[ Original Research Diffuse Lung Disease ]

Allogeneic Human Mesenchymal Stem Cells

in Patients With Idiopathic Pulmonary
Fibrosis via Intravenous Delivery (AETHER)
A Phase I Safety Clinical Trial
Marilyn K. Glassberg, MD; Julia Minkiewicz, PhD; Rebecca L. Toonkel, MD; Emmanuelle S. Simonet, MA;
Gustavo A. Rubio, MD; Darcy DiFede, RN, BSN; Shirin Shafazand, MD; Aisha Khan, PhD; Marietsy V. Pujol, MBA;
Vincent F. LaRussa, PhD; Lisa H. Lancaster, MD; Glenn D. Rosen, MD; Joel Fishman, MD, PhD;
Yolanda N. Mageto, MD, MPH; Adam Mendizabal, PhD; and Joshua M. Hare, MD

BACKGROUND: Despite Food and Drug Administration approval of 2 new drugs for idiopathic
pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high.
Preclinical and clinical data support the safety of human mesenchymal stem cells as a
potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in
patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was
the first study designed to evaluate the safety of a single infusion of bone marrow–derived
mesenchymal stem cells in patients with idiopathic pulmonary fibrosis.
METHODS: Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3
cohorts and dosed with a single IV infusion of 20, 100, or 200
106 human bone marrow–
derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline
patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis.
The primary end point was the incidence (at week 4 postinfusion) of treatment-emergent
serious adverse events, defined as the composite of death, nonfatal pulmonary embolism,
stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test
abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter.
Secondary efficacy end points were exploratory and measured disease progression.
RESULTS: No treatment-emergent serious adverse events were reported. Two nontreatment-
related deaths occurred because of progression of IPF (disease worsening and/or acute
exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC
and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide.
CONCLUSIONS: Data from this trial support the safety of a single infusion of human
mesenchymal stem cells in patients with mild-moderate IPF.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.
CHEST 2017; 151(5):971-981

KEY WORDS: bone marrow; idiopathic pulmonary fibrosis; mesenchymal stem cells; safety trial

FOR EDITORIAL COMMENT SEE PAGE 951

ABBREVIATIONS: 6-MWT = 6-min walk test; DLCO = diffusing MedDRA = Medical Dictionary for Regulatory Activities;
capacity of the lungs for carbon monoxide; FDA = Food and Drug MSCs = mesenchymal stem cells
Administration; hMSCs = human mesenchymal stem cells; AFFILIATIONS: From the Departments of Medicine (Drs Glassberg,
HRCT = high-resolution CT; IPF = idiopathic pulmonary fibrosis; Minkiewicz, Shafazand, Khan, Fishman, and Hare; Mss Simonet,

journal.publications.chestnet.org 971
Idiopathic pulmonary fibrosis (IPF) is a progressive airway inflammation, and restore alveolar fluid balance
and debilitating lung disease characterized by in acute lung injury.10-15
interstitial fibrosis with decreasing lung volumes and
In addition to safety data from preclinical studies, human
pulmonary insufficiency, eventually resulting in death.1
trials have also demonstrated the safety and tolerability of
Because of the insidious onset of symptoms, however,
IV allogeneic mesenchymal stem cells (hMSCs).16-23 A
most patients receive a diagnosis at late stages of the
single-center, open-label phase Ib study assessed the safety
disease after significant fibrosis has occurred. Diagnosis
and tolerability of multiple IV doses of adipose-derived
is established by the pathologic finding of usual
stromal cell-stromal vascular fraction (n ¼ 14) for the
interstitial pneumonia and/or by high-resolution CT
treatment of IPF. Although short-term infusion toxicities
(HRCT).2-4
and long-term ectopic tissue formation were reported,
The natural history of this disease is characterized by no adverse events related to the study treatment were
inexorable progressive decline interspersed with observed.21 In another single-center phase I study,
“exacerbations” or periods of accelerated disease, which patients with IPF received IV placenta-derived hMSCs
are often fatal.1 Although 2 new drugs were recently (n ¼ 8). In this study, most adverse events were mild and
approved by the Food and Drug Administration (FDA) self-limiting and no deaths were reported.19
for patients with IPF, neither is curative.5,6
Our study, the Allogeneic Human Cells in Patients With
In preclinical studies, mesenchymal stem cells (MSCs) Idiopathic Pulmonary Fibrosis via Intravenous Delivery
have shown promise as a potential novel treatment for (AETHER) trial, was the first human trial designed to
lung disease.7-9 Studies of MSCs have shown that they evaluate the safety of bone marrow–derived human
contribute to tissue regeneration, home to sites of lung allogeneic mesenchymal stem cells in patients with mild
injury, contribute to tissue remodeling, decrease chronic to moderate IPF.

Methods inconclusive diagnosis). Patients with other infiltrative diseases,

connective tissue disease, pulmonary hypertension, peripheral capillary
Study Design and Participants
oxygen saturation <93% at rest at sea level, life expectancy shorter
AETHER was a single-center, nonrandomized, non–placebo-controlled than 1 year, and those actively listed for any organ transplant were
phase I study of 9 patients with mild to moderate IPF. The study was excluded. Concomitant therapies, except oxygen supplementation and
conducted at the University of Miami Miller School of Medicine pulmonary rehabilitation, were prohibited.
(Miami, FL). Eligible patients were between the ages of 40 and 90, had
a diagnosis of IPF according to American Thoracic Society guidelines, Eleven patients were enrolled between October 30, 2013, and
an FVC of at least 50% predicted, and a diffusing capacity of the lungs September 9, 2014 (Fig 1). Two participants withdrew before
for carbon monoxide (DLCO) of at least 30% predicted.1 Patients treatment (1 from clinical instability and exacerbation of disease
received diagnoses by HRCT (lung biopsy was required in instances of [patient 008] and another from an unforeseen inability to attend the
week 4 safety visit [patient 009]). All patients provided written
informed consent before enrollment and were treated according to
the protocol approved by the University of Miami Institutional
DiFede, and Pujol), Surgery (Drs Glassberg and Rubio), and Pediatrics
(Dr Glassberg), University of Miami Leonard M. Miller School of Review Board (protocol approval #20120924).
Medicine, Miami, FL; Department of Medicine (Dr Toonkel),
The primary end point was the incidence (at week 4 postinfusion) of
Florida International University Herbert Wertheim College of Medi-
cine, Miami, FL; University of Miami Interdisciplinary Stem Cell any treatment emergent serious adverse events, defined as the
Institute (Mss DiFede and Pujol and Drs Khan and Hare), Miami, FL; composite of death, nonfatal pulmonary embolism, stroke,
Department of Cardiology (Dr LaRussa), University of Louisville, hospitalization for worsening dyspnea, and clinically significant
Louisville, KY; Department of Medicine (Dr Lancaster), Vanderbilt laboratory test abnormalities. This definition of treatment-emergent
University Medical Center, Nashville, TN; Bristol-Myers Squibb (Dr adverse events was made on the basis of single-dose IV MSC clinical
Rosen), Lawrenceville, NJ; Department of Medicine (Dr Mageto), trials in cardiovascular disease and aging. These trials used 30-day
University of Vermont College of Medicine, Burlington, VT; and The treatment-emergent adverse events as a primary safety end
EMMES Corporation (Dr Mendizabal), Rockville, MD. point.18,24,25 Secondary efficacy end points were exploratory and
This article was presented at the American Thoracic Society 2016 related to disease progression (rate of acute exacerbations as defined
International Conference, May 18, 2016, San Francisco, CA. by consensus guidelines, and decline of lung function as measured
FUNDING/SUPPORT: Financial support for the AETHER trial came by absolute FVC and DLCO).
from the Lester and Sue Smith Foundation.
CORRESPONDENCE TO: Marilyn Glassberg, MD, Department of
Medicine, Interstitial Lung Disease Program, University of Miami Procedures
Miller School of Medicine. 1600 NW 10th Ave RMSB 7056 (D-60), Patients were assigned to 1 of 3 cohorts and received treatment
Miami, FL 33136; e-mail: [email protected] between November 21, 2013, and October 13, 2014. Allocation ratio
Copyright Ó 2016 American College of Chest Physicians. Published by to cohorts was 1:1:1 (n ¼ 9), with enrolled patients sequentially
Elsevier Inc. All rights reserved. assigned to the 3 cohorts. Dose escalation occurred between cohorts
DOI: http://dx.doi.org/10.1016/j.chest.2016.10.061 as shown in Table 1.

972 Original Research [ 151#5 CHEST MAY 2017 ]

 Enrolled
(n = 11)

Excluded
(n = 2)
1 patient excluded due to clinical instability and acute exacerbation
1 patient excluded due to unforseen inability to attend week for safety visit

Interim
Cohort 1 Cohort 2 Safety Cohort 3
Treated
(n = 3) (n = 3) Analysis (n = 3)
(n = 9)
2 × 107 hMSCs 1 × 108 hMSCs 4 weeks after 2 × 108 hMSCs
Cohort 2 complete

Discontinued
Completed Follow Up (n = 2)
(n = 7) 1 patient died of acute exacerbation and respiratory failure
1 patient died of progression of IPF

Figure 1 – Clinical trial participant flow chart.

Patients in the study received a standard dose of hMSCs rather than Screening of allogeneic donors followed standard transplant practices
weight-based doses made on the basis of results from previous and all allogeneic donors met allogeneic donor eligibility criteria as
studies in patients with cardiovascular disease.16 Detailed study outlined in 21 CFR Part 1271. Donor eligibility screening included
procedures are listed in Table 2. At the initial screening visit, testing for antibodies against HIV-1/2, human T-lymphocyte virus
informed consent was obtained and medical history was reviewed. I/II, hepatitis C virus, hepatitis B core (IgG and IgM), and
Baseline studies included physical examination, routine bloodwork, cytomegalovirus; nucleic acid testing for HIV-1, hepatitis C virus,
urinalysis, ECG, echocardiogram, HRCT, spirometry, DLCO, lung and West Nile virus; and testing for the surface antigen of the
volumes, 6-min walk test (6-MWT), and quality of life hepatitis B virus, Trypanosoma cruzi enzyme-linked immunosorbent
questionnaires. Treatment infusion was considered day 1. Adverse assay, and rapid plasma reagin.
events were reviewed at day 1, week 1, and at all visits thereafter.
The primary end point was assessed starting at week 4 until week For each donor, a total of 60 mL of bone marrow was aspirated from
60 and additionally 28 days thereafter. Secondary efficacy end the posterior iliac crest. The mononuclear cell fraction was isolated
points were measured at baseline and every 12 weeks until week 60. using a density gradient with lymphocyte separation media (specific
gravity, 1.077). Low-density cells were collected and washed with
Plasma-Lyte A containing 1% human serum albumin. Washed cells
Isolation of hMSCs
were sampled and viable cell numbers determined. The bone marrow
Because of the potential for pregnancy-induced antibodies to men’s mononuclear cells were seeded into 225 cm2 tissue culture flasks in
antigens, hMSCs were obtained only from men. Two men aged 24 alpha Minimal Essential Medium containing 20% fetal bovine serum.
and 25 years underwent bone marrow aspiration. Donors were After 14 days of culture, passage zero (P0) cells were harvested by
neither related nor human leukocyte antigen–matched to recipients. trypsin treatment and expanded into 60 individual flasks. These
flasks were incubated for a further 7 to 10 days before harvesting of
MSCs by trypsin treatment (P1 cells). All procedures used in the
TABLE 1 ] Dosing Schedule of AETHER Participants preparation of the investigational product followed protocols
Cohort Subject ID Dosing Date previously published by the sponsor (Joshua M. Hare).26

Cohort 1 001 November 21, 2013 Safety and Monitoring

2
107 hMSCs/ 002 January 22, 2014 After administration of hMSCs, patients were observed overnight in the
infusion ICU for any clinically significant changes in respiratory or cardiovascular
(20 million) 003 February 26, 2014 parameters. Vital signs were assessed 2 hours before infusion, at the start
of the infusion, and every 15 minutes after infusion.
Cohort 2 004 April 17, 2014
1
108 hMSCs/ 005 May 9, 2014 The incidence and nature of all serious adverse events were reviewed and
infusion independently evaluated by the data safety monitoring board to determine
whether they could be related to MSC administration. The data safety
(100 million) 006 May 15, 2104 monitoring board was responsible for reviewing data for each cohort
Cohort 3 007 September 5, 2014 before dose escalation and for making recommendations regarding the
continuation of the trial on the basis of the interim safety analysis
2
108 hMSCs/ 010 October 8, 2014
performed 4 weeks after treatment of the last patient in cohort 2.
infusion
(200 million) 011 October 13, 2014 A nonsafety-related temporary hold was placed on the study on June
30, 2015, by the FDA. All 9 participants were dosed before the hold;
AETHER ¼ Allogeneic Human Mesenchymal Stem Cells in Patients therefore, the dosing schedule was not affected. Adverse events were
With Idiopathic Pulmonary Fibrosis via Intravenous Delivery trial; graded according to the Medical Dictionary for Regulatory Activities
hMSCs ¼ human mesenchymal stem cells. (MedDRA) scale.

journal.publications.chestnet.org 973
974 Original Research

TABLE 2 ] AETHER Schedule of Assessments

Screening Baseline Day 1 Day Week 1 Week 2 Month 1 Month 3 Week Month 6 Week Month 9 Week Month 12 Week Month 15 Week
Visit  28 d 2-4 wk Week 1 2 (Day 7) (Day 14) (Week 4) 12 (3-5 d) 24 (3-5 d) 36 (3-5 d) 48 (3-5 d) 60 (3-5 d)
Informed consent x
Full medical history x
Physical x x x x x x x x x x x x
examination
Chem7, LFTs, PT/ x x x x x x x
INR
Urinalysis, CBC, and x x x x x x x x
metabolic profile
Spirometry x x x x x x
DLCO x x x x x x
Echocardiogram x x
ECG x x x x x x x x x x x x
Treatment x
Review adverse x x x x x x x x x
events
HRCT x x x
6-MWT x x x x x x
Lung volumes x x x x x x
[

QOL questionnaires x x x x x x x
151#5 CHEST MAY 2017

CBC ¼ complete blood count; Chem7 ¼ sodium, potassium, chloride, uric acid, glucose, blood urea nitrogen, creatinine; DLCO ¼ diffusing capacity of the lungs for carbon monoxide; HRCT ¼ high-resolution CT;
LFTs ¼ liver function tests (alanine transaminase, alkaline phosphatase, aspartate transaminase, bilirubin, albumin, total protein, gamma glutamyl transpeptidase); PT/INR ¼ prothrombin time (PT) along with its
derived measures of prothrombin ratio and international normalized ratio (INR); QOL ¼ quality of life. See Table 1 legend for expansion of other abbreviations.
]
Statistical Analysis for safety analyses and projected enrollment rates. A 2-tailed Student
No formal statistical justification was performed to determine sample t test was used to evaluate differences in secondary end points from
size. Cohort size was determined on the basis of expected requirements baseline. A P value < .05 was considered statistically significant.

Results and at 2 hours postinfusion. None of the participants

Table 3 summarizes the baseline characteristics of the experienced clinically significant changes in any of these
9 patients receiving treatment. Mean age of patients was parameters and all patients received the full treatment
71.6 (6.13) years, and all patients were white men of dose.
Hispanic/Latino or Caucasian descent. Mean time from
A total of 21 adverse events occurred in 7 patients in the
diagnosis was 22 months. On the basis of baseline total
modified intention-to-treat set (Table 6). The most
lung capacity, FVC, DLCO, 6-MWT results, and the use
frequently recorded adverse events included bronchitis
of supplemental oxygen, patients in cohort 3 appear
(3 patients) and common cold (2 patients). Of the
to have had more advanced disease than patients in
21 adverse events recorded, only 1 (generalized
cohorts 1 and 2. Eight patients received a diagnosis by
anxiety disorder in patient 007 that began at 8 weeks
HRCT; 1 required a lung biopsy because of a lack of
postinfusion) was classified as possibly related to the
honeycombing on the baseline HRCT.
study intervention (grade 3; MedDRA). No probable
Eleven patients were enrolled in the study, but 2 patients (grade 4; MedDRA) or definite (grade 5; MedDRA)
withdrew before treatment. A total of 9 patients (3 per adverse events were reported.
cohort) received treatment, and 7 patients completed the There were no instances of treatment-emergent
study (Fig 1). Two patients in cohort 3 died before study adverse events. No events of worsened dyspnea or acute
completion, 1 at 10 weeks and 3 days postinfusion and exacerbation were reported within 30 days of treatment.
the other died at 29 weeks and 6 days postinfusion One patient experienced worsened dyspnea at 4 weeks
(Table 4). Reported results are made on the basis of and 5 days postinfusion (patient 007), and the same
the modified intention-to-treat set, which includes all patient experienced an acute exacerbation at 7 weeks
9 patients that received treatment. and 3 days postinfusion.
Table 5 summarizes patients’ respiratory and Three serious adverse events (2 instances of death
hemodynamic parameters at baseline, during treatment, [patients 007 and 010] and 1 instance of respiratory

TABLE 3 ] Baseline Characteristics of Treated Patients

Cohort 1 Cohort 2 Cohort 3
2
107 hMSCs/ 1
108 hMSCs/ 2
108 hMSCs/
Characteristic Infusion Infusion Infusion All Cohorts
Age, y, mean (SD) 71.00 (7.21) 73.33 (4.04) 70.33 (8.62) 71.6 (6.13)
Men, No. (%) 3 (100) 3 (100) 3 (100) 9 (100)
Race, white, No. (%) 3 (100) 3 (100) 3 (100) 9 (100)
Ethnicity, Caucasian, No. (%) 1 (33.3) 2 (66.7) 3 (100) 6 (67)
Ethnicity, Hispanic/Latino, No. (%) 2 (66.7) 1 (33.3) 0 (0) 3 (33)
Time from diagnosis #1 y, No. (%) 2 (66.7) 0 (0) 1 (33.3) 3 (33)
Time from diagnosis $1 y, No. (%) 1 (33.3) 3 (100) 2 (66.7) 6 (67)
HRCT diagnosis, No. (%) 2 (66.7) 3 (100) 3 (100) 8 (88.9)
HRCT þ biopsy diagnosis, No. (%) 1 (33.3) 0 (0) 0 (0) 1 (11.1)
TLC, L, mean (SD) 4.15 (0.59) 4.39 (1.22) 3.93 (0.21) 4.16 (0.71)
FVC, % predicted, mean (SD) 76.00 (18.73) 69.67 (21.55) 56.33 (8.39) 67.33 (17.23)
FVC, mL, mean (SD) 2.88 (0.45) 2.77 (0.82) 2.49 (0.23) 2.75 (0.52)
DLCO, % predicted, mean (SD) 69.67 (21.78) 44.33 (4.62) 45.33 (11.24) 53.11 (17.60)
6-MWT, meters, mean (SD) 415 (58.66) 493 (48.77) 340 (186.35) 416 (120.52)
Baseline supplemental O2, No. (%) 0 (0) 1 (33.3) 2 (66.7) 3 (33.3)

TLC ¼ total lung capacity. See Table 1 and 2 legends for expansion of other abbreviations.

journal.publications.chestnet.org 975
TABLE 4 ] Modified Intention-to-Treat Set
Cohort 1 Cohort 2 Cohort 3
Subject Status 2
107 hMSCs/Infusion 1
108 hMSCs/Infusion 2
108 hMSCs/Infusion Total, No. (%)
Started, No. (%) 3 (100) 3 (100) 3 (100) 9 (100)
Completed, No. (%) 3 (100) 3 (100) 1 (33.3) 7 (78)
Not completed, No. (%) 0 (0) 0 (0) 2 (66.7) 2 (22)

Data are No. of participants (%). Modified intention-to-treat set ¼ participants treated with hMSCs, regardless of study completion. See Table 1 legend for
expansion of abbreviations.

failure [patient 007]) occurred in cohort 3. Patient 007 bone marrow–derived hMSCs in patients with IPF. All
experienced an acute exacerbation and subsequent study objectives followed the recommendations of the
respiratory failure resulting in death at 10 weeks and FDA and the American Thoracic Society.1
3 days postinfusion. Patient 010 experienced progression
AETHER trial met its primary end point of safety,
of IPF (defined as disease worsening according to
showing that the administration of hMSCs is safe in
MedDRA), resulting in death at 29 weeks and 6 days
patients with IPF up to 2
108 cells/infusion. The
postinfusion. None of these serious adverse events was
intervention was well-tolerated in all patients and there
determined to be treatment-related.
were no treatment-emergent serious adverse events
Table 7 shows the progression of lung function reported. A majority of patients (78%) experienced
parameters over the course of the study. Data for treatment unrelated adverse events including, but not
participants 007 and 010 are not available beyond limited to, bronchitis, common cold, and sinusitis
week 4. Figure 2 shows progression of select respiratory (Table 7), which one might expect given the long
parameters up to 60 weeks postinfusion. Data combined duration of the study and the characteristics of the
for all cohorts (n ¼ 7) demonstrated a mean absolute population being studied.
decline in % predicted FVC of 3.0% and a 5.4% decline
There were 2 events of nonstudy-related death from
in % predicted DLCO. Overall, 6-MWT improved by
disease progression and acute exacerbation of IPF. As
36 weeks postinfusion (þ1% improvement from
expected in IPF, those enrolled in the AETHER trial
baseline), and declined to -4.4% from baseline by week
had variable rates of disease progression. Although
60 (Fig 2). These data are considered exploratory
the clinical course of this disease is unpredictable, the
because the study was not powered for efficacy analyses
natural history is typically one of steady decline of lung
and lacked a placebo-control arm.
function punctuated by acute exacerbations. Baseline
lung function parameters suggest that patients in cohort
Discussion 3 had significantly more advanced disease than patients
AETHER was the first clinical trial conducted over in cohorts 1 and 2. The 2 subjects who died were both
60 weeks to support the safety of a single IV infusion of in cohort 3 and had the lowest baseline FVC values and

TABLE 5 ] Respiratory and Hemodynamic Parameters at Baseline and After hMSC Infusion
2 h Before Infusion (Baseline) Start/During Infusion 2 h After Infusion
HR MAP SpO2 HR MAP SpO2 HR MAP
Subject ID (beats/min) (mm Hg) (%) (beats/min) (mm Hg) (%) (beats/min) (mm Hg) SpO2 (%)
001 69 120/73 95 76 121/70 96 79 115/74 96
002 67 116/71 97 75 108/63 95 74 115/60 97
003 65 158/68 99 63 150/49 99 68 134/55 98
004 54 132/61 98 56 120/68 100 62 129/72 99
005 54 153/83 97 58 162/77 98 56 154/76 94
006 70 152/72 99 65 148/82 100 67 130/80 99
007 61 127/63 94 58 137/58 94 58 140/55 95
010 61 158/76 97 60 165/74 98 66 155/74 96
011 56 139/78 98 57 126/71 98 61 97/49 95

HR ¼ heart rate; MAP ¼ mean arterial pressure; SpO2 ¼ peripheral capillary oxygen saturation.

976 Original Research [ 151#5 CHEST MAY 2017 ]

TABLE 6 ] Adverse Events: Pooled Data From the AETHER Trial
Cohort 1 (n ¼ 3) Cohort 2 (n ¼ 3) Cohort 3 (n ¼ 3)
2
107 hMSCs/ 1
108 hMSCs/ 2
108 hMSCs/
Adverse Events Infusion Infusion Infusion Total, No. (%)
Treatment-emergent adverse events 0 0 0 0
Any adverse events 3 1 3 7 (78)
Most frequent adverse eventsa
Bronchitis 3 0 0 3 (33)
Common cold 1 0 1 2 (22)
Less frequent adverse events
Sinusitis 1 0 0 1 (11)
Squamous cell carcinoma 1 0 0 1 (11)
Worsening hypoxia 0 0 1 1 (11)
Dyspnea 0 0 1 1 (11)
Increased cough 0 0 1 1 (11)
Mild sore throat 1 0 0 1 (11)
Rhinitis 0 0 1 1 (11)
Body aches 0 0 1 1 (11)
Leg swelling 1 0 0 1 (11)
Prostatitis 0 0 1 1 (11)
Generalized anxiety disorderb 0 0 1 1 (11)
Serious adverse event(s)
Respiratory failure 0 0 1 1 (11)
Progression of idiopathic pulmonary 0 0 2 1 (22)
fibrosisc
Fatal adverse event(s) 0 0 2 2 (22)

See Table 1 legend for expansion of abbreviations.

a
Adverse events reported by more than one patient in the study.
b
Adverse event possibly related to the study.
c
Corresponds to MedDRA term “IPF,” which includes disease worsening and exacerbations of IPF.

6-MWT distances. One of the 2 patients also had the for IPF, we noted substantial inter- and intra-subject
lowest baseline DLCO overall. In light of a presumed variability in the direction and magnitude of change
1-year mortality risk of approximately 20% in patients of lung function parameters.19,21 The average absolute
with moderately advanced disease,27 the observed decline in % predicted FVC and DLCO by the end of this
death of 2 of 9 subjects was not unexpected. Prior trials study were below the previously mentioned thresholds
using intravenously delivered MSCs, primarily in the for IPF disease progression. However, this small phase I
cardiovascular literature, have not shown increased study was designed to evaluate safety and was not
mortality related to MSC treatment.16,24 Additionally, powered to detect significant changes in lung function.
although concerns that MSCs may contribute to lung Although encouraging, these data are preliminary and
fibrosis have been raised in the past,28-31 there are no should not be interpreted as proof of efficacy of hMSCs
preclinical or human studies that have demonstrated in IPF disease progression.
this relationship.
Results from the ASCEND (A Randomized, Double-
Secondary end points were exploratory and related to Blind, Placebo Controlled, Phase 3 Study of the Efficacy
disease progression. On the basis of Consensus and Safety of Pirfenidone in Patients With Idiopathic
Statement guidelines for patients with IPF, a decline in Pulmonary Fibrosis) trial of pirfenidone for the treatment
the absolute FVC $10% or $15% in the absolute DLCO of IPF suggest that the use of supplemental oxygen and
over 3 to 6 months represents progression of disease.1,32 FVC at baseline significantly correlates with rate of
As with other phase 1 trials of cell-based therapies disease progression.5 In the ASCEND trial, subjects who

journal.publications.chestnet.org 977
TABLE 7 ] Progression of Lung Function Parameters
Subject ID Baseline Week 12 Week 24 Week 36 Week 48 Week 60
TLC, L, Mean
001 3.60 3.21 3.90 3.12 3.16 3.12
002 4.08 4.59 4.04 4.63 4.76 4.80
003 4.78 5.08 4.07 4.39 4.39 3.34
004 5.79 4.39 4.97 4.50 5.81 5.62
005 3.85 3.66 3.53 4.45 4.17 4.39
006 3.54 3.47 3.31 3.62 4.29 4.52
007 3.73 N/A N/A N/A N/A N/A
010 4.14 N/A N/A N/A N/A N/A
011 3.91 4.09 4.25 4.18 4.67 4.85

FVC, L, Mean
001 2.48 2.14 2.56 2.20 2.26 1.95
002 3.38 3.64 2.98 3.39 3.34 3.34
003 2.91 2.85 2.92 2.65 2.69 2.83
004 3.76 3.50 3.67 3.62 3.75 3.61
005 2.18 2.20 2.17 2.05 2.07 2.03
006 2.58 2.62 2.4 2.54 2.42 2.48
007 2.25 N/A N/A N/A N/A N/A
010 2.51 N/A N/A N/A N/A N/A
011 2.70 2.76 2.50 2.47 2.75 2.94

DLCO, % Predicted, Mean

001 63 50 50 52 46 45
002 52 50 44 46 40 43
003 94 79 84 80 72 79
004 47 42 49 50 47 46
005 47 44 51 44 39 45
006 39 41 33 33 41 43
007 48 N/A N/A N/A N/A N/A
010 33 N/A N/A N/A N/A N/A
011 55 63 58 58 58 51

6-MWT, meters, Mean

001 471 460 417 540 450 360
002 420 402 270 315 381 300
003 354 393 405 465 420 366
004 531 423 495 540 560 486
005 510 540 540 525 432 393
006 438 396 405 390 432 405
007 225 N/A N/A N/A N/A N/A
010 240 N/A N/A N/A N/A N/A
011 555 540 540 537 630 510

N/A ¼ not applicable. See Table 2 legend for expansion of other abbreviations.

required supplemental oxygen experienced a higher rate progression. In line with these findings, 3 subjects in the
of disease progression, whereas those with a higher AETHER trial used supplemental oxygen at baseline and
baseline FVC experienced a lower rate of disease 2 died during the course of the study.

978 Original Research [ 151#5 CHEST MAY 2017 ]

 A B
100
100
90
90
80
% Predicted FVC

% Predicted DLCO
80
70
70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
Baseline 12 24 36 48 60 Baseline 12 24 36 48 60
Week Week

C
550
6-MWT distance (m)

500

450

400

350

300
Baseline 12 24 36 48 60
Week

Figure 2 – Secondary efficacy outcomes during the 60-week study period. A, Changes in mean % predicted FVC for overall study period. B, Changes in
% predicted diffusing capacity of the lungs for carbon monoxide (DLCO). C, Changes in 6-min walk test (6-MWT) distance. N ¼ 7 for all data.

Results from the ASCEND trial also suggest that single IV administration of hMSCs up to 2
108 cells/
baseline body weight is correlated with a decreased rate infusion for the treatment of IPF.19,21 Limitations of
of disease progression in treated subjects weighing up to the current study include its small sample size, lack of
approximately 85 kg (187.5 lb). For patients with body randomization, and lack of a placebo arm. Current
weights greater than 85 kg, disease progression was safety findings support the role of more extensive
found to be similar in both the treatment and placebo studies of the safety and efficacy of hMSCs in the
groups. The average body weight of subjects in the treatment of IPF. Before larger randomized placebo-
AETHER study was 86.36 (8.34) kg; only 4 of 9 controlled studies are done to evaluate efficacy, further
subjects weighed less than 85 kg at baseline. Both safety studies should be conducted with larger numbers
patients who died during the study weighed more than of patients as well as patients with more advanced IPF.
85 kg. AETHER did not analyze disease progression in One challenge will be to establish the optimal number
relation to body weight; however, future trials could aim of infusions and the appropriate dosing interval.
to enroll subjects with similar baseline body mass index Another challenge will be to identify early stage
to ensure a uniform weight-based dose of hMSCs. An patients most likely to benefit from the intervention.
alternative approach could be to dose patients by body Ultimately, well-designed and meticulously conducted
weight as in previous hMSC trials.16-20,23 phase II/III clinical trials of hMSCs for the treatment of
IPF will be required to evaluate their efficacy as a
In agreement with other studies of IPF patients treated potential therapeutic modality for this devastating
with cell therapies, the data support the safety of a disease.

journal.publications.chestnet.org 979
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