shifted from “glycemic control” to “glycemic control with emphasis on the prevention and treatment of complications.” In the《Technical Guidelines
for Clinical Development of Drugs for Adult T2DM》《成人 ( 2型糖尿病藥物臨床研發技術指導原則》 ) published in 2023, the CDE explicitly mentions that “the effect of the test drug on each
component of the metabolic syndromes in addition to hyperglycemia should be considered from the beginning of the project,” and recommends that body weight, blood lipids, liver transaminases, and
blood pressure be used as efficacy indicators for the development of other clinical benefits of hypoglycemic drugs. According to the mechanism of action, current oral hypoglycemic drugs can be
classified as: (1) drugs with main function to promote insulin secretion; and (2) drugs with other mechanisms to lower blood glucose. Considering the heterogeneity of diabetic patients and the
multiple metabolic abnormalities, diabetic patients always need individualized treatment regimens, combination therapy or choosing different mechanisms of glucose-lowering therapeutic drugs for
different patients.
155
Appendix
such as acute pancreatitis and CVDs. Lifestyle changes and dietary modifications are the current standard treatment for patients with SHTG. Existing
pharmacological interventions primarily include the use of fibrates, omega-3 fatty acids, statins and niacin, but these treatment options either have limited
efficacy or are associated with significant safety concerns. Furthermore, while the existing therapies for SHTG offer a benefit in treating high TGs, they offer
limited benefit in the treatment of the constellation of metabolic issues in orbit around or underlying the TG levels.
• UDCA is the only drug which is approved in China for PBC. Obeticholic Acid (OCA), which is not approved in China, is the only approved medicine as second-
line therapy in the U.S. and Europe for PBC patients who have an inadequate response to or are unable to tolerate UDCA.
• And there are significantly increased pruritus rates and LDL-C levels in patients with OCA treatment.
• Our clinical results show that HTD1801 delivers a comprehensive therapeutic effect for patients through multiple mechanisms including metabolic improvement,
liver protection, anti-inflammation and antioxidative stress.
• Even though the low diagnosed rate for T2DM is approximate 50% in 2022,
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Appendix
• NAFLD has a two-three-fold increased risk of progression to NASH and a two-fold increased risk of ultimate progression to hepatocellular carcinoma. In
《 Management of Chinese adults with T2DM and NAFLD: an expert consensus》( 《中國成人2型糖尿病合併非酒精性脂肪性肝病管理專家共識》) announced
by Chinese Diabetes Society and Chinese Society of Endocrinology in 2021, it has been pointed out that the therapeutical target in treating this patient
population is to well control the progression of both T2DM and NAFLD, and to control and improve the other CVD risk factors. Therefore, an ideal drug for T2DM
and NAFLD patients should lead to comprehensive benefits with high safety. With a deeper understanding of patients’ treatment needs and disease
development mechanisms, the treatment strategy for T2DM has shifted from “glycemic control” to “glycemic control with emphasis on the prevention and
treatment of complications.” In the《Technical Guidelines for Clinical Development of Drugs for Adult T2DM》《成人 ( 2型糖尿病藥物臨床研發技術指導原則》 )
published in 2023, the CDE explicitly mentions that “the effect of the test drug on each component of the metabolic syndromes in addition to hyperglycemia
should be considered from the beginning of the project,” and recommends that body weight, blood lipids, liver transaminases, and blood pressure be used as
efficacy indicators for the development of other clinical benefits of hypoglycemic drugs. According to the mechanism of action, current oral hypoglycemic drugs
can be classified as: (1) drugs with main function to promote insulin secretion; and (2) drugs with other mechanisms to lower blood glucose. Considering the
heterogeneity of diabetic patients and the multiple metabolic abnormalities, diabetic patients always need individualized treatment regimens, combination
therapy or choosing different mechanisms of glucose-lowering therapeutic drugs for different patients.
such as acute pancreatitis and CVDs. Lifestyle changes and dietary modifications are the current standard treatment for patients with SHTG.
157
Appendix
• Furthermore, while the existing therapies for SHTG offer a benefit in treating high TGs, they offer limited benefit in the treatment of the constellation of metabolic
issues in orbit around or underlying the TG levels.
• UDCA is the only drug which is approved in China for PBC. Obeticholic Acid (OCA), which is not approved in China, is the only approved medicine as second-
line therapy in the U.S. and Europe for PBC patients who have an inadequate response to or are unable to tolerate UDCA.
• And there are significantly increased pruritus rates and LDL-C levels in patients with OCA treatment.
• UDCA is an endogenous, secondary bile acid firstly approved by the FDA for the non-surgical treatment of cholesterol gallstones dissolution and then later for
the treatment of PBC.
• Patients with PBC have been also recently reported to have significantly different gut microbiota relative to healthy volunteers with some strains being
associated with worse outcomes.
• NASH is a multi-factorial disease, meaning that it arises from the complex interplay of multiple factors, including genetic, environmental, and lifestyle factors.
Insulin resistance, which is often associated with obesity, is a key factor in the development of NASH. Insulin resistance leads to the accumulation of fat in the
liver and increases oxidative stress, inflammation, and liver cell damage.
• The most common causes of death in patients with NASH are cardiovascular disease and end-stage liver disease. NASH is considered a significant public
health concern due to its potential to progress to advanced liver disease, including cirrhosis and liver cancer.
• NASH is a growing health issue, particularly in developed countries, due to the rising rates of obesity and metabolic syndrome.
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• While lifestyle modifications and management of underlying conditions can help slow or stop the progression of NASH, there are currently no approved
pharmacologic therapies that comprehensively ameliorate the full spectrum of NASH, from inflammation and liver cell damage to fibrosis and cirrhosis.
Therefore, there is a significant need for safe and effective pharmacologic therapies to treat NASH – specifically therapies that comprehensively ameliorate the
pathologic spectrum of NASH. Effects on cardiometabolic parameters such as lipid metabolism, glycemic control, and body weight are also important
considerations given the prevalence of such comorbidities in patients with NASH. Lastly, given the pathogenetic complexity and heterogeneity of the disease,
there is growing interest in developing therapies that target multiple pathways involved in the development and progression of NASH.
• T2DM is one of the most common metabolic disorders worldwide, which is characterized by chronic hyperglycemia resulting from insulin deficiency due to
pancreatic â-cell dysfunction and insulin resistance. It is a multifactorial disease involving multiple genes and environmental factors, both genetic and
environmental components being important determinants of insulin resistance and pancreatic â-cell dysfunction, resulting in a cycle of complex metabolic
alterations. In an excessive nutritional state, similar to that found in obesity, hyperglycemia and hyperlipidemia are often present in patients with T2DM,
favoring insulin resistance and chronic inflammation. Pancreatic â-cells are subject to toxic pressures including inflammation, inflammatory stress,
endoplasmic reticulum stress, metabolic/oxidative stress, and amyloid stress, leading to a loss of islet integrity. Chronic hyperglycemia along with the other
metabolic aberrations (i.e., dyslipidemia) in T2DM ultimately results in damage to various organ systems, leading to the development of life-threatening
complications, primarily being microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications leading to a 2-fold to 4-fold
increased risk of cardiovascular diseases. Such comorbidities of T2DM represent a major cause of death and disabilities resulting in substantial societal and
economic burdens. Cardiovascular disease is the most common cause of death among adults with T2DM.
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• The increased incidence of T2DM reflects an aging population as well as a rise in sedentary lifestyles and poor dietary choices.
• The goal in treating these patients is to halt or reverse the progression of T2DM and NAFLD thereby reducing the risk of clinical outcomes associated with
advanced disease. Therefore, an ideal therapy for patients with T2DM and NAFLD should provide comprehensive benefits across a wide variety of parameters
which encapsulate the spectrum of these diseases.
• The diagnosis of hypertriglyceridemia (“HTG”) is defined by the presence of serum triglycerides (“TGs”) greater than 150 mg/dL with SHTG being defined by
TGs greater than or equal to 500 mg/dL. Nearly all patients with SHTG have a genetic predisposition plus an additional condition or factor known to raise
serum TGs (e.g., diabetes mellitus, alcohol abuse, or oral estrogen therapy). There have been multiple reports describing the associations of obesity,
metabolic syndrome, insulin resistance, and T2DM with HTG/SHTG. The higher the TG levels, the higher the risk of acute pancreatitis, a potentially life-
threatening complication of SHTG. It has been reported that up to 10% of all cases of acute pancreatitis are related to HTG/SHTG. Furthermore, TG levels
have been shown to be significantly associated with risk of coronary heart disease.
• Furthermore, while the existing therapies for SHTG offer a benefit in treating high TGs, they offer limited benefit in the treatment of the constellation of
metabolic issues in orbit around or underlying the TG levels (e.g., T2DM, NAFLD/NASH, obesity). For example, fenofibrate and gemfibrozil may result in
elevated LDL-c and are contraindicated for subjects with active liver disease (e.g., NAFLD/NASH). Based on these findings, there still remains a medical need
for safe and effective therapies for the treatment of adult patients with SHTG - therapies that address not only TG levels but also comorbid conditions.
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• In summary, while progress has been made in the management of metabolic and digestive diseases, there are still unmet needs that need to be addressed to
improve patient outcomes. Metabolic and digestive diseases are complex and heterogeneous, with significant variability in disease presentation, progression,
and response to treatment. Hence, there is a need for multi-targeted therapies that can address the underlying mechanisms of these diseases and provide
more effective and safer treatment options. Even in crowded market segments, HTD1801 and other pipeline candidates have the potential to become market
leaders in that they have been purposefully designed to address the shortcomings of existing therapies.
• AH is a type of alcohol-associated liver disease (“ALD”) characterized by acute liver inflammation. A variety of genetic, lifestyle and environmental factors may
contribute to AH, including alcohol consumption, obesity and ethnicity. Severe cases of AH can lead to the progression of liver fibrosis and cirrhosis, even a
high risk of death. Toll-like receptor 4 (“TLR4”) is an activator of some proinflammatory cytokines that play an important role in mediating the innate immune
response during the progress of AH.
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Appendix for verification
• HTD1801 is the first primary sclerosing cholangitis (“PSC”) drug that has obtained Fast Track Designation from the FDA, followed by an Orphan Drug Designation in the U.S., according to CIC.
• The regulatory approval processes of the NMPA, FDA, EMA, TGA, Health Canada and other comparable regulatory authorities are time-consuming and may evolve over time
• The time required to obtain the approval of the NMPA, FDA, EMA, TGA, Health Canada and other comparable regulatory authorities is inherently uncertain and depends on numerous factors, including the substantial
discretion of the regulatory authorities. Generally, such approvals take years to obtain following the commencement of pre-clinical studies and clinical trials. In addition, approval policies, regulations or the type and
amount of clinical data necessary to gain approval may change during the course of a drug candidate’s clinical development and may vary among jurisdictions.
• We, our CROs for our clinical programs and our clinical investigators are required to comply with GCPs, which are regulations and guidelines enforced by the NMPA, FDA, EMA, TGA, Health Canada and other
comparable regulatory authorities for all of our drugs in clinical development. If we or any of our CROs or clinical investigators fail to comply with the applicable GCP, the clinical data generated in our clinical trials may
be deemed unreliable and the NMPA, FDA, EMA, TGA, Health Canada or other comparable regulatory authorities may require us to perform additional clinical trials before approving our marketing applications.
• Once our drug candidates are approved, they will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling, record-keeping, post-marketing studies,
and submission of safety, efficacy, and other post-market information in China, the U.S., Europe, Canada, Australia, Mexico and other potential jurisdictions. For example, in order to produce drugs for sales, we may
become subject to extensive laws and regulations enforced by the NMPA, FDA, EMA, TGA, Health Canada and other applicable regulatory authorities, including those ensuring that quality control and manufacturing
procedures conform to current GMP regulations. Moreover, any new legislation addressing drug safety issues could result in increased costs to ensure compliance with ongoing regulatory requirements.
• The NMPA, FDA, EMA, TGA, Health Canada or other applicable regulatory authorities may withdraw its approval if compliance with regulatory requirements and standards is not maintained or if problems occur after
the drugs reach the market.
• Investment in pharmaceutical or biotechnology companies is highly speculative.
• [CIC has confirmed that it is a market practice in the biotechnology pharmaceutical industry for similar cooperation agreement to be entered into for a long term or for an indefinite term, primarily due to the substantial
amount of capital committed by the collaboration partners and the risks involved.]
• [CIC has confirmed that the Commercialization Agreement entered into by the Company and Shenzhen Hepalink is in line with the industry practice.]
• it is impractical and difficult for the Company to set a term of not exceeding three years in respect of the Commercialization Agreement, as the Licensed Products have a product life cycle of more than three years from its
development stage to commercialization;.
•
• [as confirmed by CIC, it is common in the biotechnology pharmaceutical industry where similar long-term licensing arrangement or licensing arrangement with an indefinite-term are adopted]
• the amount of the royalty payment to be paid by Shenzhen Hepalink annually pursuant to the Commercialization Agreement as the revenue to be derived from the sale of Licensed Products depends on the actual
addressable market of the Licensed Products, which will in turn depend on various factors including [the acceptance by the medical community and patient access, drug pricing, reimbursement and the number of
affordable patients]
• HTD4010 is a toll-like receptor 4 (“TLR4”) inhibitor potentially capable of dampening the innate immune response and the resulting liver inflammation, a major contributor to AH pathogenesis.
• Our end-to-end FUSIONTXTM platform encompasses the entire drug development value chain and propels our drug candidates from bench to bedside. Through our FUSIONTXTM, a multicomponent drug discovery and
development platform, we strive to use real world data to map the network biology of the diseases, screen known molecules with desired therapeutic benefits and design novel, multifunctional drug candidates with
synergistic effects across multiple organs. We believe that drug discovery and design through FUSIONTXTM enables systematic, precise and efficient early-stage drug development that potentially facilitates a higher rate
of clinical success at an accelerated pace and reducing development risks, thereby enabling the sustained expansion of our pipeline.
• Global leader in developing novel multifunctional, multi-target therapeutics for metabolic and digestive diseases with significant worldwide health burden
• We are a world leader in the development of novel, multifunctional and multi-target therapeutics for metabolic and digestive diseases to address this unmet global medical need. We design our molecular entities to be
multifunctional, combining compounds with known therapeutic activity in our target indications to create new drug candidates with potentially novel therapeutic effects to address the shared, multi-factored causes
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• of many related diseases. For example, our Core Product, HTD1801, is created by combining the compounds BRR and UDCA into a novel molecular entity. As BRR and UDCA are known for their ability to improve
glycemic control and provide liver protection, respectively, the synergistic effect of this combination allows HTD1801 to potentially target the various pathways underlying multiple metabolic and digestive diseases. Our
focus on addressing the common underlying causes of disease allows us to develop “pipeline-in-a-product” drug candidates such as HTD1801 that have the potential to treat multiple metabolic and digestive diseases such
as NASH, T2DM, PSC and SHTG. Our preclinical and clinical studies have validated our drug discovery and design approach, demonstrating that we can safely achieve therapeutic synergies and better address disease
complexity, with the potential to treat a broad range of metabolic and digestive diseases and their comorbidities.
• We design and develop multifunctional, multi-target compounds via our proprietary FUSIONTXTM drug discovery and development platform. The FUSIONTXTM platform distills our unique insight and extensive drug
discovery and development expertise into a systematic and [well-validated] drug design process. It uses real-world data to understand disease biology, screen known molecules and design novel multifunctional drug
candidates to improve treatment outcomes. The FUSIONTXTM platform has been instrumental in building our world-leading pipeline of novel therapeutics for metabolic and digestive diseases. Our Core Product,
HTD1801, results from the successful application of our FUSIONTXTM platform. In addition, HTD1801 is the first PSC drug candidate to receive a FTD from the FDA, demonstrating regulatory validation of our
approach.
• HTD1801, a first-in-class new molecular entity with the potential to become a blockbuster backbone therapy for NASH, T2DM, SHTG and other metabolic and digestive diseases
• Our Core Product HTD1801 is a multifunctional, multi-target new molecular entity that we believe has the potential to be a backbone therapy for multiple metabolic and digestive diseases. In our clinical trials, HTD1801
has demonstrated superior safety and clinical efficacy in NASH, T2DM, SHTG, PSC and PBC, representing a “pipeline-in-a product” profile. We are expeditiously advancing HTD1801 through global registrational
clinical trials to make it available as quickly as possible for patients suffering from these unmet medical needs worldwide.
• The unique design of HTD1801 covalently combines two molecular components that have a long history of safe therapeutic use in humans, namely BBR and UDCA. Compared to treatments with BBR or UDCA as single
agents or treatment with an equimolar physical mixture of BBR and UDCA as combination therapy, the unique physio-cochemical properties of our covalently bonded HTD1801 enhances drug solubility and lipophilicity,
which we believe have led to the superior efficacy and therapeutic synergy demonstrated in its clinical trials for metabolic and digestive diseases. Additionally, the covalent nature of HTD1801 synchronizes the
dissolution profiles of its two components, [resulting in synchronized bioavailability of BBR andUDCA] which further enhance their synergistic effects.
• For NASH, our most advanced indication for HTD1801. The chart below demonstrated HTD1801’s advantage over its peers for the NASH indication based on [publicly available data which are non-head-to-head studies].
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• For T2DM, HTD1801 has the potential to become a recommended therapy for patients who also suffer from metabolic comorbidities such as nonalcoholic fatty liver disease (“NAFLD”) and dyslipidemia, etc
• This strong clinical evidence supports the therapeutic potential of HTD1801 in SHTG. We plan to initiate a global Phase II clinical trial of HTD1801 for SHTG in [the United States] in 2023.
• For PSC, HTD1801 provides a unique and comprehensive treatment coverage of the gut-liver-biliary system, acting through multiple mechanisms of action to address the diverse involvement of PSC in these organ
systems
• Robust pipeline of new molecular entities developed from our FUSIONTXTM platform, each with significant commercial potential and a therapeutic profile to address unmet needs in metabolic and digestive diseases
• We believe that we have built an industry-leading pipeline of multifunctional, multi-target therapeutics to address the unmet needs in metabolic and digestive diseases. Leveraging our proprietary FUSIONTXTM
platform, we have identified multiple pathways that are dysregulated in metabolic and digestive diseases and selected and combined known compounds to modulate these pathways for synergistic therapeutic benefits.
• [We conduct extensive disease pathogenic analysis using real-world data to map the network biology of diseases, screen known molecules with desired therapeutic benefits and design novel, multifunctional, multi-
target new molecular entities to achieve synergistic effects and reduce the burden of metabolic and digestive diseases across multiple organ systems. Our proprietary FUSIONTXTM platform enables systematic, precise
and efficient early-stage drug discovery and development. We believe that FUSIONTXTM will facilitate a higher rate of clinical success at an accelerated pace as compared to industry benchmarks. Our technology is
well recognized by the international scientific community and has been presented at internationally renowned academic conferences. For instance, our abstract was selected for inclusion in the “Best of The Liver
Meeting 2021” program created by the American Association for the Study of Liver Diseases Scientific Program Committee to highlight key oral and poster presentations. As a result, we believe our pipeline of new
molecular entities for metabolic and digestive diseases offers the highest potential for therapeutic paradigm shift and clinical success, as well as unparalleled value.
• Similar to our approach with HTD1801, the other assets in our pipeline are based on compounds that have a long history of safe therapeutic use in humans and modulate multiple pathways to address the complex
nature of metabolic and digestive diseases. We believe that we are uniquely positioned globally with a broad and balanced pipeline of best-in-class and first-in-class therapies for metabolic and digestive diseases.
• Differentiated approach to drug discovery focusing on known compounds (including naturally-derived compounds) that have a long history of therapeutic use in humans, which provide insights into the compounds’
efficacy, safety and tolerability
• Our pipeline is comprised of new molecular entities based on compounds that have a long history of therapeutic use in humans, which provide insights into the compounds’ efficacy, safety and tolerability. In some
cases, the naturally derived compounds have been used medicinally for hundreds of years and are known to modulate multiple pathways to produce a therapeutic effect. For example, the compound artemisinin, also
known as qinhaosu (青蒿素), is distilled from the dried leaves or flower clusters of the sweet wormwood plant. Artemisinin is a widely used drug for the treatment of malaria, which has demonstrated various
therapeutic benefits and anti-fibrotic effects. Another example of this approach is flavonoid phlorizin. Derived from apple bark and having a history of use in Africa as alternative medicine for treating diabetes,
flavonoid phlorizin was used as the lead structure in the design of canagliflozin, dapagliflozin and empagliflozin, a class of FDA-approved compounds for treating diabetes based on its distinct mechanism of action that
not only reduces patient blood sugar levels but also provides comprehensive cardio- and reno-protective effects. Similarly, the saliva of the Gila monster was the source of the first marketed GLP-1 analogue, exenatide.
GLP-1 analogues have been used to treat diabetes and more recently have shown significant efficacy in treating obesity.
• By starting with these therapeutically validated compounds with known safety profiles as building blocks, we believe that the new molecular entities we design have a higher probability of being pharmacologically
active and tolerable versus drug candidates identified through other discovery approaches. These approaches often involve the identification of a single disease-relevant target and the discovery of novel chemical entity
with no history of human consumption against that target. We believe that such approaches have contributed in part to the high failure rate in drug development, particularly due to undesirable safety and tolerability and
insufficient efficacy demonstrated by these drug candidates once they enter human clinical trials.
• Significant commercial opportunity in metabolic and digestive diseases for HTD1801 and our pipeline of other highly differentiated therapeutic candidates
• The increasing industry focus on metabolic and digestive diseases has facilitated increasing investment in our R&D. According to CIC, there exists significant commercial opportunities in NASH, T2DM, SHTG, PSC
and PBC markets, and demographic trends support continued market growth. With our innovative pipeline, proprietary FUSIONTXTM platform and differentiated drug discovery approach, we believe we are best
positioned to address the [most prevalent] indications with significant unmet medical needs.
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• Given the disease’s pathogenetic complexity and heterogeneity, the treatment of NASH is trending toward a multifunctional therapeutic approach.
• According to CIC, China has the [largest] number of T2DM patients in the world.
• We have consistently been able to attract industry-leading experts and renowned key opinion leaders (“KOLs”) to participate in our drug discovery and development projects, which speaks to the solid foundation of our
research and development process and reflects the cutting-edge nature and clinical potential of our drug candidates.
• In addition to the world-renowned KOLs, we are also a leader in global drug development with deep expertise in navigating the drug approval process. Our exceptional regulatory capabilities are demonstrated by the
successful application for FDA FTD for our HTD1801, the first for a PSC drug candidate. This achievement was the result of our strategic communications with the FDA, supported by compelling evidence demonstrating
the potential of HTD1801 to address a significant unmet clinical need.
• Our multi-jurisdictional regulatory expertise is particularly strong in our key markets of China, the United States and Europe. We have used this expertise to strategically inform our drug development plan, making
strategic decisions regarding the direction of our drug development focus to take full advantage of the local regulatory environment. For example, we have focused on developing HTD1801 for T2DM in China while
focused on NASH indication globally to leverage the efficient regulatory approval pathway to accelerate IND applications and early-phase clinical trials in the United States and to advance clinical trials in the indications
with significant unmet medical needs from the large patient population in China. We design trials to allow clinical data from each regional trial to be used for pooled analysis and for use in supporting registrations in
China, the United States and Europe. In addition, clinical data from multi-regional clinical trials will enable future indication expansion for the drug investigated. We keep in-house the core clinical development functions
such as clinical trial design, planning and management while utilizing CROs for clinical trial execution.
• World class R&D capabilities bolstered by visionary management team with deep expertise in metabolic and digestive diseases
• Our world-class R&D team has strong expertise, deep understanding and broad experience in digestive, liver and metabolic diseases, as well as a broad understanding of their [comorbidities]. Our R&D team pioneered
the identification of synergistic effects by modulating multiple pathways in chronic diseases, giving us a unique advantage addressing the unmet clinical needs of complex disease.
• Our management team is led by our founder and CEO, Dr. Liping Liu, a pioneer in the field of metabolic and digestive diseases
• We will leverage our global leadership in designing innovative drug candidates based on compounds, including naturally-derived compounds, with known safety history of therapeutic use in humans to continue
developing pipeline assets treating complex metabolic and digestive diseases. We will continue to optimize and enhance our FUSIONTXTM platform. We will upgrade and optimize our discovery, design and development
of potential drug candidates to maximize the potential of our novel platform.
• We will keep building on our deep experience in R&D and strict adherence to clinical and manufacturing protocols ensure efficacy, safety and commercial viability of our innovative drug candidates. In particular, we will
strictly follow the clinical protocols of randomized, double-blind, placebo-controlled trials, maintain high standards in manufacturing consistency and quality control, as well as establish solid composition of matter patent
protection in major jurisdictions. To date, we have obtained crystal structure and crystalline form patents to improve our IP protection.
• HTD1801 is a novel salt formed from two active moieties, BBR and UDCA. The two active moieties work in tandem in the salt form with unique microstructure to produce distinct and improved properties of HTD1801.
HTD1801 has significantly different physico-chemical characteristics compared to each of the BBR and UDCA active moieties or their physical mixture, including distinct X- ray powder diffraction, melting point,
infrared spectrum, solubility or dissolution and LogD. Further, HTD1801 exhibits improved pharmacokinetic (“PK”), efficacy and safety profiles, which is believed to owe to the unique interaction of BBR:UDCA in the
ionized salt form. Those improved properties are not observed with either of the individual active moieties or their physical mixture. Given the unique attributes of the HTD1801, the FDA has recognized the differentiated
therapeutic potential of our new molecular entity HTD1801 and confirmed that HTD1801 is distinct from its individual constituent components or their physical mixture.
• blockbuster backbone therapy capable of simultaneously lowering blood glucose, protecting the liver and reducing the risks of CVDs. The indications for HTD1801 span NASH, T2DM, SHTG [HTG?], PSC and PBC,
with a focus on comorbidities and a potential for indication expansion. In China, we received government support from “Major National Science and Technology Projects for New Drug Development” under the "National
13th Five-Year Plan", further accelerating the speed of domestic market approval for HTD1801. In the United States, we have received from FDA a FTD for HTD1801 for the NASH and PSC indications, as well as an
ODD for the PSC indication. According to CIC, HTD1801 is the first PSC drug candidate to receive a FTD from the FDA. The FTD designation is based on available clinical and non-clinical data that demonstrate the
potential to address an unmet medical need and is intended to facilitate an expedited regulatory review process.
• We have an integrated global operation with established R&D centers in Mainland China, Hong Kong, the United States and Australia. Our global presence is evidenced by our multi-center clinical trials with sites in the
United States, Canada, Australia and China, together with other regions in the plan, which requires global experience and knowledge. With our accumulated extensive successful experience in building a broad pipeline of
innovative therapies for metabolic and digestive diseases, we expect to provide the market with a steady roll-out of competitive products that aim to address unmet clinical needs.
• Leveraging our disruptive FUSIONTXTM development approach, we design our molecular entities to be multifunctional, synergizing compounds. Our FUSIONTX TM approach focuses on known drug candidates to reduce
R&D costs and ensure safety profile, while invigorating them with potentially novel therapeutic effects to address the shared, multi-factored causes of many related diseases.
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• By starting with therapeutically validated compounds with known safety profiles as building blocks, we believe the new molecular entities we design are more probable of being pharmacologically active and tolerable.
This also reduces R&D costs as compared to starting with drug candidates before proof-of-concept. Our pipeline is comprised of new molecular entities based on established compounds that have a long history of
therapeutic use in humans, which provide insights into the compounds’ efficacy, safety and tolerability. We also focus on utilizing naturally derived compounds which have been used medicinally for hundreds of years and
are known to modulate multiple pathways to produce a therapeutic effect. For example, artemisinin, also known as qinhaosu (青蒿素), is distilled from plants and has demonstrated various therapeutic benefits and anti-
fibrotic effects. Our Core Product HTD1801 contains two active moieties derived from natural ingredients, BBR and UDCA, both with an established efficacy and long-term safety profiles in humans.
• Creating novel drug candidates with FUSIONTXTM approach. Innovation is in our DNA and the R&D of novel effective therapies is the foundation of our success. Our FUSIONTXTM approach combines the available data
from historical therapeutic use and scientific research with our deep understanding of metabolic and digestive diseases to select the optimal combination of known and naturally derived compounds. Leveraging our
extensive disease pathogenic analysis with real-world data and R&D capabilities, we then explore, construct and optimize chemical structure and efficacy or safety profiles of drug candidates to create multifunctional,
multi-target new molecular entities to achieve synergistic effects across multiple organ systems. Our FUSIONTXTM development approach enables systematic, precise and efficient early-stage drug discovery and
development. We believe that FUSIONTXTM will facilitate a higher rate of clinical success at an accelerated pace as compared to industry benchmarks. In contrast, approaches adopted by our peers often involve the
identification of a single disease-relevant target and the discovery of novel chemical entity with no history of human consumption against that target. We believe that those approaches have contributed in part to the high
failure rate in drug development, particularly due to undesirable safety and tolerability and insufficient efficacy demonstrated by these drug candidates once they enter human clinical trials.
• Focusing on significant unmet medical needs. Metabolic and digestive diseases are prime areas where our FUSIONTXTM approach could make a significant impact, due to their complex and inter-related nature. Given
their high prevalence, there is also significant unmet medical need.
• By treating the patients with a holistic view, we believe we are uniquely positioned to capture the market opportunities with drug candidates developed under our FUSIONTXTM approach.
• Our preclinical and clinical studies have validated our FUSIONTXTM approach, demonstrating that we can safely achieve therapeutic synergies and better address disease complexity, with the potential to treat a broad
range of metabolic and digestive diseases and their comorbidities. Our focus on addressing the common and multiple underlying causes of disease via the FUSIONTXTM approach has led to the discovery and development
of “pipeline-in-a-product” drug candidates such as HTD1801, which has already shown potential in treating NASH, T2DM, SHTG, PSC and PBC in clinical trials. As an ionic salt formed from BBR and UDCA with an
innovative structure, HTD1801 represents a novel molecular entity that offers the benefits of treating chronic metabolic and non-viral liver diseases in a single treatment, yielding more comprehensive therapeutic benefit
in patients across multiple indications. HTD1801 has received FTD from the FDA for both NASH and PSC, demonstrating regulatory validation of our approach.
• HTD1801, a “pipeline-in-a product”, first-in-class new molecular entity with the potential to become a blockbuster backbone therapy for NASH, T2DM and other metabolic and digestive diseases
• Our Core Product HTD1801 is a multifunctional new molecular entity that we believe has the potential to be a backbone therapy for multiple metabolic and digestive diseases based on its safety and efficacy profile as
well as ease of administration.
• 1+1 >2. HTD1801 is a novel salt formed from two active moieties, BBR and UDCA. The two active moieties work in tandem in the salt form with unique microstructure to produce distinct and improved properties of
HTD1801. HTD1801 has significantly different physico-chemical characteristics compared to each of the BBR and UDCA active moieties or their physical mixture, including distinct X- ray powder diffraction, melting
point, infrared spectrum, solubility or dissolution and LogD. Further, HTD1801 exhibits improved PK, efficacy and safety profiles, which is believed to owe to the unique interaction of BBR:UDCA in the ionized salt
form. Those improved properties are not observed with either of the individual active moieties or their physical mixture. Given these unique attributes of HTD1801, the FDA has recognized that HTD1801 as distinctive
from its individual constituent components or their physical mixture with therapeutic potential.
• Pipeline-in-a-product. In our clinical trials, HTD1801 has demonstrated a good safety profile and strong efficacy across NASH, T2DM, SHTG, PSC and PBC, demonstrating a “pipeline-in-a product” profile. Offering
multiple clinical benefits to patients, HTD1801 is the [only single] drug being developed with efficacy in NASH and T2DM, while also providing cardiovascular protection.
• MRI-PDFF is commonly used to assess treatment response in early-phase, proof-of-concept clinical studies in NASH and has been shown to be closely correlated with liver steatosis grades from histology.
• HTD1801 has the potential to become a blockbuster backbone therapy for T2DM patients who also suffer from metabolic comorbidities such as NAFLD and dyslipidemia.
• The chart below demonstrated HTD1801’s advantage over its peers for T2DM and NASH indication based on publicly available data which are non-head-to-head studies.
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For PSC, HTD1801 provides a unique and comprehensive treatment of the gut-liver-biliary system, acting through multiple mechanisms to address the complex pathogenesis of PSC, including a choleretic effect achieved by
displacing toxic bile acids from the bile acid pool and a variety of anti-inflammatory effects.
In the United States, HTD1801 has received a FTD designation by the FDA for NASH and a FTD designation for PSC, the first for a PSC drug candidate.
Our HTD4010 is a Phase I clinical-stage, first-in-class polypeptide drug for the treatment of complex, life-threatening diseases such as AH,
The increasing industry focus on metabolic and digestive diseases has driven our increasing investment in R&D. According to CIC, there exists significant commercial opportunities in NASH, T2DM, SHTG, PSC and PBC
markets, and demographic trends support continued market growth. With our innovative pipeline and disruptive FUSIONTXTM development approach, we believe we are best positioned to address metabolic and digestive
diseases with significant unmet medical needs, representing a huge global market size of US$323 billion in 2022.
We have consistently been able to attract industry-leading experts and renowned KOLs to participate in our drug discovery and development projects, which speaks to the solid foundation of our research and development
process and reflects the cutting-edge nature and clinical potential of our drug candidates. In addition to the world-renowned KOLs, we are also a leader in global drug development with deep expertise in navigating the drug
approval process. Unlike most companies conducting clinical trials in China, we were one of the first companies to initiate multi-regional clinical trials in the United States as our first clinical trial site. Our multi-jurisdictional
regulatory expertise is particularly strong in our key markets of China, the United States and Europe. We have used this expertise to strategically inform our drug development plan, making strategic decisions regarding the
direction of our drug development focus to take full advantage of the local regulatory environment.
We believe our ability to successfully develop drug candidates is the primary factor affecting our long-term competitiveness, as well as our future growth and development. Developing high quality drug candidates requires
significant investments of financial resources over a prolonged period of time, and our core strategy is to continue making sustained investments in this area. As a result of this commitment, our pipeline of pre-clinical- and
clinical-stage drug candidates has been steadily advancing and expanding.
These moieties work in tandem in the salt form to produce, through their interaction, distinct and improved properties of HTD1801 that are not observed with either of the individual active moieties. A substantial portion of
the beneficial effect of the novel HTD1801 salt appears to be derived from the interaction of its BBR and UDCA moieties conferring improved physicochemical properties, solubility, and pharmacokinetic (PK) properties.
BBR is an isoquinoline alkaloid with a long history of use for its wide-ranging biological effects, particularly antimicrobial effects, in Chinese, Indian and Japanese medicine and is an approved drug for the treatment of
intestinal infection in mainland China, Japan and Taiwan, according to CIC. BBR is also known to improve glycemic control and commonly used as an over-the-counter remedy for diabetes and pre-diabetes. In the U.S. and
Canada, BBR is also used in various dietary supplements for different indications, including glycemic and cholesterol control.
UDCA is a secondary bile acid approved by the FDA for the treatment of primary biliary cholangitis (PBC) and the dissolution of cholesterol gallstones. Clinical practice demonstrated that UDCA (15-20 mg/day) improves
serum liver tests and certain surrogate markers of the disease’s prognosis. According to CIC, UDCA is known for its beneficial effects on the liver by displacing toxic bile acids and protecting against apoptosis, through wide-
ranging immunomodulatory, anti-inflammatory, anti-fibrotic and antimicrobial actions. UDCA’s efficacy in other liver diseases have also been extensively studied in nonclinical and clinical studies, both as a single agent and
in combination therapy with agents such as vitamin E and lipid-lowering fibrate drugs.
Non-alcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM)
HTD1801 is effective in NASH through multiple pathways, which address the core aspects of the disease including induction of the insulin receptor, activation of adenosine monophosphate (AMP) kinase, and induction of the
low-density lipoprotein (LDL) receptor. The BBR moiety induces the insulin receptor to improve insulin resistance, and also induces AMP kinase, thereby leading to stimulation of hepatic fatty acid oxidation, fatty acid
oxidation and glucose uptake by skeletal muscle as well as inhibition of cholesterol and triglyceride synthesis and de novo lipogenesis. Finally, the BBR moiety induces the LDL receptor to lower circulating levels of LDL
cholesterol (LDL-C). BBR thus acts systemically but is also known to act locally within the gastrointestinal tract via modulation of the microbiome. However, when administered as an individual moiety, BBR is very poorly
soluble with low bioavailability. Potential contributions of UDCA include anti-apoptotic effects, lowering serum tumor necrosis factor α concentrations, decreasing endoplasmic reticulum stress, and improving hepatic insulin
sensitivity. The UDCA moiety of HTD1801 is thought to act systemically but its conjugates or metabolites may have a local gastrointestinal tract effect. Based on a review of the literature, UDCA appears to have only modest
effects in NASH, and best effects are observed at high doses (UDCA doses of 28-30 mg/kg of body weight), hence resulting in little clinical value. The beneficial effect of HTD1801 in NASH is due to its crystalline structure,
improved physicochemical properties as well as the enhanced bioavailability of BBR, improving both the hepatic and metabolic features of NASH.
The rationale for the use of HTD1801 for the treatment of T2DM is consistent with that for the treatment of NASH, including induction of the insulin receptor, activation of AMP kinase, and induction of the LDL receptor.
Specific to improved glucose metabolism, activation of the AMP kinase pathway by BBR inhibits gluconeogenesis, and increases insulin sensitivity. Moreover, results from published studies indicate that BBR promotes
glycolysis, and inhibits the intestinal absorption of carbohydrates in the diet. Nonclinical and clinical data show that UDCA can ameliorate insulin resistance and promote insulin secretion. UDCA also exhibits clear anti-
inflammatory and anti-oxidative stress effects and protects hepatocytes.
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Primary Sclerosing Cholangitis (PSC) and PBC

HTD1801 is thought to be effective in PSC through multiple mechanisms of action. The mechanisms of action of UDCA have been well studied in a variety of cholestatic liver diseases, including PBC and PSC. Some of the
key actions of UDCA include its choleretic effect (a cytoprotective effect probably achieved by displacing toxic bile acids from the bile acid pool) and a variety of anti-inflammatory effects. In addition, UDCA has been
shown to mediate some positive changes in the gut microbiome, an important contributor to the pathogenesis of PSC. BBR is thought to act both locally within the gastrointestinal tract and biliary tree but also systemically.
BBR has antimicrobial activity against a wide variety of microbes, including bacteria and yeast. In particular, BBR has activity against Klebsiella pneumoniae, a bacterium thought to be a pathobiont that is causally associated
with development of PSC. BBR also has beneficial effects on the gut microbiome. BBR is excreted in part unchanged in bile, which may be beneficial in PSC, as bacteria and yeast are often found in the bile of patients with
PSC, even when they do not have clinical evidence of ascending cholangitis. BBR has significant anti-inflammatory activity as well as anti-fibrotic actions that are relevant mostly within the liver, where BBR has been shown
to be concentrated. Plant-derived BBR has been shown to have beneficial effects in lowering alkaline phosphatase (ALP) in patients with treatment-refractory PSC and PBC, and BBR has been shown to attenuate cholestatic
liver and bile duct injury in multidrug resistance knockout mice, which is an animal model of cholestasis.
The addition of BBR to UDCA, as a salt, in the form of HTD1801 has potential to provide benefit to patients with PBC. Patients with PBC have been recently reported to have significantly different gut microbiota relative to
healthy volunteers with some strains being associated with worse outcomes. While UDCA alone has been observed to improve the microbiome of patients with PBC, they may further benefit from the reported anti-microbial
properties of BBR in improving the gut microbiome. Plant-derived BBR has been shown to have beneficial effects in lowering ALP in patients with treatment-refractory PSC and PBC and BBR has been shown to attenuate
cholestatic liver and bile duct injury in multidrug resistance knockout mice, which is an animal model of cholestasis.
Severe hypertriglyceridemia (SHTG)
The rationale for use of HTD1801 for the treatment of severe hypertriglyceridemia is consistent with its use in NASH and T2DM. HTD1801 is effective in SHTG via activation of AMP kinase, and by improving systemic
insulin resistance. Induction of the LDL receptor positively regulates lipoprotein metabolism. In addition, BBR via HTD1801 may reduce the degradation of the LDL receptor. The LDL-receptor facilitates the cellular uptake
of apolipoprotein B/apolipoprotein E carrying particles by receptor mediated endocytosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), binds to the LDL-receptor on the cell surface and facilitates its degradation as
well as prior to the LDL-receptor reaching the cell surface during synthesis. BBR results in inhibition of PCSK9 transcription via the hepatocyte nuclear factor 1 binding site. Furthermore, there have been examples of BBR
treatment resulting in an increase in LDL receptor mRNA and protein. The combination of reducing the degradation of the LDL receptor along with the induction of LDL receptor expression would be expected to increase the
clearance of proteins that bind the LDL receptor, resulting in a reduction in triglycerides. Other effects on cardiometabolic parameters such as glycemic control and body weight are important considerations, given the
prevalence of such comorbidities in patients with SHTG.
NASH is characterized by ballooning degeneration and lobular inflammation with or without perisinusoidal fibrosis, in addition to steatosis in the liver. Patients with NASH can progress to cirrhosis and are at increased risk of
death resulting from liver disease.
As there is no approved drug for NASH treatment, for patients within late-stage NASH, the disease is almost irreversible. In both the U.S. and China, treatment of NASH can be divided into behavior intervention, drug
intervention and surgical intervention. The treatment of NASH is currently limited to lifestyle change and specific treatment of comorbidities, and no evidence-based pharmacological therapy is approved. The NASH
treatment is moving forwards multi-mechanistic strategy of combination therapy, given the complexity in pathophysiology and heterogeneity nature of the disease.
T2DM is one of the most common metabolic disorders worldwide, and is closely linked to the epidemic of obesity.
PSC is a rare, chronic cholestatic liver disease characterized by intrahepatic and/or extrahepatic bile duct injury. Inflammation and fibrosis of the bile ducts lead to structuring, impaired bile flow, and progressive liver
dysfunction.
There is no approved therapy for PSC globally. PSC was identified as one of the largest unmet clinical needs in the treatment of liver disease by EASL. PSC also has a high incidence of liver-related morbidity and mortality.
PBC is an autoimmune disease attributable to multiple genetic, lifestyle and environmental factors. PBC is characterized by damage to and destruction of the intra-hepatic biliary epithelial cells, which then lead to the
accumulation of bile acids, generation of oxidative stress and increased inflammation, typically followed by liver fibrosis and cirrhosis.
As the first-line agent approved for the treatment of PBC, UDCA’s safety and effectiveness in treating PBC patients are well established. However, up to 40% of PBC patients do not achieve an adequate response to UDCA,
leaving significantly unmet medical needs for alternative treatments. OCA was approved in 2016 for use in combination with UDCA as a second-line treatment for PBC. However, since its approval, serious adverse events
(“SAEs”) such as hepatic decompensation and failure, which were fatal in some cases, have been reported among OCA users. In addition, other side effects such as LDL-C elevation and pruritus have been observed. These
SAEs have resulted in an FDA black-box warning issued to OCA in [2018].
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Hypercholesterolemia has become a serious global public health issue. The number of patients with hypercholesterolemia has increased rapidly in recent years due to an increasingly Westernized diet and lifestyle and an aging
population.
We believe that HTD1801 has a multifunctional pharmacological profile that reflects both separate and synergistic effects compared to the combination of BBR and UDCA or their simple physical mixtures in the following
aspects:Inter-molecular Synergies of BBR and UDCA
A substantial portion of HTD1801’s beneficial effects and the resulting synergistic physio-chemical properties appear to be derived from the interaction of the BBR and UDCA moieties, which is facilitated by the novel
crystalline structure of the ionic salt. Importantly, these properties cannot be replicated with the administration of the individual BBR and UDCA compounds, separately or combined. The X-ray powder diffraction results
demonstrate that HTD1801 has a clearly different crystalline structure compared with BBR-Cl and UDCA, as shown below.
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Hypercholesterolemia has become a serious global public health issue. The number of patients with hypercholesterolemia has increased rapidly in recent years due to an increasingly Westernized diet and lifestyle and an aging
population.
We believe that HTD1801 has a multifunctional pharmacological profile that reflects both separate and synergistic effects compared to the combination of BBR and UDCA or their simple physical mixtures in the following
aspects:Inter-molecular Synergies of BBR and UDCA
A substantial portion of HTD1801’s beneficial effects and the resulting synergistic physio-chemical properties appear to be derived from the interaction of the BBR and UDCA moieties, which is facilitated by the novel
crystalline structure of the ionic salt. Importantly, these properties cannot be replicated with the administration of the individual BBR and UDCA compounds, separately or combined. The X-ray powder diffraction results
demonstrate that HTD1801 has a clearly different crystalline structure compared with BBR-Cl and UDCA, as shown below.
The figure below illustrates HTD1801’s distinctive crystal structure, which underlies the novel salt’s multi-functional pharmacological profile. Adjacent UDCA anions and H2O molecules form the 3-D supramolecular
framework structure with 1-D linear channels (left panel) while the BBR cations are stacked orderly in the channels (right panel). HTD1801’s unique molecular structure can potentially translate into better efficacy with
reduced safety concerns.
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Better Characteristics of HTD1801

HTD1801 is molecular entity with the new structure formed by BBR and UDCA in a 1:1 molar ratio. Compared with BBR alone, UDCA alone and a physical mixture of BBR and UDCA in a 1:1 ratio (“PM”), and HTD1801
shows different characteristics and advantages in terms of PK profile and physicochemical properties.
With the new structure, HTD1801 demonstrates lower melting point and much improved solubility and lipophilicity compared with the poor solubility of BBR and UDCA, suggesting better oral availability of HTD1801 after
administration. In our pre-clinical studies, HTD1801 significantly enhances the bioavailability of BBR, which is recognized for its low blood concentration and poor solubility in the body when administered alone. Exposure
of BBR administered in the form of HTD1801 is increased by approximately two and six folds (at 100 mg/kg and 200 mg/kg, respectively) in one animal model, compared to the equivalent dose of BBR alone.
In addition, HTD1801 showed better synchronization of dissolution for BBR and UDCA, as shown in the same time point of 500 min of peak concentrations for both BBR and UDCA in the following figure. We believe that
the release characteristic will facilitate the interaction between the two active components of HTD1801 and further promote synergistic effects and increase the potential for other beneficial interactions.
Dissolution Curve Demonstrated Improved Dissolution of HTD1801 and Synchronization of BBR and UDCA Dissolution
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HTD1801 showed different PK characteristics in vivo compared with BBR alone, UDCA alone and PM. Both blood and liver exposure of BBR were significantly increased when administered as HTD1801, and substance
balance studies of isotopically labeled samples showed that the UDCA component of HTD1801 was more completely absorbed.
The results of a PK test in golden hamster mice demonstrated that a significant increase in BBR exposure was observed in both plasma and liver in the HTD1801 group compared to BBR or PM, as shown below. The results
showed that the exposure of BBR in plasma and liver in the 100 mg/kg and 200 mg/kg groups increased approximately 2-fold and 6-fold, respectively, compared to equal molar of BBR-Cl alone.
PK Results Demonstrated the Significant Increase in BBR Exposure of HTD1801 in Plasma and Liver
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Pre-clinical Results Showed the Synergistic Effects of HTD1801 in Mouse Model

Unlike drug combinations or a simple physical mixture of active agents, HTD1801 has exhibited synchronous dissolution behavior, distinct physicochemical properties, and superior synergistic effects, as illustrated below.
In pre-clinical study, the golden hamster mice were fed with high-fat feed to create NAFLD mouse model. The NAFLD golden hamster mice were then divided to nine groups for six-week treatment: normal control group
(treated with 0.5% CMC-Na, 10 mL/kg), model control group (treated with 0.5% CMC-Na, 10 mL/kg), HTD1801 low-dose group (treated with HTD1801 50 mg/kg), HTD1801 medium-dose group (treated with
HTD1801 100 mg/kg), HTD1801 high-dose group (treated with HTD1801 200 mg/kg), UDCA low-dose group (treated with UDCA 53.9 mg/kg), UDCA high-dose group (treated with UDCA 107.8 mg/kg), BBR-Cl low
dose group (treated with BBR-Cl 51.1 mg/kg), BBR-Cl high dose group (treated with BBR-Cl 102.2 mg/kg) and BBR and UDCA mixture group in a 1:1 ratio (treated with UDCA 53.9 mg/kg + BBR-Cl 51.1 mg/kg).
The normal control group mice were treated normal feed, and other group mice high-fat feed. The results showed that compared with the model control group, BBR alone, UDCA alone and PM, HTD1801 treatment
showed a dose-dependent reduction for the indicators of serum total cholesterol and triglycerides, low-density lipoprotein cholesterol (“LDL-C”), alanine aminotransferase, aspartate aminotransferase, total bile acid and
total bilirubin, liver weight, liver total cholesterol and triglycerides, NAFLD activity score and fibrosis. The HTD1801 200 mg/kg group showed the most significant improvement, where the indicators of LDL-C, alanine
aminotransferase, aspartate aminotransferase, total bile acid and total bilirubin, liver weight and liver triglycerides were reduced to normal levels, suggesting the NAFLD disease state was completely reversed. The
following figure showed the improvement of serum LDL-C level of HTD1801 compared with BBR alone, UDCA alone and PM.
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Note: (1) HTD1801 100 mg/kg is equivalent to equimolar BBR-Cl of 51.1 mg/kg and equimolar UDCA of 53.9 mg/kg; HTD1801 200 mg/kg is equivalent to equimolar BBR-Cl of 102.2 mg/kg and equimolar UDCA of 107.8
mg/kg;
(2) #: compared with normal control group (#: P<0.05, ##: P<0.01, ###: P<0.001); *: compared with model control group (*: P<0.05, **: P<0.01, ***: P<0.001)); △: compared with HTD1801 group (△: P<0.05, △△:
P<0.01, △△△: P<0.001）
Source: Company Data [Note to CIC: Please confirm whether the above figure can be verified. If not, please obtain further documents from the Company to verify the figure]
Because neither BBR nor UDCA has been approved by competent authorities for the treatment of NASH, T2DM, PSC, PBC diseases, we cannot use BBR or UDCA as drug control group in the HTD1801 clinical trial studies.
In light of the foregoing molecular structure and pre-clinical synergistic effect results, we believe that HTD1801 also has synergistic effects in clinical application.
The Federal Commission for Protection again health risks (COFEPRIS) is the main body in charge of Nutraceutical regulation in Mexico.
The Department of Health (DH) is responsible for overseeing the safety, efficacy and quality of all medicines marketed in Hong Kong.
In August 2016, we obtained an ODD from the FDA for the treatment of PSC, which entitles HTD1801 to a seven-year market exclusivity upon approval of commercialization.
The Pharmaceutical Drugs Directorate is Canada's regulator of prescription pharmaceutical drugs for human use.
Acute pancreatitis is characterized by sudden changes in protein expression, pancreatic cell death, and systemic inflammation, which can lead to organ dysfunction or failure. Although the exact pathogenesis has not been fully
elucidated, [pancreatic cell death (necrosis) and inflammatory response] are believed to play a central role in acute pancreatitis. Studies have shown that a rapid and robust increase in serum pancreatitis-associated protein level
in the early stage of pancreatitis is beneficial in the control of disease and results in improved prognosis. HTD4010, a synthetic peptide mirroring a known active sequence within pancreatitis-associated protein, is expected to
have the same activities as pancreatitis-associated protein in stopping the progress of acute pancreatitis disease state and promoting prognostic repair. HTD4010 may also play a protective role in preventing infectious
complications related to acute pancreatitis, leveraging pancreatitis-associated protein’s [anti-inflammatory and] anti-bacterial properties.
Despite an increasing global disease burden, there are no approved therapy for acute pancreatitis except for ulinastatin approved in China and several other countries. Existing treatment options for acute pancreatitis are largely
supportive, including fluid therapy and pain control. Drug therapies, such as [ulinastatin,] octreotide and gabexate, are used only to ease the symptoms, but have not shown adequate effectiveness in controlling acute
pancreatitis and its lethal complications. To date, there are [five] drug candidates for acute pancreatitis under clinical development [globally].
Overview. This was a Phase I, first-in-human, randomized, double-blind, single ascending doses study to assess the safety, tolerability, PK and PD profile of HTD4010 in healthy adults in Australia. The primary endpoint was
incidence, severity and causality of adverse events.
Trial design. A total of 32 healthy subjects were randomized 3:1 to receive single doses at four levels (50, 100, 200, or 300 mg) of HTD4010 or placebo. The PK procedures involved collecting 5 mL of peripheral blood from
the arm contralateral to that of drug administration at the following time points: pre-dose (5 min prior to dosing) and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h post dose. To maintain the study blind, blood samples were
taken from all subjects receiving either HTD4010 or placebo.
Trial status. We initiated the Phase I clinical trial of HTD4010 in healthy adults in Australia in [October 2015] and completed the study in [March 2016].
Safety data. All AEs reported were mild in intensity, which were all resolved without action taken. No subjects withdrew due to an AE, and no SAEs were reported. HTD4010 was well-tolerated up to the highest dose level
(300 mg).
PK finding. This study indicate that single doses of HTD4010 exhibit linear PK over doses ranging from 50 to 300 mg.
We are developing HTD2802, a multi-functional drug targeting to treat inflammatory bowel disease (“IBD”). IBD is comprised of two major categories: Crohn’s disease, which can affect any part of the gastrointestinal tract,
and ulcerative colitis, which is restricted to the colon. The causes of IBD remains unclear, but Crohn’s disease and ulcerative colitis are believed to have similar types of contributing genetic and environmental factors. For
many patients, the existing drugs fail to adequately control the symptoms and complications from IBD. It is estimated that [one in three] people with ulcerative colitis have severe symptoms that do not improve with
medication, who may need to undergo surgery to remove an inflamed section of the colon, according to CIC. Similarly, around 70% of people with Crohn’s disease need surgery to repair damage to their digestive system and
treat complications of the disease. HTD2802 has shown positive effects on weight loss, stool formation and fecal occult blood and in reducing inflammatory cytokine and pathological injury in preclinical studies.
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We are developing HTD1804, a small molecule drug targeting to treat obesity, a rising global health risk associated with a wide range of comorbidities, primarily cardiovascular disease and T2DM. Preclinical studies have
shown that HTD1804 may be an important modulator in energy metabolism, cardiovascular protection and lipid- and sugar-lowering effects.
We are developing HTD1805, a multi-functional small molecule drug aimed to treat diabetic neuropathy, or nerve disorders associated with diabetes. Although it is the most common complication of diabetes which affects
approximately half of all diabetes patients, there are currently no FDA approved disease-modifying therapies for diabetic neuropathy. In preclinical studies, HTD1805 potently suppressed lipid oxidation and protein
glycosylation in nerve tissues, preventing the progression of diabetes and diabetic neuropathy caused by high blood glucose levels.
Leveraging our profound understanding of metabolic and digestive disease biology, we have developed FUSIONTXTM, a multi-component drug development platform through which we strive to use real world data to map the
network biology of the disease, screen known molecules with desired therapeutic benefits, and design novel, multi-functional drug candidates with synergistic effects across multiple organs. FUSIONTXTM embodies our drug
development goal to enhance overall clinical benefits and improve patient compliance, while increasing accessibility and lowering treatment costs.
The following flowchart illustrates our drug discovery and design process conducted through the FUSIONTXTM platform and a description of major steps in the process using HTD1801 for PSC as an example:
Step One: Mapping the network biology of complex diseases. Leveraging our profound expertise in metabolic and digestive diseases, we identified the gut-liver axis’ critical role in PSC’s pathogenesis and progression
through an in-depth analysis of the existing studies and real world data. We also took into consideration epidemiological and natural history studies that showed an essential relationship between IBD, gut microbiota
imbalance and PSC. We studied clinical use cases for PSC, where physicians often prescribe off-label vancomycin for PSC patients, supporting the feasibility of benefiting PSC patients through the modulation of gut
microbiota.
Step Two: Screening known molecules for desired therapeutic benefits. We gather and evaluate the pharmacology profiles of known molecules through real-world data mining, based on which we screen and select those
molecules with the most desirable therapeutic benefits. For example, we observed UDCA’s use as a common off-label treatment for PSC, and its multi-pathway mechanisms of action, such as immunomodulation, hepatocyte
protection, and displacement of toxic bile acids. Meanwhile, we took note of UDCA’s shortcomings, including an increased risk of hepatotoxicity at high doses, which we sought to counteract throughout the drug development
process.
Step Three: Matching the selected molecules with targeted pathogenic pathways. We categorize the molecules selected in step two according to their distinctive mechanisms and then, based on real-world safety data,
identify the lead molecule candidates for each targeted pathogenic pathway. For example, bearing in mind our focus on the gut-liver axis, we chose UDCA over other molecules known for their hepatocyte protection
effects, and BBR as a top candidate among agents with gut microbiota modulatory properties.
Step Four: Validating active moieties and molecular structure. After rounds of dose-matching experiments, we decided on UDCA and BBR as the final active moieties for HTD1801, based on their compatibility from
having comparable molecular weight and effective dose. At this stage, we focused on synergizing the therapeutic benefits, and mitigating the potential side effects of individual moieties. For HTD1801, for example, we
built on BBR’s well-known beneficial effects on intestinal inflammation and explored its role as an alternative to vancomycin in altering gut microbiota, which can potentially reduce the risks of hepatic SAEs associated
with high-dose UDCA. We further discovered that a novel salt form would offer preferred synergistic physio-chemical properties, including improved solubility and synergized dissolution and melting point, compared to
a simple physical mixture of UDCA and BBR (as in the case of drug combination). In our nonclinical studies, HTD1801 significantly enhances the bioavailability of BBR, which, when administered alone, is recognized
for its low blood concentration and poor solubility in the body. For more details, see “– Our Product Pipeline– HTD1801– Molecular Structure.”
Step Five: Designating the drug candidate. We conduct preclinical pharmacological and PK/PD studies for each new molecular entity [or combination therapy] we have designed. Only entities that have passed these
preliminary tests with a validated safety profile will be designated as our drug candidates. The preclinical studies we have conducted demonstrate that HTD1801, in its unique ionized salt form, exhibits distinct PK/PD
properties and an enhanced efficacy [and safety] profile compared to BBR alone, UDCA alone, or a physical mixture of the two compounds, and thus has the potential to offer improved overall clinical benefits beyond a
simple combination of BBR and UDCA. For more details, see “– Our Product Pipeline– HTD1801– Molecular Structure.”
Our FUSIONTXTM platform serves as the foundation for our continued discovery and design of multi-functional drugs. In addition to our in-house know-how, we have also leveraged external AI technologies as a
supplementary analytical tool for genomic, macrogenomic, proteomic and metabolomic big data.
The clinical development unit of our platform manages all stages of clinical trials, including protocol design, operation, and the collection and analysis of clinical data. Our rapid trial advancements are driven by (i) our
strategic decision to initiate clinical phase trials globally with our outstanding preclinical results, (ii) rigorous trial design
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With the support of our partner hospitals, we are capable of recruiting participants from specific populations for studies that would otherwise be difficult to fulfill enrollment.
We conduct clinical translational research to assess the effectiveness of treatment, evaluate different ways to customize therapies, and improve personalized medicine guidelines using the new data generated.
In terms of the involvement and contributions of each of the major CROs to the development of our product candidates, the pre-clinical CROs mainly provide us with services related to pre-clinical toxicity and safety
evaluations, such as animal studies, of our product candidates in accordance with our study design and under our supervision. The clinical CROs provide us with an array of services necessary for complex clinical trials in
accordance with our trial design and under our supervision. CROs generally provide a comprehensive suite of services to assist us in implementing and managing clinical trials, including trial preparation, source data
verification, clinical safety management, data management, and report preparation.
According to the GCP and relevant regulations, access to clinical trial data has been strictly limited to authorized personnel.
Our Core Product, HTD1801, a new molecular entity, is a pivotal-stage, self-developed, multi-functional, first-in-class drug candidate to treat a range of metabolic and digestive disease, including NASH, T2DM, PSC and
HTG. HTD1801 contains two active moieties derived from natural ingredients, berberine (BBR) and ursodeoxycholic acid (UDCA), both with an established efficacy and long-term safety profiles in humans. We have
obtained Fast Track Designation (FTD) for HTD1801 for PSC and NASH, as well as Orphan Drug Designation (ODD) for PSC, from the FDA. According to CIC, as of the Latest Practicable Date, HTD1801 is the first and
only PSC drug candidate that obtained FTD from the FDA, which facilitates an expedited regulatory review process and, potentially, earlier drug approval. Our Phase II and Phase I promising clinical data demonstrated
HTD1801’s therapeutic potential in the treatment of NASH, T2DM and PSC with favorable safety profiles.
In both the U.S. and China, treatment of NASH can be divided into lifestyle intervention, weight loss recommendation, and drug intervention. The treatment of NASH is currently limited to lifestyle change and specific
treatment of comorbidities, and no evidence-based pharmacological therapy is approved. The NASH treatment is moving forwards multi-mechanistic strategy of combination therapy, given the complexity in pathophysiology
and heterogeneity nature of the disease. To date, there is no NASH drug approved for commercialization in the U.S. and China. There are seven NASH drugs under Phase III clinical development globally and [•] NASH drugs
under clinical development in China.
In 2021, worldwide prevalence of NAFLD among people with T2DM is 55.5%.
There is currently no approved drugs for T2DM and NAFLD, and most of drugs under development are designed targeting single target. There are 13 T2DM with NAFLD drugs under clinical development globally and two
T2DM with NAFLD drugs under clinical development in China.
HTD 1801 is precisely engineered to target the disease’s complex pathogenic mechanisms through a multi-functional synergistic approach
Leveraging our profound understanding of metabolic and digestive disease biology, we have developed FUSIONTXTM, a development platform to optimize and screening drugs with muti-function, through which we strive to
use real world data to map the network biology of the disease, screen known molecules with desired therapeutic benefits, and design novel, multi-functional drug candidates with synergistic effects across multiple organs.
FUSIONTXTM embodies our drug development goal to enhance overall clinical benefits and improve patient compliance, while increasing accessibility and lowering treatment costs, and also greatly increasing the success rate
of drug development.
Step Five: Designating the drug candidate. We conduct preclinical pharmacological and PK/PD studies and preliminary toxicity studies for each new molecular entity [or combination therapy] we have designed.
Our industry is highly competitive and subject to rapid and significant change. While we believe that our fully-integrated platform, our pipeline of drug candidates in clinical and preclinical trials and our experienced
management team provide us with competitive advantages, we face potential competition from many different sources working to develop therapies targeting the same indications against which we are developing our drug
candidates. These include major pharmaceutical companies, academic institutions, government agencies and research institutions. Any drug candidates that we successfully develop and commercialize will compete both with
existing drugs and with any new drugs that may become available in the future
Our Core Product, HTD1801, a new molecular entity, is a pivotal-stage, self-developed, multi-functional, multi-target, first-in-class, “pipeline-in-a-product” drug candidate to serve multiple metabolic and digestive indications,
including NASH, T2DM, SHTG, PSC and PBC.
NASH, T2DM and SHTG are interrelated metabolic diseases. In an insulin resistance state, more insulin is required to obtain the same metabolic effects, namely glucose uptake in the muscle, suppression of lipolysis and of
hepatic glucose production. Insulin resistance is present in muscle, liver and adipose tissue in NASH. Therefore, hepatic glucose production and adipose tissue lipolysis are only in part suppressed by insulin, resulting in
higher fasting glucose and free fatty acid concentrations, increasing the risk of HTG in these patients and predisposeing to lipotoxicity. To overcome insulin resistance, the pancreas is stimulated to secrete more insulin, and
the workload of pancreatic beta cells is increased, leading to beta-cell dysfunction and a reduction of beta-cell mass over time, thus a major risk factor for the development of hyperglycaemia and T2DM. In addition,
glucotoxicity is defined as chronically elevated glucose concentrations causing glucose-induced insulin resistance, cellular 177
dysfunction and a cycle of progressive metabolic deterioration. Glucotoxicity and lipotoxicity are closely interrelated and both contribute to worsening insulin resistance and impaired insulin secretion. Both lipotoxicity and
glucotoxicity also contribute to oxidative stress, mitochondrial dysfunction, lipogenesis, inflammation, and finally to beta-cell dysfunction and vice versa. In NASH, lipotoxicity and insulin resistance have been recognised as
pathophysiological mechanisms responsible of development and progression to a more severe form of this disease. T2DM is a chronic condition of glucotoxicity, although also lipotoxicity is often present and are responsible
not only of insulin resistance but also of impaired insulin secretion.
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HTD 1801 is precisely engineered to target the disease’s complex pathogenic mechanisms through a multi-functional synergistic approach.
HTD1801 Has Better Characteristics and Synergistic Effects HTD1801 is a novel salt formed from two active moieties, BBR and UDCA, in a 1:1 molar ratio. The two active moieties work in tandem in the salt form with
unique microstructure to produce distinct and improved PK profile and physicochemical properties of HTD1801, compared with BBR alone, UDCA alone and a physical mixture of BBR and UDCA in a 1:1 ratio (“PM”). In
particular, HTD1801 demonstrates lower melting point and much improved solubility and lipophilicity compared with the poor solubility of BBR and UDCA, suggesting better oral availability of HTD1801 after
administration. In addition, HTD1801 showed better synchronization of dissolution for BBR and UDCA. We believe that the release characteristic will facilitate the interaction between the two active components of HTD1801
and further promote synergistic effects and increase the potential for other beneficial interactions.Unlike drug combinations or a simple physical mixture of active agents, HTD1801 has exhibited synchronous dissolution
behavior, distinct physicochemical properties, and superior synergistic effects in hamster model, as illustrated below.
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In a pre-clinical NAFLD golden hamster model, compared with placebo and equal molar treatments of BBR alone, UDCA alone or PM, the HTD1801 200 mg/kg treatment for six weeks showed much better improvements,
where indicators of LDL-C, alanine aminotransferase, aspartate aminotransferase, total bile acid and total bilirubin, liver weight and liver triglycerides were reduced to normal levels, suggesting the NAFLD disease state was
completely reversed.
More importantly, combined results from clinical trial studies of hypercholesterolemia (HTD1801.PCT004) and NASH (HTD1801.PCT012) with up to four or 18 weeks of HTD1801 1000 mg BID and placebo treatment
showed much improved effects for triglycerides, LDL-C, HDL-C and body weight, as shown in the following figure.
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Insulin resistance leads to excessive production and defective clearance of triglycerides. Abnormal lipid metabolism in T2DM is related to insulin resistance and abdominal obesity. Elevated triglyceride level predicts
incident T2DM, so an optimal treatment should address comorbid T2DM and SHTG. The data demonstrate that HTD1801 could represent “next generation” of triglycerides lowering and target favorable effects on
hyperglycemia, dyslipidemia, weight, T2DM and SHTG in patients.
HTD1801 Treatment Demonstrates Clinical Efficacy
In subjects with NASH and T2DM, treatment with HTD1801 resulted in meaningful improvements in liver fat content as assessed by MRI-PDFF. The beneficial effect of HTD1801 on liver fat was accompanied by
additional improvements in liver health including liver biochemistry (ALT, AST, GGT), and non-invasive markers of fibrosis (APRI and FIB-4). HTD1801 1000 mg BID was associated with a 3.5 kg weight loss in only 18
weeks. HTD1801 treatment was associated with marked improvements relative to placebo in LDL-c and triglycerides – both independent risk factors for cardiovascular disease. A positive effect of HTD1801 on glucose
metabolism, in particular, a reduction in HbA1c (-0.6%) was observed with HTD1801 1000 mg BID that was statistically significant compared with placebo.
In subjects with hypercholesterolemia, serum lipid levels generally decreased in a dose-dependent fashion following treatment with HTD1801, with maximum reductions relative to placebo being observed after 14 days
of treatment. Statistically significant improvements were observed with HTD1801, at various dose levels, compared with placebo for triglycerides, total cholesterol, LDL-C, non-HDL-C, VLDL-C, and lipoprotein-a.
In subjects with PSC, there was a clinically meaningful and statistically significant decrease in ALP from Baseline to Week 6 with both doses of HTD1801 (500 mg BID and 1000 mg BID) compared to an increase in
ALP in the placebo group (which was likely related to the withdrawal of UDCA in those subjects with prior usage) and a clear signal for benefit in subjects who had not been on UDCA prior to enrollment in this study. Greater
ALP responses in the active treatment groups compared to placebo were apparent as early as Week 2 and sustained through Week 6, and more subjects receiving active treatment met the secondary ALP endpoints at Week 6
than subjects receiving placebo. A dose response was also evident across multiple efficacy endpoints. GGT, ALT, and AST also were reduced with both doses of HTD1801 compared to a worsening in these liver
biochemistries in subjects treated with placebo.
In subjects with PBC, following treatment with HTD1801 1000 mg BID, improvements in ALP were observed by Week 2 with a -7.7% reduction in ALP at Week 12 (p=0.0768). Following discontinuation of study
drug at Week 12, a clear rebound in ALP back to levels higher than baseline was observed. Improvements were observed across multiple endpoints including total bilirubin, GGT, serum lipids (triglycerides, LDL-C and total
cholesterol) and markers of inflammation (IgG and hs-CRP).
Our HTD4010 is a first-in-class polypeptide drug for the treatment of complex, life-threatening diseases such as AH, which is caused by chronic heavy alcohol abuse or a sudden, drastic increase in alcohol
consumption. It is characterized by severe inflammation and, ultimately, liver failure and death. There is currently no approved treatment for AH and only a few drug candidates are in clinical development. The current
standard of care focuses on symptom management, including abstinence, treating inflammation and providing nutrition. Our HTD4010, however, has the potential to address the underlying disease mechanism. In animal
studies, for example, HTD4010 demonstrated potent beneficial effects for AH, significantly increasing survival rates, alleviating characteristic signs of severe liver injury and reducing systemic inflammation. Our completed
Phase I clinical trial of HTD4010 on healthy subjects also demonstrated its favorable safety profile.
The existing IBD drugs fail to adequately control the symptoms and complications in many patients.
Our FUSIONTXTM development strategy
Leveraging our profound understanding of metabolic and digestive disease biology, we have developed FUSIONTXTM, a development strategy to develop drugs with multi-function, through which we strive to use real world
data to map the network biology of the disease, screen known molecules with desired therapeutic benefits, and design novel, multi-functional drug candidates with synergistic effects across multiple organs. FUSIONTXTM
embodies our drug development goal to enhance overall clinical benefits and improve patient compliance, while increasing accessibility and lowering treatment costs, and also greatly increasing the success rate of drug
development.
The following flowchart illustrates our drug discovery and design process conducted through the FUSIONTXTM development strategy and a description of major steps in the process using HTD1801 for NASH as an example:
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Step One: Mapping the network biology of complex diseases. Leveraging our profound expertise in metabolic and digestive diseases, we identified the driving role of metabolism disorders and the other important aspects
(such as oxidative stress and inflammation, liver wound-healing process, gut-liver axis, etc.) in NASH’s pathogenesis and progression through an in-depth analysis of the existing studies and real world data. We also took into
consideration epidemiological and natural history studies that showed an essential relationship between obesity, T2DM, insulin resistance, hypertension , dyslipidemia and NASH, supporting that NASH is not a pure hepatic
disease but a complex metabolic liver disease.
Step Two: Screening known molecules for desired therapeutic benefits. We gather and evaluate the pharmacology profiles of known molecules through real-world data mining, based on which we screen and select those
molecules with the most desirable therapeutic benefits. For example, we observed UDCA’s use as a common hepatic protection treatment with high reputation in safety, and its multi-pathway mechanisms of action, such as
anti-apoptotic effects, lowering serum TNF-α concentrations, decreasing endoplasmic reticulum stress, and improving hepatic insulin sensitivity. Meanwhile, we took note of UDCA’s shortcomings; UDCA appears to have
only modest effects in NASH, which may be led by its modest effects in metabolism improvement. The possible increased risk of hepatotoxicity at very high doses was also noted.
Step Three: Matching the selected molecules with targeted pathogenic pathways. We categorize the molecules selected in step two according to their distinctive mechanisms and then, based on real-world safety data, identify
the lead molecule candidates for each targeted pathogenic pathway. For example, bearing in mind our focus on both the metabolism improvement and hepatic protection, we chose UDCA over other molecules known for their
hepatocyte protection effects, and BBR as a top candidate among agents with comprehensive metabolism modulatory properties. These two active moieties together were hypothesized to improve both the hepatic and
metabolic features of NASH.
Step Four: Validating active moieties and molecular structure. After rounds of dose-matching experiments, we decided on UDCA and BBR as the final active moieties for HTD1801, based on their compatibility from having
comparable molecular weight and effective dose. At this stage, we focused on synergizing the therapeutic benefits, and mitigating the potential side effects of individual moieties. For HTD1801, for example, we built on
BBR’s well-known effects on metabolism modulation and UDCA’s hepatic protection effect, to achieve the multi-therapeutical effects for NASH. We further discovered that these moieties, BBR and UDCA, would work in
tandem in a novel salt form to produce, through their interaction, distinct and preferred synergistic properties that were not observed with either of the individual active moieties or the physical mixture of both (as in the case
of drug combination). The novel salt form would offer preferred physio-chemical properties, including improved solubility and synergized dissolution and melting point. In our nonclinical studies, HTD1801 significantly
enhances the bioavailability of BBR, which, when administered alone, is recognized for its low blood concentration and poor solubility in the body. For more details, see “– Our Product Pipeline– HTD1801– Molecular
Structure.”
Clevudine (Levovir), an anti-HBV agent that was later approved in Korea and several other Asian countries.
We have independently developed HTD1801 and completed multi-dimensional patent layout in the main countries of global drug market, including China, the U.S., Europe, Japan and Korea.
Our rapid trial advancements are driven by (i) our strategic decision to initiate clinical phase trials globally with our outstanding preclinical results, (ii) rigorous trial design, (iii) long-term partnership with various hospitals
and principal investigators from different regions globally and (iv) seamless execution.
We collaborate with CROs and SMOs to conduct and support our preclinical and clinical studies in line with industry practice.
All studies of our product candidates on humans are conducted in compliance with the applicable laws, regulations and in line with the industry standards.
According to CIC, our insurance policy is in line with the industry practice,
The advantage of “pipeline-in-a-product” is significant.
Leverage our drug discovery capabilities and team expertise to build a robust pipeline based on the multi-mechanism approach
Our Core Product, HTD1801, a new molecular entity, is a gut-liver anti-inflammatory metabolic modulator.
Therefore, hepatic glucose production and adipose tissue lipolysis are only in part suppressed by insulin, resulting in higher fasting glucose and free fatty acid concentrations, increasing the risk of HTG in these patients and
predisposition to lipotoxicity.
HTD1801 treats NASH through multiple pathways, which address the core aspects of the disease including induction of the insulin receptor, activation of AMP kinase, and induction of the LDL receptor.
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However, when administered as an individual moiety, BBR has low bioavailability due to its poor solubility.
HTD1801 is a new oral small molecule compound based on BBR and UDCA with unique and innovative design that makes it more superior than the combination of BBR and UDCA.
Further, key findings of studies have been published in prestigious peer-reviewed journals including Nature Communications and the American Journal of Gastroenterology.
BBR is also known to improve glycemic control and commonly used as an over-the-counter remedy for diabetes, pre-diabetes and dyslipidemia.
Clinical practice demonstrated that UDCA (15-20 mg/day) improves serum liver tests and certain surrogate markers of prognosis in PBC.
We have conducted 11 clinical studies of HTD1801 in China, the United States, Canada, and Australia, with a cumulative enrollment of over 500 subjects. In completed clinical trials, HTD1801 demonstrates promising
efficacy in reduction of liver fat content, improvement of both glucose and lipid metabolism, weight loss as well as improvement in markers of liver fibrosis and inflammation. For details of those clinical results, see “—
summary of clinical trials of HTD1801” below in this section.
Combining innovation and druggability for synergistic therapeutic effects: HTD1801 is the world’s first innovative molecular entity based on two moieties with proven efficacy and safety
HTD1801 exhibits unique physico-chemical properties which are distinct from the BBR alone, UDCA alone or their equimolar physical mixture. The enhanced solubility and lipophilicity have been observed for HTD1801,
and additionally the dissolution profiles of BBR and UDCA in HTD1801 exhibit a more “synchronized” pattern (i.e. peak dissolution for both BBR and UDCA moieties from HTD1801 occurring at the same time), which
further points to a unique interaction of the moieties in HTD1801 and which may further enhance the beneficial interactions (e.g. lipophilic ion pairing, micellar solubilization) because of the simultaneous availability of the
moieties in solution. Furthermore, improved exposure of BBR and UDCA from the oral administration of HTD1801 has been observed in both systemic and enterohepatic circulation from preclinical studies. And in the
golden hamster model of high fat diet-induced hyperlipidemia and NAFLD, compared to BBR alone, UDCA alone and a physical mixture of BBR and UDCA in a 1:1 ratio, HTD1801 demonstrated better efficacy in
improvement of lipid profiles, reduction of liver fat content, reduction of liver enzymes and other biomarkers related to liver functions, and improvement of hepatic pathology. As such, a written response from the FDA
confirms that the data appear adequate to demonstrate that HTD1801 is distinct from UDCA alone, BBR alone, or a physical mixture of UDCA and BBR.
“Pipeline-in-a-product” with blockbuster potential
Data from a number of clinical trials demonstrate that HTD1801 has comprehensive therapeutic benefits to patients through multiple mechanisms such as improvement of metabolism, protection of liver and bile, anti-
inflammation and anti-oxidative stress. It is an oral therapeutic drug that can simultaneously lower blood sugar, protect liver and comprehensively improve cardiovascular risk factors with no risk of weight gain. HTD1801 has
demonstrated good safety and robust efficacy in clinical trials across However, when administered as an individual moiety, BBR has low bioavailability due to its poor solubility.
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However, when administered as an individual moiety, BBR has low bioavailability due to its poor solubility.
HTD1801 exhibits unique physico-chemical properties which are distinct from the BBR alone, UDCA alone or their equimolar physical mixture. The enhanced solubility and lipophilicity have been observed for HTD1801,
and additionally the dissolution profiles of BBR and UDCA in HTD1801 exhibit a more “synchronized” pattern (i.e. peak dissolution for both BBR and UDCA moieties from HTD1801 occurring at the same time), which
further points to a unique interaction of the moieties in HTD1801 and which may further enhance the beneficial interactions (e.g. lipophilic ion pairing, micellar solubilization) because of the simultaneous availability of the
moieties in solution. Furthermore, improved exposure of BBR and UDCA from the oral administration of HTD1801 has been observed in both systemic and enterohepatic circulation from preclinical studies. And in the
golden hamster model of high fat diet-induced hyperlipidemia and NAFLD, compared to BBR alone, UDCA alone and a physical mixture of BBR and UDCA in a 1:1 ratio, HTD1801 demonstrated better efficacy in
improvement of lipid profiles, reduction of liver fat content, reduction of liver enzymes and other biomarkers related to liver functions, and improvement of hepatic pathology. As such, a written response from the FDA
confirms that the data appear adequate to demonstrate that HTD1801 is distinct from UDCA alone, BBR alone, or a physical mixture of UDCA and BBR.
“Pipeline-in-a-product” with blockbuster potential
Data from a number of clinical trials demonstrate that HTD1801 has comprehensive therapeutic benefits to patients through multiple mechanisms such as improvement of metabolism, protection of liver and bile, anti-
inflammation and anti-oxidative stress. It is an oral therapeutic drug that can simultaneously lower blood sugar, protect liver and comprehensively improve cardiovascular risk factors with no risk of weight gain. HTD1801 has
demonstrated good safety and robust efficacy in clinical trials across NASH, T2DM, SHTG, PSC and PBC, yielding comprehensive therapeutic benefits in patients across multiple indications. We believe the demonstrated
good safety and robust efficacy strongly support the “pipeline-in-a-product” potential of HTD1801 for additional metabolic and digestive diseases with suboptimal or no approved therapies.
We believe the good safety and robust efficacy profile strongly supports the “pipeline-in-a-product” potential of HTD1801 for selected metabolic and digestive diseases with suboptimal or no approved therapies.
Our Core Product HTD1801, a new molecular entity, is a gut-liver anti-inflammatory metabolic modulator which targets multiple pathways pivotal to metabolic regulation, including those associated with metabolic and
digestive diseases.
The UDCA moiety of HTD1801 is thought to act both systemically and with local gastrointestinal tract effect.
We are a globally integrated biopharmaceutical company focused on the discovery, development and commercialization of first-in-class multifunctional and multi-target therapies for the treatment of metabolic and digestive
diseases with significant unmet medical needs. We have developed a robust product pipeline covering nine indications in metabolic and digestive diseases, and our Core Product, HTD1801 (berberine ursodeoxycholate), a new
molecular entity, is a gut-liver anti-inflammatory metabolic modulator. It is created by forming a novel salt between two active moieties, berberine (“BBR”) and ursodeoxycholic acid (“UDCA”). HTD1801 has demonstrated
good safety and robust efficacy across multiple clinical trials, including: a Phase IIa study in nonalcoholic steatohepatitis (“NASH”) in United States, a Phase II study in type 2 diabetes (“T2DM”) in China, and a Phase Ib
study in T2DM in China, a Phase II study in primary sclerosing cholangitis (“PSC”) in the United States and Canada, a Phase II study in primary biliary cholangitis (“PBC”) in the United States, and a Phase Ib/IIa study in
hypercholesterolemia in Australia. We believe the demonstrated good safety and robust efficacy strongly supports the ‘pipeline-in-a-product’ potential of HTD1801 for selected metabolic and digestive diseases with
suboptimal or no approved therapies.
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Our goal is to provide multifunctional and multi-target therapies that treat complex metabolic and digestive diseases with a systemic approach, providing more effective and safer options to improve overall clinical benefits of
patients. Achieving good balances of efficacy and safety is the key to develop multifunctional and multi-target therapies. The successful development of HTD1801 enabled us to establish the FUSIONTXTM drug discovery
approach. FUSIONTXTM is a multi-component drug development approach, through which we integrate real world clinical data, network pharmacology, known and established molecules with desired therapeutic benefits to
design novel, multi-functional drug candidates to treat complex diseases with a systemic approach.We believe our approach in creating multifunctional products are paradigm-shifting which could lead to discovery and
development of the next generation therapies in many diseases. The two active moieties BBR and UDCA in our Core Product HTD1801 have a long history of medicinal applications as remedies for gut and liver diseases in
traditional Chinese medicine. In HTD1801, BBR and UDCA work in tandem in the salt form with unique microstructure to produce distinct and improved properties of HTD1801. The improved properties are not observed
with either of the individual active moieties or their physical mixture.
We are a globally integrated company with operations in Mainland China, Hong Kong, the United States and Australia. Our global presence, experience and knowledge allow us to conduct high quality multi-center clinical
trials with sites in the United States, Canada, Australia and China in a cost-effective and time-efficient manner. With our accumulated extensive successful experience in building and developing a broad pipeline of innovative
therapies for metabolic and digestive diseases, we expect to provide the market with a steady roll-out of competitive products that aim to address unmet clinical needs in complex metabolic and digestive diseases.
We are a globally integrated biopharmaceutical company focused on the discovery, development and commercialization of first-in-class multifunctional and multi-target therapies for the treatment of metabolic and digestive
diseases with significant unmet medical needs. Metabolic and digestive diseases’ pathogenesis and progress are commonly impacted by multiple factors through complex network of interactions, associated with various
comorbidities. And the prevalence of these disease has increased significantly in recent years due to changing lifestyles, rising obesity rates and aging populations. The high prevalence and the complicated disease
management requirements lead to significant unmet medical need and great market potential.
Treat the patient as a whole. One important feature of metabolic and digestive disease which gives rise to significant unmet medical needs is the co-existence of highly interrelated morbidities in patients. Current treatments
focus on single-target drugs or combinations do not fully address the complications of the interrelated comorbidities.
A drug discovery approach ensures higher probability of success in disruptive innovation. Achieving good balances of efficacy and safety is the major challenge in developing multifunctional and multi-target therapies. The
successful development of HTD1801 enabled us to establish the FUSIONTXTM drug discovery approach that ensures higher probability of success for the design of multifunctional and multi-target drug candidates, through
which, we integrate real world clinical data, network pharmacology, known and established molecules with desired therapeutic benefits and known safety profiles to design novel, multi-functional drug candidates to treat
complex diseases with a systemic approach. Drug discovery and design through this approach enables systematic, precise, and efficient early-stage drug development that potentially facilitates a higher rate of clinical success
at an accelerated pace and lowers development risks, enabling our sustained pipeline expansion.
Global competitiveness and recognition. With solid global IP protection, we implement global development strategy for our drug candidates. The superiority and innovation of our assets have been recognized by regulatory
agencies and international academic communities. HTD1801 has been granted fast track designation (“FTD”) by the FDA for NASH and PSC, respectively. FTD is often granted by FDA for the new drugs or biologics that are
intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. In addition, our abstract was selected for inclusion in the “Best of The Liver Meeting 2021” program
created by the American Association for the Study of Liver Diseases Scientific Program Committee to highlight key scientific achievements presented in the annual conference. As a result, we believe our pipeline of new
molecular entities offers high potential for therapeutic paradigm shift and clinical success for metabolic and digestive diseases, as well as unparalleled commercial value.
“Pipeline-in-a-product” with blockbuster potential. HTD1801 has demonstrated good safety and robust efficacy in clinical trials across NASH, T2DM, SHTG, PSC and PBC, yielding comprehensive therapeutic benefits in
patients across multiple indications. We believe the demonstrated good safety and robust efficacy strongly supports the ‘pipeline-in-a-product’ potential of HTD1801 for additional metabolic and digestive diseases with
suboptimal or no approved therapies. The advantage of ‘pipeline-in-a-product’ is undeniable. Development cost can be allocated more efficiently, creating discrete commercial opportunities without additional discovery,
preclinical, CMC development and early clinical development. Many of the blockbuster drugs in metabolic diseases can be deemed as ‘pipelines-in-a-product’, such as semaglutide and dapagliflozin.
Collective results from our Phase Ib T2DM trial, Phase II T2DM trial and Phase IIa NASH and T2DM trial suggest that HTD1801 has broad efficacy on glucose homeostasis, other cardiometabolic markers and liver health,
supporting a differentiated profile compared to other anti-diabetic agents.
Robust pipeline of new molecular entities with therapeutic profile to address unmet needs in metabolic and digestive diseases Leveraging the patient-centric strategy, we have developed a robust pipeline of multifunctional,
multi-target therapeutics to treat metabolic and digestive diseases with significant unmet medical needs. In addition to HTD1801, our pipeline comprises clinical and preclinical assets to address a wide range of indications,
including AH, obesity, IBD and other metabolism disorders.
There has been an increasing industry focus on metabolic and digestive diseases in recent years, which has driven our continued investment in research and development, in that we focus on the development of new and more
effective treatments for these important health issues. According to CIC, presently there are significant commercial opportunities across multiple metabolic and digestive diseases including T2DM, NASH, SHTG, PSC and
PBC markets. Notably, demographic trends support continued market growth. With our innovative pipeline, we believe that we are well positioned to address these growing therapeutic areas which represent significant unmet
medical need. There are several reasons why the industry has been focusing more on these types of diseases. One major factor is the growing prevalence of these conditions. Diabetes and NASH, for example, have become
global epidemics, affecting millions of people worldwide. 185
As a result, there is a large and growing market for treatments and medications that can help manage these conditions. Another factor driving the industry’s focus on metabolic and digestive diseases is the increasing
understanding of the underlying biology of these conditions. Advances in genetics, biochemistry, and other fields have helped Industry to better understand the underlying mechanisms of these therapeutic areas, opening new
avenues for drug development. In addition, there is a growing recognition of the link between metabolic and digestive diseases and other health issues. For example, NASH and T2DM are major risk factors for heart disease
and stroke, while digestive diseases can be linked to a range of other conditions, including autoimmune disorders and certain types of cancer.
In summary, while progress has been made in the management of metabolic and digestive diseases, there are still unmet needs that need to be addressed to improve patient outcomes. Metabolic and digestive diseases are
complex and heterogeneous, with significant variability in disease presentation, progression, and response to treatment. Hence, there is a need for multi-targeted therapies that can address the underlying mechanisms of these
diseases and provide more effective and safer treatment options. Even in crowded market segments, HTD1801 and other pipeline candidates have the potential to become market leaders in that they have been purposefully
designed to address the shortcomings of existing therapies.
Our R&D team has strong expertise, a deep understanding, and broad development experience in metabolic and digestive diseases. Our R&D team pioneered the identification of compounds intended to modulate multiple
pathways underlying chronic diseases, providing a unique advantage in addressing the unmet clinical needs across complex pathologies. Our in-house R&D team is led by a deep bench of world-class scientists with more than
20 years of drug development experience.
Our management team is led by our founder and CEO, Dr. Liping Liu, a pioneer in the field of metabolic and digestive diseases We engage a world-renowned expert team of clinical and regulatory advisors, including key
opinion leaders in liver and metabolic disease, to advise our development strategies to maximize our probability of success. We have consistently been able to attract industry-leading experts and renowned KOLs to participate
in our drug discovery and development projects, which speaks to the solid foundation of our research and development process and reflects the cutting-edge nature and clinical potential of our drug candidates. In addition to
the world-renowned KOLs, we are also a leader in global drug development with deep expertise in navigating the drug approval process. Our multi-jurisdictional regulatory expertise is particularly strong in our key markets of
China, the United States and Europe.
Part of our clinical strategy is to focus on therapeutic indications that are interrelated (i.e. T2DM, NASH and SHTG) allowing the company to design clinical programs in a way that enables databases from multiple programs
to be leveraged across indications and regions (i.e. China and US)
These moieties work in tandem in the salt form with unique microstructure to produce distinct and improved properties of HTD1801 that are not observed with either of the individual active moieties or their physical mixture.
HTD1801 exhibits improved physico-chemical characteristics and PK, efficacy and safety profiles, which is believed to owe to the unique interaction of BBR:UDCA in the ionized salt form. Given these unique attributes of
the HTD1801, the FDA has recognized that HTD1801 is distinct from its individual constituent components or their physical mixture and has therapeutic potential.
BBR has beneficial effects on the gut microbiome, which may lead to further benefits to both PSC and PBC patients.
There has been an increasing industry focus on metabolic and digestive diseases in recent years, which has driven our continued investment in research and development, in that we focus on the development of new and more
effective treatments for these important health issues. According to CIC, presently there are significant commercial opportunities across multiple metabolic and digestive diseases including T2DM, NASH, SHTG, PSC and
PBC markets, together representing a large global market size of US$323 billion in 2022. Notably, demographic trends support continued market growth. With our innovative pipeline, we believe that we are well positioned to
address these growing therapeutic areas which represent significant unmet medical need.
Another factor driving the industry’s focus on metabolic and digestive diseases is the increasing understanding of the underlying biology of these conditions. Advances in genetics, biochemistry, and other fields have helped
Industry to better understand the underlying mechanisms of these therapeutic areas, opening new avenues for drug development. In addition, there is a growing recognition of the link between metabolic and digestive diseases
and other health issues. For example, NASH and T2DM are major risk factors for heart disease and stroke, while digestive diseases can be linked to a range of other conditions, including autoimmune disorders and certain
types of cancer.
Positive progress of HTD1801 in multiple clinical pipelines: efficacy endpoints have been met in multiple studies globally with good safety and tolerability HTD1801 has demonstrated good safety and robust efficacy in
clinical trials across NASH, T2DM, SHTG, PSC and PBC, yielding comprehensive therapeutic benefits in patients across multiple indications. We believe the demonstrated good safety and robust efficacy strongly supports
the ‘pipeline-in-a-product’ potential of HTD1801 for additional metabolic and digestive diseases with suboptimal or no approved therapies. The advantage of ‘pipeline-in-a-product’ is undeniable. Development cost can be
allocated more efficiently, creating discrete commercial opportunities without additional discovery, preclinical, CMC development and early clinical development. Many of the blockbuster drugs in metabolic diseases can be
deemed as‘pipelines-in-a-product’, such as semaglutide and dapagliflozin.
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For NASH, we have completed a randomized, double-blind, placebo-controlled Phase IIa study of HTD1801 in patients with NASH and T2DM in the United States. The study met the primary endpoint, which showed that
HTD1801 resulted in statisticallysignificant, meaningful improvements in liver fat content, as assessed by MRI-PDFF, compared to placebo. MRI-PDFF is commonly used to assess treatment response in early-phase, proof-
of-concept clinical studies in NASH and has been shown to be closely correlated with liver steatosis grades from histology. The beneficial effect of HTD1801 on liver fat was accompanied by additional improvements in liver
health including liver biochemistry (ALT, AST, GGT), and non-invasive markers of fibrosis and inflammation (cT1, APRI and FIB-4). Treatment with HTD1801 also resulted in weight loss and significant improvements in
LDL cholesterol and triglycerides, both of which are independent risk factors for cardiovascular disease. A positive effect of HTD1801 on glucose metabolism was evident. We have been granted a FTD of HTD1801 for the
treatment of NASH, which allows us to communicate with the FDA more frequently and giving us a competitive advantage in the regulatory approval process.We are currently conducting a Phase IIb study of HTD1801 in
patients with NASH and T2DM in the United States and plan to initiate the same indication in Hong Kong, Mexico and Mainland China in the second half of 2023. For T2DM, our completed Phase Ib and Phase II clinical
trials in China has demonstrated a strong therapeutic effect in improving glucose metabolism, including statistically significant decreases in HbA1c and fasting glucose levels, which may be the result of decreased insulin
resistance. In the clinical trials, improvements in other disease-relevant parameters were also observed. With HTD1801 treatment, liver biomarkers (ALT, AST, GGT) were also reduced. HTD1801 also led to improvement of
lipid profiles, such as reduction of LDL-c and non-HDL-c levels. Collective results from our Phase Ib T2DM trial, Phase II T2DM trial and Phase IIa NASH and T2DM trial suggest that HTD1801 has broad efficacy on
glucose homeostasis, other cardiometabolic markers and liver health, supporting a differentiated profile compared to other anti-diabetic agents.We plan to initiate Phase III registrational trials of HTD1801 for the treatment of
T2DM in China in the second half of 2023. Based on the comprehensive benefits observed for HTD1801 treatment, coupled with its safety profile and ease of administration, we believe that HTD1801 has the potential to
become a blockbuster backbone therapy for T2DM patients who also suffer from metabolic comorbidities such as NAFLD and dyslipidemia.
The chart below demonstrated HTD1801’s advantage over its peers for T2DM and NASH indications based on publicly available data which are non-head-to-head studies.
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For SHTG, preclinical studies demonstrated that HTD1801 could significantly improve lipids in hamster models of dyslipidemia and NAFLD. In addition, in a pooled analysis of clinical studies of NASH and
hypercholesterolemia, focusing on subjects with baseline TGs above 200 mg/dL (hypertriglyceridemia), treatment with HTD1801 was associated with robust reductions in TG levels. The effect on TG levels in the HTG
population was paralleled by improvement of key cardiometabolic parameters including a decrease in LDL-C, an increase in HDL-C, improved glucose levels and marked weight loss. This clinical evidence supports the
therapeutic potential of HTD1801 in SHTG.
For PSC, HTD1801 provides a unique and comprehensive treatment of the gut-liver-biliary system, acting through multiple mechanisms to address the complex pathogenesis of PSC, including a choleretic effect achieved by
displacing toxic bile acids from the bile acid pool and a variety of anti-inflammatory effects. In addition, HTD1801 treatment has demonstrated positive changes in the gut microbiome, an important contributor to the
pathogenesis of PSC. A Phase II clinical trial of HTD1801 for PSC in the United States and Canada met its primary endpoint, with the HTD1801 treatment group demonstrating a statistically significant reduction in serum
alkaline phosphatase, a key biomarker indicating the presence of cholestatic liver disease, compared to the placebo group. HTD1801 treatment was also associated with improvements in markers of liver injury and
inflammation. In addition to its efficacy profile, HTD1801 demonstrated a good safety profile in this patient population including liver-related safety.
A completed Phase II open-label study in the United States demonstrated proof of concept of HTD1801 for the treatment of PBC patients with an incomplete response to UDCA treatment. Upon transition from UDCA to
HTD1801, efficacy across multiple endpoints was observed with HTD1801 therapy, including a reduction in ALP and GGT, markers of cholestatic injury, as well as a reduction in total bilirubin levels, indicative of improved
liver function. Markers of inflammation and blood lipids generally improved with HTD1801. Our Phase II clinical results suggest that additional benefits are obtained with HTD1801 monotherapy over UDCA alone,
potentially in part driven by the BBR moiety of HTD1801 and the improved physicochemical characteristics of HTD1801. In addition to the efficacy profile, HTD1801 demonstrated a good safety profile in this patient
population including liver-related safety. In particular, pruritus, a common symptom of PBC, showed improvement with HTD1801 treatment.
Combining innovation and druggability for synergistic therapeutic effects: HTD1801 is the world’s first innovative molecular entity based on two traditional natural products HTD1801 is a novel salt formed from two active
moieties, BBR and UDCA. The two active moieties work in tandem in the salt form with unique microstructure to produce distinct and improved properties of HTD1801. HTD1801 has significantly different physico-
chemical characteristics compared to each of the BBR and UDCA active moieties or theirphysical mixture, including distinct X-ray powder diffraction, melting point, infrared spectrum, solubility or dissolution and LogD.
Further, HTD1801 exhibits improved PK, efficacy and safety profiles, which is believed to owe to the unique interaction of BBR:UDCA in the ionized salt form. Those improved properties are not observed with either of the
individual active moieties or their physical mixture. Given these unique attributes of HTD1801, the FDA has recognized that HTD1801 as distinctive from its individual constituent components or their physical mixture with
therapeutic potential.
In addition, BBR and UDCA are natural products with a long history of human medicinal use. The safety and pharmacological activity of the two drugs have been verified by numerous previous studies, thereby adequately
supporting the druggability of HTD1801. In addition, HTD1801 improves water solubility and lipophilicity of both BBR and UDCA by synchronized release to promote maximum synergy. The following following figure
demonstrates dissolutioncurves of HTD1801-BBR and HTD1801-UDCA compared with mixture-BBR and mixture-UDCA in simulated fasting state intestinal fluid, indicating much improved and synchronized dissolution of
HTD1801-BBR and HTD1801-UDCA.
188
In addition, as shown in the following figure, HTD1801 also increases bile recovery of UDCA, resulting in more complete absorption of UDCA.
189
In the golden hamster model of high fat feed induced hyperlipidemia and NAFLD, compared to BBR alone, UDCA alone and a physical mixture of BBR and UDCA in a 1:1 ratio, HTD1801 demonstrates efficacy advantages
for improvement of blood lipids, liver fat accumulation, liver enzymes and other liver biochemical indicators and pathology. As such, based on the clear advantages in terms of physicochemical properties, PK, and PD, a
written response from the FDA confirms that the nonclinical data appear adequate to demonstrate that the PK and PD characteristics of HTD1801 are distinct from the PK and PD characteristics of UDCA alone, BBR alone, or
a physical mixture of UCDA and BBR in animal models. Therefore, HTD1801 has an effects of 1+1>2.
Treating both symptoms and root causes of different diseases: HTD1801 has a differentiated pipeline layout to target comorbidities in the field of chronic metabolic diseases
A number of clinical trial data prove that HTD1801 has comprehensive therapeutic benefits to patients through multiple mechanisms such as improvement of metabolism, protection of liver and gall, anti-inflammation and
anti-oxidative stress. It is currently the only oral therapeutic drug that can simultaneously lower blood sugar, protect liver and comprehensively improve cardiovascular risk factors with no risk of weight gain. We have applied
indication of HTD1801 to cover three major diseases, namely T2DM, NASH and SHTG, and also focused on patients with comorbidities. Thus, HTD1801 has a broad range of indications for expansion and is an exemplary
embodiment of our pursuit in treating different diseases by treating its root with one comprehensive therapy (異病同治).
190
Favorable policies to support the listing: Dual application strategy in both China and the U.S. promotes modernization and internationalization of Chinese medicine As of the Latest Practicable Date, for HTD1801, 11 clinical
trials have been initiated or completed with more than 500 subjects enrolled in the aggregate, and the efficacy and safety have been well evidenced in different populations in these trials. HTD1801 has entered the late
development stage for various indication projects, with our good expectation of success. In China, we received government support from “Major National Science and Technology Projects for New Drug Development” under
the “National 13th Five-Year Plan”, further accelerating the speed of domestic market approval for HTD1801. In the United States, we have received FTD from FDA for NASH, and for PSC indications, as well as an ODD for
the PSC indication. According to CIC, HTD1801 is the first PSC drug candidate to receive a FTD from the FDA.
191
192
193
194
195
196
HTD4010 is a long synthetic peptide composed of 15 amino acids, homologous to an active peptide fragment of the human regenerating islet-derived protein 3α (“Reg3α”), or “pancreatic associated protein (PAP).” HTD4010
acts as a TLR4 inhibitor potentially capable of dampening the innate immune response and liver inflammation of AH pathogenesis. Thus, HTD4010 has anti-apoptotic, anti-inflammatory, anti-bacterial, and pro-regenerative
effects in the pancreas, GI tract and other tissues, both in vitro and in vivo.
Achieving good balances of efficacy and safety is the major challenge in developing multifunctional and multi-target therapies. The successful development of HTD1801 enabled us to establish the FUSIONTXTM drug
discovery approach that ensures higher probability of success for the design of multifunctional and multi-target drug candidates, through which, we integrate real world clinical data, network pharmacology, known and
established molecules with desired therapeutic benefits and known safety profiles to design novel, multi-functional drug candidates to treat complex diseases with a systemic approach. Drug discovery and design through this
approach enables systematic, precise, and efficient early-stage drug development that potentially facilitates a higher rate of clinical success at an accelerated pace and lowers development risks, enabling our sustained pipeline
expansion. We believe our approach in creating multifunctional drug candidates are paradigm-shifting which could lead to disruptive discovery and development of the next generation therapies in many diseases.
We collaborate with top clinical experts in various areas as our principal investigators, leverage the operational capabilities of industry-leading CROs and SMOs, and rely on well-known academic medical institutions and
clinical trial centers in China and abroad
197
• Company is a globally integrated biopharmaceutical company specializing in the discovery, development and commercialization of first-in-class, multifunctional,
multi-targeted, original new drugs for the treatment of metabolic and digestive diseases with significant unmet medical needs.
• The grant of IND approval by the FDA for us to commence the Phase II clinical trial of HTD1801 in the United States for NASH, PBC and PSC demonstrates that
the Phase I clinical trial of HTD1801 in Australia is accepted and regarded as comparable to a completed Phase I clinical trial in the United States by the FDA. It
is common practice that a foreign clinical trial being accepted by the FDA provided that the trial meets certain criteria as set out by the FDA. The FDA will accept
a well-designed, well conducted, non-IND foreign study as support for an IND if the study meets certain criteria, including that (i) the study was conducted in
accordance with ICH GCP and (ii) if the FDA is able to validate the data from the study through an onsite inspection, if necessary. The ICH GCP Guidelines
have been incorporated by reference in the Therapeutic Goods Regulations 1990 in Australia, and therefore compliance with the ICH GCP Guidelines is a
prerequisite for approval for conducting a clinical trial in Australia. The FDA would also be able to validate the data from the Phase I clinical trial of HTD1801 in
Australia through an onsite inspection if it deems necessary.
• As HTD1801 is a self-developed product and it has been developed for more than five years prior to Listing, our clinical development demonstrates that for each
indication of T2DM, NASH, PSC and PBC above, it has been developed beyond concept stage, namely it has completed Phase I trial and the competent
authorities had no objections to initiate Phase II study, it is eligible as Core Product under GL92-18.
198
Updated pages for HKEX response 1st Comment
SHTG Market size
Market size of SHTG drug market
Market size of SHTG drug market， 2018-2032E
China 10.5% 9.3%

the U.S. 8.8% 7.8%
Europe 8.0% 7.1% 4,802.4
Total 8.6% 7.6% 4,551.1
4,297.5 692.2
4,040.5 646.5
601.6
3,783.1
557.4
3,526.4
514.2
3,271.8
472.2
3,020.6 1,966.4
431.5 1,862.7
2,772.1 392.0 1,757.8
2,529.1 354.1 1,651.2
2,292.5 1,544.3
317.9 1,437.8
2,063.3 283.3 1,332.4
1,842.4 250.7 1,228.7
1,742.3 1,125.6
1,647.3 220.0 1,025.0
204.4
189.8 927.3
833.1
700.7 742.7
661.2 2,143.8
1,938.1 2,041.9
1,724.5 1,831.9
1,508.0 1,616.3
1,292.4 1,399.9
1,081.8 1,186.2
837.1 879.8 979.5
796.3
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
PBC Market size
Market size of PBC drug market
Market size of PBC drug market， 2018-2032E
China 5.8% 10.7%

the U.S. 9.0% 28.4%
Europe 9.8% 28.9% 2,376.3
Total 8.2% 25.4% 2,197.4
1,993.6 591.7
554.6
1,756.4
507.5
1,473.0 448.8
377.5 1,020.0
1,119.2 942.4
1,015.8 853.8
946.2 297.6
878.0 750.2
811.3 270.2
746.3 256.3 625.8
682.9 242.3
621.0 228.5
543.6 581.1 214.8
200.8 473.0
179.0 186.6 398.7 430.0
171.5 368.1
309.4 338.3 764.6
281.3 632.2 700.4
236.3 254.3 557.4
219.4 469.7
291.2 315.6 348.7
200.7 222.2 244.5 267.5
152.7 165.9 180.1
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
HTD1801 Market size
Total addressable population of HTD1801
Total addressable population of HTD1801 in China, the U.S. and Europe
CAGR 2018-2022 2022-32E Million people

NASH 2.9% 3.5%
T2DM 1.4% 1.7%
PSC&PBC 1.8% 2.3%
SHTG
1.4% 1.8%
Total 351.6 353.8 355.9
2.4% 2.3% 339.9 345.7
328.4 334.1
317.0 322.8
305.6 311.3
294.6 300.1
284.1 288.9 120.2 121.4
112.9 115.9 118.9
104.2 107.0 109.9
96.1 98.7 101.4
88.3 90.9 93.5
85.8
214.3 217.0 219.8 222.6 225.3 228.1 228.9 229.7

194.3 196.7 199.7 202.6 205.5 208.4 211.3
1.3 1.3 1.3 1.4 1.4 1.4 1.4 1.5 1.5 1.5 1.5 1.6 1.6 1.6 1.6
2.6 2.6 2.7 2.7 2.7 2.8 2.8 2.8 2.9 2.9 2.9 3.0 3.0 3.1 3.1
2018 2019 2020 2021 2022 2023E 2024E 2025E 2026E 2027E 2028E 2029E 2030E 2031E 2032E
Note:
• The total addressable population of HTD180 includes the respective addressable population of the underlying indications. Due to comorbidities between
each of the metabolic and digestive diseases, the actual total addressable population is smaller than what is presented above
Source: GHDx, National Bureau of Statistics of China, Literature search, China Insights Consultancy 202
NASH market growth drivers and entry barriers
Growth drivers Content
Expansion of vulnerable population • As a metabolic disease, NASH is associated with risk factors such as obesity, T2DM, abnormal fat levels in the blood, age,
and obstructive sleep apnea, among others. As the world obesity and T2DM population grow, so will the NASH population
grow steadily.
Novel treatments to fulfil unmet needs • As of May 2023, in China, the US and Europe, there have not been any approved medications indicated for NASH. As
disease understanding of NASH and after the first novel treatment indicated for NASH approved, the NASH patients will
quickly adopt these newly-approved drugs, thus driving significant growth of NASH drug markets.
Growing spending power • Increased per capita disposable income in China have made it easier for patients to afford more expensive medical fees.
Usually when innovative treatments become available, they tend to be comparably expensive. With growing spending
power, more and more patients will be able to afford these novel medications, thus driving the growth of NASH drug
markets.
Entry barriers Content

Technological barrier • The development of novel treatment for NASH requires advanced disease understanding and technological capabilities,
especially when the pathogenesis of NASH is still pending further research. Companies and manufacturers that are
equipped with advanced technologies and know-how would not be competitive in this market.
Regulatory barrier • The development of drugs and medications is strictly regulated. Companies and manufacturers with little experience in
drug development and who are unfamiliar with relevant regulations and lacking in compliance knowledge would not be
able to compete in this market.
Capital barrier • Drug development process is a lengthy and capital-intensive activity, which requires enormous amount of capital
investment and other kinds of resources to be consistently invested. New entrants are expected to have strong financial
capabilities and liquidity.
Talent barrier • The innovative drug industry is a technology-intensive and multi-disciplinary industry, involving many disciplines such as
biology, medicine, pharmacology, and clinical research etc. The research and development, and production of innovative
treatments are in high demand for candidate with great talents, and many medical technicians, biological technicians and
other professional staff are needed in product development, registrational clinical research and market research.
Therefore, it is difficult for newly-entered enterprises to hire more high-end talents with multi-domain knowledge in the
short term, which directly leads to the slow business development and low efficiency of newly-entered enterprises.
Sales and marketing barrier • Sales and marketing activities are critical in the pharmaceutical industry, and especially so for innovative treatments. It
takes advanced know-how to promote innovative treatment that doctors and patients are not familiar with. Newly-entered
companies will have difficulty to construct a sales and marketing team with rich experiences from scratch.
203
T2DM market growth drivers and entry barriers
Growth drivers
Strengthened public awareness • As a major concern in public health, governments, medical institutions and associations around the world are constantly
promoting to increase public awareness of the disease of T2DM, and the know-how to manage T2DM. This will promote
the increase in diagnosis and treatment of T2DM, which will in turn drive the T2DM drug market.
Increase of diagnosis rate • As the current diagnosis rate for T2DM is still low around the globe, the growth of T2DM drug market will be driven by
increasing diagnosis rate of T2DM, which in turn will lead to growing diagnosed patients, thus more patients would
become aware of their T2DM status, which will drive the sales of T2DM drugs.
Novel treatment • Aside from Metformin, more and more novel treatment and innovative drugs have entered the market, fulfilling unmet
needs in the T2DM population. As innovative treatments targeting GGP-1, DPP-4 and SGLT-2 and other novel
medications enter the T2DM drug market, the T2DM drug market will grow steadily.
Entry barriers
Technological barrier • The development of novel treatment for T2DM requires advanced disease understanding and technological capabilities.
As newer targets such as GLP-1, DPP-4 and SGLT-2 emerge, it requires companies and manufacturers to look for novel
treatment targets to be successful in the T2DM drug market. The overall level of technology in R&D of new entrants will
not be sufficient to drive drug discovery and subsequent development.
Capital barrier • Drug development process is a lengthy and capital-intensive activity, which requires enormous amount of capital
investment and other kinds of resources to be consistently invested. In the T2DM market, incumbents and large
enterprises have been constantly investing in drug discovery and development. New entrants are expected to have strong
financial capabilities and liquidity.
Talent barrier • The innovative drug industry is a technology-intensive and multi-disciplinary industry, involving many disciplines such as
biology, medicine, pharmacology, and clinical research etc. The research and development, and production of innovative
treatments are in high demand for candidate with great talents, and many medical technicians, biological technicians and
other professional staff are needed in product development, registrational clinical research and market research.
Therefore, it is difficult for newly-entered enterprises to hire more high-end talents with multi-domain knowledge in the
short term, which directly leads to the slow business development and low efficiency of newly-entered enterprises.
Sales and marketing barrier • Sales and marketing activities are critical in the pharmaceutical industry, and especially so for innovative treatments. It
takes advanced know-how to promote innovative treatment that doctors and patients are not familiar with. Newly-entered
companies will have difficulty to construct a sales and marketing team with rich experiences from scratch. 204
PBC market growth drivers and entry barriers
Expansion of vulnerable population • The pathogenesis of PBC has not been fully understood, and the major population group susceptible to PBC is older
women. As the awareness and level of clinical diagnosis increase, with the growing aging population, PBC is projected to
have a growing prevalence.
Novel treatments to fulfil unmet needs • As of May 2023, UDCA and FXR antagonists are the only drugs approved for treatment of PBC. However, they have
respective limitations such as only 60% of the PBC patients respond well to UDCA, and FXR antagonists have black box
warnings regarding their safety profile. The limitations in currently available treatments present significant unmet needs in
PBC treatment, and novel treatments that fulfill unmet needs are expected to drive the growth of PBC drug market

Technological and talent barrier • The pathogenesis of PBC is still pending further research. In addition, due to the slow progression of PBC, sometimes
surrogate endpoints are needed in clinical assessment. The complex activities involved in developing new drugs to treat
PBC require high-level technological know-how and clinical development professionals. It is difficult for newly-entered
enterprises to recruit talents with specific knowledge in the short term, which directly leads to the slow product
development of newly-entered enterprises.
Capital investment barrier • Drug development process is a lengthy and capital-intensive activity, which requires enormous amount of capital
investment and other kinds of resources to be consistently invested. For example, in the PBC field, the patient population
is relatively small, patient recruitment requires significant investment and resources. New entrants are expected to have
such strong financial capabilities and liquidity to sustain business operation and product development.
205
PSC market growth drivers and entry barriers
Increase of diagnosis rate • The pathogenesis of PSC has not yet been clearly identified, and multiple risk factors such as genetics, environment,
autoimmune conditions and metabolism of bile acids could lead to PSC. The major population group susceptible to PSC is
male aged between 20 and 57 years old. As PSC becomes more studied and understood and its standard of diagnosis
becomes more developed, the diagnosis rate will increase, which will drive the growth of PSC market.
Novel treatments to fulfil unmet needs • As of May 2023, there have not yet been drugs indicated for PSC approved. This presents significant unmet needs to
address for the PSC patients and improve their prognosis. After novel treatments that fulfill these unmet needs are
approved, PSC patients are expected to adopt these innovative drugs, thus driving the growth of PSC market.

Technological and talent barrier • As of May 2023, the first medication to be approve for treating PSC is still to be expected. Scientific researches and
clinical developments are constantly dedicated to the field of PSC and looking for pathways or targets to treat PSC. These
activities typically demand high-level insights and technologies in areas of PSC, metabolism or autoimmunology, and
require a team of talents with research focus on the underlying topics. This Presents the technological and talent barrier
for the PSC drug market.
investment and other kinds of resources to be consistently invested. For example, in the PBC field, the patient population
is relatively small, patient recruitment requires significant investment and resources. New entrants are expected to have
such strong financial capabilities and liquidity to sustain business operation and product development.
206
SHTG market growth drivers and entry barriers
Expansion of vulnerable population • Hypertriglyceridemia results from the combination of genetic factors and lifestyle causes such as excessive alcohol intake
and foods rich in saturated fat. Also, obesity, metabolic syndrome, T2DM and other conditions have been associated with
hypertriglyceridemia. These risk factors and comorbidities together contributes to the expansion of vulnerable population
of SHTG.
Novel treatments to fulfil unmet needs • For SHTG, the current treatment options have their respective limitations. Significant unmet clinical needs prevail in
SHTG treatment, especially the need to simultaneously reduce triglycerides and further improve lipid metabolism and
weight management. After novel treatment choices are introduced to the market, the SHTG drug market is expected to
grow steadily,

Technological and talent barrier • Sever hypertriglyceridemia has complex pathogenesis and etiology that are still under scientific research and pending
further disease understanding as a metabolic disease. Drug development in this field requires multi-faceted talents who
are familiar with regulations, clinical trials, the field of metabolic diseases and other areas that are key to the development
and commercialization of innovative therapies in SHTG treatment. This presents a critical technological and talent barrier
that prevents new entrants to enter the market and conduct clinical research and other business operations.
investment and other kinds of resources to be consistently invested. New entrants are expected to have such strong
financial capabilities and liquidity to sustain business operation and product development.
207
Comps summary
Comps summary for HTD1801, as of LPD
NMPA
Indication FDA Approval FDA III FDA II FDA I NMPA III NMPA II NMPA I
Approval
See current
T2DM disclosure1
Over 70 29 20 Over 1,000 Over 60 14* 66
9*, including Over 60 active

MASH 0 of approvals
NDA trials
32 0 2* 12* 16
PSC 0 of approvals 2* 9* 0 0 0 2* 0
PBC 18*
SHTG Over 100 15* 139 (over 100) 2*
• * means competitive landscape presented as pipeline table

• 1 among the FDA-approved T2DM drugs, as of the LPD, a total of 302 drugs of metformin and 57 drugs of insulin had been approved

End of Report

Industry Report On Metabolic Disorders and Digestive Diseases Drug Market

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Industry Report on Metabolic disorders and

Digestive diseases drug market

Terms and abbreviations

Terms and abbreviations

aspartate aminotransferase to platelet ratio index, a

ARB Angiotensin Receptor Blockers

Terms and abbreviations

Terms and abbreviations

CTCAE Common Terminology Criteria for Adverse Events DR Diabetic Retinopathy

EASL European Association for the Study of the Liver

Cardiovascular Diseases, conditions affecting the heart

end-of-phase meeting; a meeting held when the clinical

DHA Docosahexaenoic Acid EPA Eicosapentaenoic Acid

Terms and abbreviations

Source: China Insights Consultancy 5

Terms and abbreviations

Terms and abbreviations

Source: China Insights Consultancy 7

Terms and abbreviations

Terms and abbreviations

GLP-1R glucagon-like peptide-1 receptor

GLP-1RA glucagon-like peptide-1 receptor agonist

Introduction, methodology and assumptions

Source: China Insights Consultancy 10

I. Industry overview of metabolic disorders and digestive diseases

Overview of Metabolic disorders and Digestive diseases

Overview of Metabolic disorders and Digestive diseases

Prevalent Cases of Metabolic disorders and Digestive diseases

CAGR 2018-22 2022-32E Million cases

5,539 5,628 5,717

2,378 2,516 2,551 2,586 2,621 2,656 2,691 2,727

2018 2022 2026E 2027E 2028E 2029E 2030E 2031E 2032E

Source: China Insights Consultancy 13

Global market size of major metabolic disorders and digestive diseases

Global market size of major metabolic disorders and digestive diseases

CAGR 2018-22 2022-32E Billion USD

204 210 216 223 229

Potential impact of the multi-target drug approach

Potential impact of the multi-target drug approach

From single-target to multi-functional drug approach

From single-target to multi-functional drug approach

Multi-target drug approaches

Multi-target drug approaches

• Two (or more) • Simple dosage schedule

• HCC & RCC** & Thyroid

Treatment options comparison

Treatment options comparison

Fixed Dose Multi-

• Traditional treatments are symptom-by-symptom, organ-

• Though drug combination therapies tend to have better

• Single-target drug usually have multiple side effects such

Patient • With multi-functional drugs, patients trade a handful of

Rational design of multi-target drugs

Rational design of multi-target drugs

Current challenges of rational design of multi-target drugs

• Small molecule discovery

Limitations of target-based drug design

Limitations of target-based drug design

Introduction and Advantages of FUSIONTXTM Platform