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Microbiome Modulator
Drugs – The New Generation
of Therapeutic

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 Hannah Sally, Drug Analyst II, CNS, Autoimmune/Inflammation and Ophthalmology

Introduction
The discovery and deep investigation of the much focused upon investigating how exactly its
microbiome has been one of the most cutting-edge interactions within the body contribute to health
advances in biomedical research of recent times. and disease. As a deeper understanding of these
Every human being hosts between 10–100 trillion interactions is gained, the floodgates have opened
symbiotic micro-organisms, including bacteria, for drug development companies to investigate
viruses, and archaea. The collective genomes of the potential of microbiome modulating therapies
these micro-organisms form what is known as the for the treatment of disease. This white paper
human microbiome.1 The microbiome impacts provides an overview of the novel microbiome
human physiological functions in many ways, such modulator industrial development landscape using
as contributing to metabolic functions, protecting Pharmaprojects data, and analyzes the potential for
against pathogens, and interacting with immune treating multiple diseases.
system development.2 Research is now very

Industrial Drug Development Landscape

Pharmaprojects has tracked trends in drug The development of microbiome modulators is
development each year from 1980 until present, primarily at the early stages, with most candidates
which reveal a boom in the development of novel in preclinical development and few reaching clinical
microbiome modulator candidates over the past trials. The magnitude of growth in this area can be
six years (Figure 1). Industrial interest began in explained mostly by the more than six-fold increase
2011, with two microbiome modulators in active in drugs at preclinical stage (as shown in Figure
development at that time. As of January 2018, the 2). But, over the past three years more candidates
number of these drugs in development stands at have entered clinical trials, and currently there are
70. The sudden spark in industrial interest is recent, three candidates at Phase III status. At this point in
as seen by the 65% increase in the number of time, there are no drugs approved for use as human
microbiome modulators being developed over the therapeutics, and therefore, the market is wide open
past two years. in this space.

Figure 1: Number of microbiome modulators in active development, by year, 2011–17

80
70
70
60
Drug count

50
40
27
30
13
20
4 5
10
2 2
0
2011 2012 2013 2014 2015 2016 2017

Source: Pharmaprojects®, January 2018

1. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI (2007) The Human Microbiome Project. Nature, 449(7164), 804–810.
2. Shreiner AB, Kao JY, Young VB (2015) The gut microbiome in health and in disease. Current Opinion in Gastroenterology, 31(1), 69–75.

2 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

Figure 2: Number of microbiome modulators at each development phase, 2015–17

60
53
50

40

30
21
20
8 9
10
2 4 2 2 2 3
1 1
0
2015 2016 2017 2015 2016 2017 2015 2016 2017 2015 2016 2017

Preclinical Phase I Phase II Phase III

Source: Pharmaprojects®, January 2018

Which Companies are Investing in this Research Area?

A total of 26 smaller companies are exploring in terms of microbiome research, with 10 drugs
this new area of research. 10 of these companies currently in development. The company harnesses
are developing more than two novel microbiome its propriety discovery and design platform to
drugs (Table 1), the majority of which purely focus understand how the microbiome may be involved
on products targeting the microbiome. Assembly in specific indications, and is developing Ecobiotic
Biosciences and Enterome are the only companies drugs (a collection of specific bacteria), which aim to
in this list that also research drug development in restore it to a healthy state.
other areas. Seres Therapeutics is the clear leader

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 3

Table 1: Companies developing more than two novel microbiome modulators

Company Number of microbiome modulators in pipeline

Seres Therapeutics 10

Assembly Biosciences 7

Evelo Bioscience 6

Vedanta Biosciences 5

Fimbrion 4

ImmuneBiotech 3

MatriSys Bioscience 3

Second Genome 3

Caelus Health 3

Enterome 3

Source: Pharmaprojects®, January 2018

Although no Big Pharma companies have originated therapeutics for Crohn’s disease, a subtype of IBD.
any microbiome drug development technologies, AbbVie is also interested in the IBD therapeutic
a few have shown interest in this area and area, and formed a licensing agreement with
formed research collaborations with other smaller Synlogic in 2016. Under terms of this agreement,
companies. Janssen (Johnson & Johnson) is the companies will collaborate using Synlogic’s
pursuing development in this area for the treatment proprietary development platform, to discover
of inflammatory bowel disease (IBD). Janssen novel synthetic biotic medicines which modulate
in-licensed Vedanta’s preclinical asset, VE-202, the microbiome. Enterome also entered a research
in 2015, and took over development and future collaboration agreement with Bristol-Myers Squibb in
commercialization of the drug for IBD. Janssen 2016. The companies will work together to discover
also formed a collaborative research agreement and develop microbiome-derived biomarkers, drug
with Enterome in 2016. This collaboration aims targets, and bioactive molecules for the treatment
to discover bioactive molecules and novel targets of immuno-oncology indications.
of the gut microbiome, and develop them as

4 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

Novel Drug Development by Therapeutic Area
The human microbiome is the aggregate of the Figure 3 presents the counts of drugs in
genomes of all microbes which reside on or within development for diseases categorized by
the body. The microbiota population can become therapeutic area (TA). Presently, a large proportion of
imbalanced when there are more ‘bad’, pathogenic novel microbiome modulators are being investigated
bacteria present than ‘good’ bacteria, which is for infectious diseases, but gastrointestinal (GI)
called dysbiosis. Microbiota inhabit a vast number disorders are also popular. Other TAs under
of human tissues, including the gut, skin, oral development include metabolic disorders,
cavity, esophagus, oropharynx, vagina, uterus, and dermatology, oncology, and neurological disorders.
ovaries.3 Due to their presence all over the body,
imbalances in the microbiota could cause a range of
illnesses, offering immense potential for microbiome
therapeutics.

Figure 3: Number of novel pipeline microbiome modulators within each therapeutic area

3
8
24

Neurological disorders

8 Dermatological indications

Cancers

Metabolic disorders

Gastrointenstinal disorders
10 Infections

21

Note: some candidates will be in development across multiple TAs and are counted multiple times.

Source: Pharmaprojects®, January 2018

3. Huttenhower C, et al. (2012) Structure, function and diversity of the healthy human microbiome. Nature, 486(7402), 207–214.

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 5

Infectious disease hosts, which would aid transmission through
Infectious disease is the most common area of populations.5 Considering this, it is vital that the
development, as demonstrated in Figure 3. Antibiotic microbiome is investigated in infectious disease
resistance is a major global health concern, as our drug development. Accordingly, industrial research
ability to treat infectious disease is challenged by focused on developing targeted antibacterial
multi-drug resistant bacteria, the emergence of products which preserve the microbiome, or
which is linked to the excessive use of antibiotics. candidates which act to rebuild the microbiome
Thus, developing methods of pathogen control after infection, is ongoing.
that do not involve antibiotics is important and will
be an essential step in the treatment of infectious The three main areas being investigated are
disease. Additionally, when traditional antibiotics Clostridium difficile infection (C.difficile), methicillin-
are used to treat infection, they deplete the healthy, resistant Staphylococcus aureus (MRSA), and urinary
protective bacteria, as well as the pathogenic tract infections (UTIs). As seen in Figure 4, the
organisms. This disrupts the microbiome and creates majority of drugs are being developed for C. difficile,
an environment in which pathogenic drug-resistant and most function to rebuild the microbiome.
bacteria can colonize and cause disease.4 Moreover, Interestingly, those candidates that aim to preserve
research suggests that the gut microbiome can act the microbiome, whilst still targeting pathogenic
as a reservoir for antibiotic-resistant genes, where bacteria, are mostly being investigated for UTIs and
they can be transferred to other bacteria between MRSA.

Figure 4: Number of pipeline candidates which function to rebuild the microbiome, or preserve the
microbiome, for top infectious disease indications

12
11
10

6
21 4
4

2 2
2
4 2
1
0
C.diff MRSA UTIs C.diff
Microbiome rebuilding Microbiome preserving

Note: drugs in development for unspecified infectious disease excluded from chart count (n=5).
Abbreviations used in Figure: C. diff = Clostridium difficile infection; MRSA = methicillin-resistant Staphylococcus aureus infection; UTIs
= urinary tract infections

Source: Pharmaprojects®, January 2018

4. Centers for Disease Control and Prevention (2016) CDC’S Antibiotic Resistance (AR) Solutions Initiative: Microbiome. Available from: https://www.cdc.
gov/drugresistance/pdf/ARSI-Microbiome-Infographic-2017.pdf [Accessed 5 January 2018].
5. Bengtsson-Palme J, et al. (2015) The Human Gut Microbiome as a Transporter of Antibiotic Resistance Genes between Continents. Antimicrobial
Agents and Chemotherapy, 59(10), 6551–60.

6 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

More than half (13 out of 24) of all microbiome sepsis, and even death. It is considered to be one of
modulators being developed for infectious disease the leading infectious threats to public health.6 C.
are specifically indicated for the treatment of C. difficile infection is commonly seen after antibiotics
difficile infection (Figure 4). C. difficile is a common have been taken for an unrelated issue, as the
environmental bacterium, which most often resides antibiotics remove both the protective resident
in the bowel of both children and adults without bacteria as well as the pathogen targets, which
causing any issues. However, in some cases it allows for opportunistic infection and can cause so-
can act as an opportunistic pathogen and cause called antibiotic-associated diarrhea.7 Currently, six
illness, ranging from mild diarrhea to more serious drugs have reached clinical development stages for
conditions such as pseudomembranous colitis, this public health issue; these are listed in Table 2.

Table 2: Microbiome modulator candidates in clinical development for Clostridium difficile infection

Drug name Company Development phase Drug description

Orally delivered ecology of bacterial spores

SER-109 Seres Therapeutics Phase III
derived from healthy human donor

Live microbes derived from healthy

RBX-2660 Rebiotix Phase III
human donors and delivered via enema

Breaks down intravenous beta-lactam

SYN-004 Synthetic Biologics Phase II
antibiotics in the gut

SER-262 Seres Therapeutics Phase I Synthetically derived microbe ecology

Live microbes derived from healthy

RBX-7455 Rebiotix Phase I
human donors and delivered orally

FIN-403 Finch Therapeutics Phase I Synthetically derived microbe ecology

Source: Pharmaprojects®, January 2018

All candidates included in Table 2, apart from The most advanced candidates are SER-109 (Seres
Synthetic Biologics’ SYN-004, act to rebuild the Therapeutics) and RBX-2660 (Rebiotix), which are
microbiome following dysbiosis caused by C. difficile both probiotic products. SER-109 is an encapsulated
infection, by introducing groups of protective combination of purified probiotic eubacterial spores,
microbiota in the gut. The principal behind this which received breakthrough therapy designation
is to re-establish the healthy microbiota, which and orphan drug designation from the FDA in 2015.
would act to reduce numbers of C. difficile through A Phase II trial in 30 patients was completed in
outcompeting for nutrients or direct bacteriostatic 2014, and demonstrated no product-related adverse
effects. events. It is now currently in a Phase III (ESCOPAR

6. Depestel DD, Aronoff DM (2013) Epidemiology of Clostridium difficile infection. J Pharm Pract, 26(5), 464–75.
7. Beaugerie L, et al. (2003) Antibiotic-associated diarrhoea and Clostridium difficile in the community. Aliment Pharmacol Ther, 17(7), 905–912.

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 7

III) and an extension study (ESCOPAR IV) in a total individuals. XZ.700 is a second-generation
of 420 adults with C. difficile infection, expected to endolysin enzyme, which is currently in preclinical
be completed in 2019. RBX-2660 is a suspension of development, and the company plans to initiate
live bacteria and was investigated in a Phase II trial a Phase I/II trial in 2018, initially to treat atopic
in 242 subjects with recurrent C. difficile infection, dermatitis, for which S. aureus has been implicated
completed in 2017. Treatment with open-label RBX- as a contributing organism.
2660 resulted in a significant reduction in C. difficile
reoccurrence when compared with a historical Fimbrion is another company investigating
control group. It is currently in Phase III trials in targeted antibacterial products, with four currently
the US and Canada, which are also expected to be in preclinical development, specifically for the
completed in 2019. treatment of UTIs. UTIs are very common, and
it is estimated that around 50% of women will
Conversely SYN-004, which is in Phase II experience this infection at some point in their
development, works to degrade intravenous beta- lives.9 Around 10% of UTIs are caused by antibiotic-
lactam antibiotics in the gut, as a preventative resistant bacteria,10 and therefore it is vital that
measure against dysbiosis and C. difficile infection. targeted treatments are developed to prevent the
Beta-lactam antibiotics are commonly used to treat spread of resistant strains. Fimbrion is developing
many different infections in hospitalized patients. mannoside-based products which block FimH, a
This drug acts to preserve the gut microbiome bladder epithelial cell surface receptor through
during IV antibiotic treatment for non-GI infections, which pathogenic bacteria enter the bladder.
and therefore prevents dysbiosis. SYN-004 received
FDA breakthrough therapy status in May 2017, and The advantage of products which act to rebuild
initiation of a Phase III trial is expected in early the microbiome is that they potentially could
2018. be used in a multitude of conditions involving
dysbiosis. However, due to the variation seen in the
MRSA is a multi-drug resistant superbug which can microbiome between individuals, these drugs may
cause difficult-to-treat infections and is prevalent not be the “one size fits all” remedy that companies
in establishments with high numbers of vulnerable, are hoping for. Whilst drugs which act to prevent
immunocompromised people, such as hospitals and microbiome damage may be more targeted, this
nursing homes. It has been estimated that MRSA means that they may only be useful for certain
is responsible for 80,500 severe infections and over conditions and in patients with a specific treatment
11,000 deaths in the US each year.8 One company regime. For example, SYN-004 is intended to prevent
developing targeted antibacterial products for MRSA C. difficile infection in hospitalized patients who are
is Micreos. Micreos’s Phase II candidate, SA.100, is an receiving IV beta-lactam antibiotic treatment. But,
endolysin enzyme, which is targeted to specifically it will not be possible to use this drug to prevent
destroy the bacterial walls of Staphylococcus aureus C. difficile in other vulnerable patients, such as
(including MRSA), but still preserve the rest of the those undergoing chemotherapy. Nevertheless,
microbiome. This ability to preserve the microbiome it is evident that emerging microbiome therapies
makes the product more suitable for chronic usage may be the future of treating threatening infectious
than standard antibiotics, and thus it is ideal for use diseases, especially C. difficile, in the midst of
in hospitalized patients and immunocompromised antibiotic resistance.

8. Centers for Disease Control and Prevention (2016) Biggest Threats. Antibiotic/Antimicrobial Resistance. Available from: https://www.cdc.gov/
drugresistance/biggest_threats.html [Accessed 5 January 2018].
9. Fihn SD (2003) Acute Uncomplicated Urinary Tract Infection in Women. N Engl J Med, 349(3), 259–266.
10. Hooton TM (2001) Recurrent urinary tract infection in women. Int J Antimicrob Agents, 17(4), 259–68.

8 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

Gastrointestinal disorders The microbiomes of patients suffering with IBD
Within the second most common area – and its subtypes are thought to fluctuate more so
gastrointestinal disorders – 21 microbiome than in healthy patients, and this fluctuation or
modulators are currently being developed for the potential dysbiosis is believed to contribute to the
treatment of subtypes of inflammatory bowel inflammation characteristic of IBD.
disease (IBD) and irritable bowel syndrome (IBS),
with numerous candidates being developed for IBS, unlike IBD, has no associated inflammation
more than one subtype (Figure 5). IBD consists of the gut or clear cause, and is instead better
of two chronic and currently incurable diseases described as a collection of symptoms. IBS is divided
of inflammation involving the GI tract: ulcerative into three subtypes: IBS with constipation, with
colitis (UC) and Crohn’s disease. UC is inflammation diarrhea, or mixed IBS. The specific cause of IBS
of the colon and is considered the less severe is still unknown, but the gut-brain axis has been
subset of IBD, whereas Crohn’s disease can cause implicated, with stress and changes in gut bacteria
inflammation anywhere along the GI tract, and thought to result in alterations in both the nerves
results in substantial distress to sufferers. Current controlling bowel movement and fermentation
treatment options are focused on the use of anti- within the intestines.12 Treatment for IBS is focused
inflammatories (eg aminosalicylates), and biologic on symptomatic relief based on the patient’s
therapies such as anti-tumor necrosis factor drugs, presenting symptoms at the time, and includes
including Remicade (infliximab; Johnson and antispasmodics and dietary changes.13
Johnson/Merck & Co/ Mitsubishi Tanabe) and Humira
(adalimumab; AbbVie/Eisai). Despite the prevalence Of the 21 candidates currently under development
of drugs that can result in remission of symptoms for gastrointestinal indications, four are in Phase
of both UC and Crohn’s, there is still an unmet need I, with the remaining being preclinical. Figure 5
for well-tolerated treatment that can bring about presents the number of drugs in development
remission of symptoms quickly. for each disease in Phase I or preclinical stages.
Microbiome modulators are largely being
IBD and its subtypes are characterized by specific investigated for the treatment of IBD, with some
microbial signatures, and the deviation from the candidates specifically intended for Crohn’s (3/21) or
so-called “healthy plane” has been hypothesized UC treatment alone (1/21).
as a potential non-invasive diagnostic method.11

11. Halfvarson J, et al. (2017) Dynamics of the human gut microbiome in inflammatory bowel disease. Nat Microbiol, 2(5), 17004.
12. Kennedy PJ, Cryan JF, Dinan TG, Clarke G (2014) Irritable bowel syndrome: a microbiome-gut-brain axis disorder? World J Gastroenterol, 20(39),
14105–25.
13. For more information, please see Datamonitor Healthcare’s coverage of Ulcerative Colitis, Crohn’s Disease, and Irritable Bowel Syndrome. To access,
visit: https://pharmaintelligence.informa.com/products-and-services/data-and-analysis/datamonitor-healthcare

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 9

 Figure 5: Number of microbiome modulators in development for gastrointestinal indications, by phase

9
8
Number of Microbiome Modulators

8
7
6
5
4
3 3
3
2 2
2
1 1 1
1
0
IBS IBD Crohn’s IBS IBD Crohn’s UC Unspecified

Phase 1 Preclinical

Abbreviations used in figure: IBS = irritable bowel syndrome; IBD = inflammatory bowel disease; UC = ulcerative colitis

Source: Pharmaprojects®, January 2018

Three of the four Phase I candidates are Blautix designed to block adherence of pro-inflammatory
(Blautia hydrogenotrophica; 4D Pharma), Thetanix bacteria to the gut wall in the treatment of IBD.
(Bacteroides thetaiotaomicron, 4D Pharma),
and SER-287 (Seres Therapeutics), which are Blautix is a single-strain probiotic product consisting
bacterial cultures designed to modify a patient’s of Blautia hydrogenotrophica. As an acetate
gastrointestinal profile, to help with the symptoms producing bacteria, Blautix acts to reduce the levels
of IBS in the case of Blautix and IBD in the case of of carbon dioxide and hydrogen in the gut, which
Thetanix and SER-287. The fourth Phase I candidate are produced by fermentation by other bacteria.
is EB8018 (Enterome), which is a small molecule This correspondingly reduces the gas and bloating

10 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

associated with IBS.14 Blautix has been tested in a benefit in patients than currently available therapies,
Phase Ib study and met the trial’s primary endpoints and indicates SER-287 to be a very promising
of tolerability and safety. Additionally, IBS patients candidate for the future treatment of ulcerative
saw a reduction in symptoms and also a reduction colitis. The exact combination of bacteria that is
in hydrogen breath test, which as Blautix is a used in SER-287 has not been disclosed, but Seres
hydrogen-consuming bacteria, is a marker of the has indicated that by increasing the integrity of the
product’s efficacy. mucosal barrier in the colon, SER-287 acts to reduce
pro-inflammatory signaling from bacteria.
Thetanix is a probiotic product being developed
by 4D Pharma for the treatment of pediatric EB8018 is a small molecule, designed to block
Crohn’s disease. Thetanix is thought to improve bacteria that express type 1 fimbrial adhesion FimH
mucosal barrier function, resulting in a reduction from adhering to the gut wall, for the treatment
in pathogens breaching the mucosal barrier, which of Crohn’s disease. Bacteria that express FimH are
could lead to reduced inflammation and increased thought to be overabundant in patients suffering
immunity to pathogens. Thetanix is currently in a from Crohn’s, and are believed to act to increase
Phase I study, and 4D Pharma hopes to commence inflammation and therefore disease severity.15
a Phase II study in 2018. Thetanix received orphan By blocking the attachment of these bacteria, it
drug status from the FDA in 2013, which is an is hypothesized that EB8018 will act to reduce
indication of the unmet need for this indication. inflammation in the gut and improve patient
symptoms, which could have benefits over currently
SER-287 is an oral formulation of bacterial spores, available pharmacological anti-inflammatory
being developed by Seres Therapeutics for the agents, as these come with side effects such as a
treatment of ulcerative colitis. It has recently weakened immune system. EB8018 is currently in
completed a Phase Ib study, which showed a dose- a Phase I trial to test safety and pharmacokinetics,
dependent improvement in clinical remission rates in preparation for a Phase II proof-of-concept trial
in patients unresponsive to current therapies. This expected to be initiated in 2018.
means that it was able to produce a better clinical

14. Leclerc M, Bernalier A, Donadille G, Lelait M (1997) H2/CO2 Metabolism in Acetogenic Bacteria Isolated From the Human Colon. Anaerobe, 3(5),
307–315.
15 Sivignon A, Bouckaert J, Bernard J, Gouin SG, Barnich N (2017) The potential of FimH as a novel therapeutic target for the treatment of Crohn’s
disease. Expert Opin Ther Targets, 21(9), 837–847.

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 11

 Metabolic diseases being investigated in clinical trials. They are being
There are currently 10 microbiome modulators developed for a broad range of conditions, including
in development for metabolic disorders. As lactose intolerance, liver diseases, insulin-related
seen in Figure 6, the majority of drugs are in syndromes, and even the rare maple syrup urine
preclinical development, and just two drugs are disease.

Figure 6: Number of microbiome modulators in development for metabolic indications, by phase

Number of Microbiome Modulators

3 3
3

1 1 1 1
1

0
Lactose Insulin related Insulin related Liver disorder Maple syrup Unspecified
intolerance syndrome syndrome urine disease
Phase III Phase I Preclinical

Source: Pharmaprojects®, January 2018

People with lactose intolerance have an impaired Ritter Pharmaceuticals’ RP-G28 is the most
ability to digest lactose, a carbohydrate found in advanced candidate, which is currently in Phase
dairy products. This occurs when the enzyme which III trials. This orally administered, small molecule
breaks down lactose – lactase – does not function drug stimulates the growth of lactose-metabolizing
properly or production is reduced. Patients with this bacteria in the gut, and adapts the microbiome
condition experience very uncomfortable symptoms to reduce populations of gas-producing bacteria.
after consuming dairy, such as abdominal pain, A multi-center Phase IIb/III trial in 377 patients
gas, bloating, cramps, and diarrhea.16 There are no was completed in 2016. It demonstrated that RP-
treatments for this disease available for patients at G28 significantly improved symptoms of lactose
this point in time, and currently only two novel drug intolerance and also allowed patients to consume
candidates in development. a greater volume of milk without experiencing

16. Harrington LK, Mayberry JF (2008) A re-appraisal of lactose intolerance. Int J Clin Pract, 62(10), 1541–46.

12 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

symptoms. Therefore, this drug shows promise in disorders. The most advanced, Caelus Health’s
allowing these patients to increase their calcium CP-001, has reached Phase I trials, and is an oral
intake without experiencing uncomfortable formulation of Eubacterium hallii. Research has
side-effects. A further Phase III trial is planned demonstrated that this bacterium is abundant in
for the first half of 2018, and filings for market the gut of lean human individuals, and studies in
authorization in both Europe and the US are obese and diabetic mice models suggest that oral
expected in 2019. If approved, this will be the first administration improves energy metabolism and
drug ever marketed for this disorder. There is huge insulin sensitivity.21
market potential, as lactose intolerance is a very
common disorder, with approximately 65% of the The microbiome is also a potential target for the
global population experiencing reduced ability to treatment of the rare metabolic disorder, maple
digest lactose.16 syrup urine disease (MSUD). MSUD is a genetic
disorder in which an affected individual is unable
Insulin-related syndromes include a broad spectrum to process certain amino acids, which results
of diseases such as diabetes, obesity, and glucose in sweet smelling urine; giving the condition its
intolerance.17 There is currently a global obesity name. Symptoms include an inability to eat,
epidemic, with the numbers of people suffering from vomiting, lethargy, and delayed development.
obesity and associated complications, including Without treatment, this serious condition can
diabetes and cardiovascular disease, rising.18 lead to seizures, coma, and death.22 Synlogic
Research suggests that the microbiome plays a is engineering probiotic bacteria to ameliorate
role in the development of obesity and insulin errors of metabolism in a patient and reduce
resistance. An obesity-associated microbiome pathogenesis by either performing critical functions
has been identified, with a greater capacity for or delivering the genes to do so. Preclinical
energy harvest than that of lean people, through studies have demonstrated that the engineered
the breakdown of components of the diet usually bacteria successfully break down both dietary and
resistant to digestion.19 This ability to extract systematic sources of metabolites which build to
more energy from a diet can result in an excess of toxic levels in patients with MSUD.
energy over physiological requirements, and thus
produce an obese phenotype. Additionally, it has The liver is in close contact with the GI tract, and
been suggested that microbiota consortia of obese as such, has the potential to be influenced by the
people interfere with intestinal permeability and gut microbiome. Emerging evidence suggests that
increase the absorption of inflammation-inducing dysbiosis in the gut microbiome is associated with
lipopolysaccharides, resulting in impaired insulin primary sclerosing cholangitis and alcoholic and
signaling.20 non-alcoholic liver diseases. Moreover, research has
demonstrated that prebiotics and probiotics have
Therefore, microbiome modulators have great been efficacious in treating various complications
potential in treating these diseases and slowing of liver disease.23 Four companies are currently
the obesity epidemic. There are four microbiome investigating this type of therapy in the treatment of
modulator candidates in the pipeline for these various liver diseases in preclinical studies.

17. For more information, please see Datamonitor Healthcare’s coverage of Diabetes type 2. To access, visit: https://pharmaintelligence.informa.com/
products-and-services/data-and-analysis/datamonitor-healthcare
18. Uzogara SG (2017) Obesity Epidemic, Medical and Quality of Life Consequences: A Review. Open Science, 5(1). Available from: http://www.
openscienceonline.com/ [Accessed 6 February 2018].
19. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. (2016) An obesity-associated gut microbiome with increased capacity for
energy harvest. Nature, 444(7122), 1027–131.
20. Caricilli AM, Saad MJA (2013) The role of gut microbiota on insulin resistance. Nutrients, 5(3), 829–51.
21. Udayappan S, et al. (2016) Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice. NPJ Biofilms and Microbiomes, 2(1),
16009.
22. Harris-Haman P, Brown L, Massey S, Ramamoorthy S (2017) Implications of Maple Syrup Urine Disease in Newborns. Nurs. Womens. Health, 21(3),
196–206.
23. Tilg H, Cani PD, Mayer EA (2016) Gut microbiome and liver diseases. Gut, 65(12), 2035–2044.

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 13

Dermatological conditions Staphefekt (SA.100; Micreos), mentioned previously,
Eight products are under development for the also treats skin infections by reducing levels of S.
treatment of dermatological conditions: one in aureus, but through the action of an endolysin
Phase II, one in Phase I, and the rest in preclinical. originally isolated from bacteriophages. Staphefekt
The most advanced candidate is MSB-01 (MatriSys is the active ingredient in the Gladskin range of
Bio), a freeze-dried formulation of Staphylococcus creams and lotions, currently available without
hominis Sh-A9 aiming to treat atopic dermatitis prescription for patients with skin conditions with
by altering the balance of so-called ‘good and an infectious component, such as acne, eczema,
bad bacteria’ on the skin. Atopic dermatitis, also and rosacea. Staphefekt specifically targets regions
known as eczema, is characterized by dry skin and that are highly conserved in S. aureus so that it
itchiness, and is most commonly seen in children. is less likely that resistance will develop.27 Given
Treatment is currently focused on over-the-counter the growing danger and awareness of antibiotic
and prescription topical agents, with use of system resistance, this endolysin-based product could be
immunosuppressants in more severe cases.24 an attractive alternative. Staphefekt is currently
in Phase I for the treatment of atopic dermatitis,
MSB-01 contains S. hominis Sh-A9, and it is thought rosacea, and acne, whereas a second-generation
that this so-called ‘good bacteria’ can act to reduce product – XZ.700 (also mentioned previously) – is
levels of the harmful Staphylococcus aureus by being developed for atopic dermatitis. Moreover,
producing bacteriocins specific to S. aureus.25 As further development of XZ.700 in the treatment
mentioned previously, higher levels of S. aureus of acne, rosacea, diabetic wounds, and superficial
are associated with increased disease severity, and wound infections has been suggested.
the use of antibiotics is recommended.26 MSB-01’s
ability, however, to have an anti-microbial effect Early research in cancers and neurological
specific to S. aureus is more beneficial than the use indications
of broad spectrum antibiotics, as it leaves the rest There are currently 10 microbiome modulator
of the microbiome intact, which reduces the risk programs investigating microbiome therapeutics in
of opportunistic pathogens colonizing; a known early preclinical studies for the treatment of a range
side-effect of antibiotic usage. This also makes the of cancers. Microbial pathogens play a role in the
product more suitable for long-term usage, which is pathogenesis of some cancer cases, and dysbiosis
a useful attribute when treating a chronic condition of the microbiome is associated with malignancy.28
such as atopic dermatitis. Moreover, research suggests that the microbiome
plays a role in determining an individual’s response
MSB-01 is currently in a Phase II trial in adults with to cancer medication, as well as susceptibility to
moderate to severe atopic dermatitis and a positive toxic side-effects.29
S. aureus lesion. An earlier form of MSB-01 used a
collection of bacteria sourced from each patient E02315 is Enterome’s lead immuno-oncology
that exhibited antimicrobial activity, and resulted candidate, in preclinical development for the
in dramatic reductions in S. aureus while leaving treatment of glioblastoma multiforme (GBM),
the rest of the microbiome intact.25 MatriSys Bio and is a microbiome-derived cancer vaccine. By
also has a candidate in Phase I – MSB-03 – for the exposing a patient’s immune system to antigens
treatment of rosacea, which it intends to submit specific to GBM via the gut, it is thought to boost
via the 505(b)(2) regulatory pathway (a hybrid the immune response and allow cancer cells to be
between a standard NDA application and a generics more visible to T cells. Current treatment options for
application).

24. For more information on currently available treatments please see Datamonitor Healthcare’s Atopic Dermatitis treatment module. To access, visit:
https://pharmaintelligence.informa.com/products-and-services/data-and-analysis/datamonitor-healthcare
25. Nakatsuji T, et al. (2017) Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic
dermatitis. Sci Transl Med, 9(378).
26. Masenga J, Garbe C, Wagner J, Orfanos CE (1990) Staphylococcus aureus in atopic dermatitis and in nonatopic dermatitis. Int J Dermatol, 29(8),
579–582.
27. Herpers B, Frieling J (2016) An alternative approach to antibiotics. Ind Pharm, 51, 4–6.
28. Bhatt AP, Redinbo MR, Bultman SJ (2017) The role of the microbiome in cancer development and therapy. CA Cancer J Clin, 67(4), 326–344.
29. Roy S, Trinchieri G (2017) Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer, 17(5), 271–285.

14 / February 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

GBM are limited, and it is considered to be the most The gut-brain axis links the central and enteric
lethal type of brain cancer, which makes E02315 nervous systems and allows them to communicate
a potential game changer.30 Another example with each other. Currently, there are three
is the collaboration between Second Genome active preclinical drug programs investigating
and the Mayo Clinic, in which they are working the gut-brain axis and potential applications of
to characterize the bacteria present in stools of microbiome therapeutics in treating neurological
individuals with different types of cancer. They plan disorders. Recent discoveries suggest that the gut
to use these cancer-associated bacteria libraries to microbiome may play a pivotal role in influencing
identify targets and develop a microbiome-based this bi-directional communication through multiple
cancer immunotherapy. pathophysiological mechanisms. Clinical evidence
has demonstrated that there is an association
Seres Therapeutics is collaborating with research between psychological disorders (eg autism,
centers to develop SER-401, an oral therapy anxiety, and depression) and dysbiosis in the
consisting of a specialized consortium of live gut.32 Evelo Biosciences is focused on developing
bacteria to be delivered alongside immunotherapy monoclonal microbials, which are specific strains
medication (anti-PD-1), to improve its efficacy of microbe orally delivered in order to interact with
and safety. This is based on a study showing the cells of the gut. They have therapeutic potential
the impact of microbial profile on the efficacy of through their immunomodulatory functions in
anti-PD-1 treatment in patients suffering from the gut. Evelo intends to investigate their ability to
melanoma. This study showed that patients who treat a range of neuro-inflammatory (ie multiple
exhibited a greater response to treatment had sclerosis, Alzheimer’s, and Parkinson’s disease) and
higher microbial diversity, and a greater proportion psychological (ie autism, anxiety, and depression)
of Ruminococcaceae bacteria.31 Seres has used this disorders.
information to produce SER-401, with the hypothesis
that the combination of these specially selected
bacteria and PD-1 inhibitors would allow for greater
treatment efficacy.

Conclusions
As a result of groundbreaking advances in atopic dermatitis and lactose intolerance, to rare
microbiome research, industrial interest in this area and life-threatening conditions such as brain cancers
has boomed. Considering the broad spectrum of and MSUD. Moreover, microbiome therapeutics may
therapeutic areas impacted by the microbiome, play a pivotal role in battling looming global health
emerging microbiome therapies could make a threats such as the obesity epidemic, and antibiotic
tremendous difference for many patients worldwide resistance. Considering this, it is fair to conclude that
and may be the key to treating currently incurable microbiome modulators are the new generation of
diseases. The therapeutic potential is huge and therapeutic and there may be many exciting new
could impact a wide range of patients, ranging from treatments on the horizon.
those suffering from common disorders such as

30. Please see Datamonitor Healthcare’s Glioblastoma coverage for more information. To access, visit: https://pharmaintelligence.informa.com/
products-and-services/data-and-analysis/datamonitor-healthcare
31. Gopalakrishnan V, et al. (2018) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 359(6371),
97–103.
32. Carabotti M, Scirocco A, Maselli MA, Severi C (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.
Ann Gastroenterol, 28(2), 203–209.

© Informa UK Ltd 2018 (Unauthorized photocopying prohibited.) February 2018 / 15

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