Full Clinical Study Report
Protocol B5161002

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc.
Investigational Product: Domagrozumab
Clinical Study Report Synopsis: Protocol B5161002
Protocol Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multiple
Ascending Dose Study to Evaluate the Safety, Efficacy, Pharmacokinetics andPharmacodynamics of PF-06252616 in Ambulatory Boys With Duchenne Muscular
Dystrophy
Investigators: See Principal Investigator List in Section 16.1.4.1
Study Centers: The study was conducted at 35 centers in 8 countries (Australia, Bulgaria,
Canada, Italy, Japan, Poland, United Kingdom, and United States).

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Publications Based on the Study: None
Study Initiation and Completion Dates: First Participant First Visit (FPFV): 24 November
2014, Primary Completion Date: 30 April 2018, Last Participant Last Visit (LPLV): 23
November 2018
Report Date: 10 May 2019
Previous Report Date(s): Not Applicable.
Phase of Development: Phase 2
Study Objectives:
The primary safety and efficacy objectives of this study were:

To determine the safety and tolerability of multiple ascending repeat intravenous (IV)doses of domagrozumab in ambulatory boys with Duchenne muscular dystrophy(DMD).

To demonstrate the efficacy of treatment with IV doses of domagrozumab based on
an observed mean change from baseline on function (4 stair climb [4SC]) as
compared to placebo following 49 weeks of treatment.

The secondary objectives of this study were:

To characterize the effects of domagrozumab on muscle strength and other functional
assessments compared to placebo.

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To evaluate the pharmacodynamic (PD) activity of domagrozumab based on thepercent change of muscle volume from baseline as compared to placebo.

To evaluate the PD profile of domagrozumab based on growth differentiation factor 8(GDF-8, myostatin) modulation in blood.

To characterize the pharmacokinetic (PK) profile of domagrozumab.

To evaluate the immunogenicity of domagrozumab.

To characterize the long-term effects following approximately 2 years of treatment
with domagrozumab on functional assessments compared to historical control.



To characterize the effects of domagrozumab on muscle strength and functional
assessments compared to placebo in subset of participants who may demonstrate a
rapid disease decline and with relatively low variability over a 1-year period.

090177e190e5f36a\Approved\Approved On: 13-May-2019 07:24 (GMT)The exploratory objectives of this study were:To evaluate biomarkers that may be informative in demonstrating the pharmacologic
effect of domagrozumab. Specifically, to evaluate the effect of domagrozumab on
muscle quality and fat fraction as evaluated by time constant describing the
exponential decay of signal, due to spin-spin interactions (T2)-mapping and fat
fraction imaging (Dixon magnetic resonance imaging [MRI]).



To evaluate biomarkers that may be informative for monitoring hepatic liver injury inthe setting of dystrophic muscle.

To evaluate the Functional Health Status via the Pediatric Outcomes Data Collection
Instrument (PODCI).



To evaluate long-term safety of domagrozumab in participants treated for >1 year.

To evaluate duration of treatment response following withdrawal and/or continuationof treatment for >1 year.

To evaluate response in a delayed treatment group (Sequence Group 3, Period 2).

Exploratory results are not presented in this clinical study report synopsis.
METHODS
Study Design: This was a Phase 2, randomized, 2-period, blinded, placebo-controlled study
to evaluate the safety, efficacy, PK and PD of domagrozumab administered to ambulatory
boys diagnosed with DMD. At the time of primary completion, a limited number of Sponsor
personnel were unblinded in order to complete the primary analysis, while the sites and
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participants remained blinded until the study terminated early, the last study visits werecompleted and the database was locked for final analysis.
The study was designed to randomize approximately 105 eligible participants to 1 of
3 sequence groups so that the participants received investigational product and/or placebo forapproximately 96 weeks (2 treatment periods of approximately 48 weeks each). The primary
completion was reached when all enrolled participants completed through Week 49.
Sequence 1 (n=35):
Period 1: Active treatment (domagrozumab) within participant dose escalation (5, 20 and
40 mg/kg)
Period 2: Active treatment (domagrozumab) at the maximum tolerated dose (MTD) in
Period 1, which was 40 mg/kg for all participants.

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Sequence 2 (n=35):
Period 1: Active treatment (domagrozumab) within participant dose escalation (5, 20 and
40 mg/kg)
Period 2: Placebo
Sequence 3 (n=35):
Period 1: Placebo
Period 2: Active treatment (domagrozumab) within participant dose escalation (5, 20 and
40 mg/kg)
Diagnosis and Main Criteria for Inclusion: The study population consisted of ambulatory
male participants, ages 6 to <16 years, diagnosed with DMD.
Study Treatment: Study drug information is summarized in Table S1. Each dose level was
explored in a dose escalating fashion within participants, starting with the lowest dose. At
each dose level, domagrozumab was administered every 4 weeks for a total of 16 weeks(4 doses). Dose escalation within a participant occurred following review of all available
safety data through the planned fourth dose within each dose level.

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Table S1. Investigational Product Description
Investigational Product
Description

Vendor Lot
Numbers

Pfizer Lot
Numbers

Strength/
Potency

DosageForm

Placebo for domagrozumab for injection
Domagrozumab powder for injection,
100 mg/vial
Domagrozumab powder for solution forinfusion, 260 mg/vial
Domagrozumab powder for injection,
100 mg/vial
Domagrozumab powder for solution forinfusion, 260 mg/vial
Placebo for domagrozumab for injection
Placebo for domagrozumab for injection
Domagrozumab powder for injection,
100 mg/vial

CMPLI003-14
PLI031-15

14-003280
15-006041

0 mg/vl
100 mg/vl

Liquid solution
Lyophile

S3239717-001610

260 mg/vl

Lyophile

PLI030-14

14-003281

100 mg/vl

Lyophile

N1989716-001457

260 mg/vl

Lyophile

CMPLI023-16
PLI051-11
PLI054-11

16-005013
12-000205
12-000910

0 mg/vl
0 mg/vl
100 mg/vl

Liquid solution
Liquid solution
Lyophile

Efficacy Evaluations:Primary Efficacy Endpoint: Mean change from baseline on the 4SC as compared toplacebo by Week 49.
Secondary Efficacy Endpoints:


Mean change from baseline as compared to placebo on function tests including,forced vital capacity (FVC), Northstar Ambulatory Assessment (NSAA), range of
motion (ROM), performance of upper limb (PUL), 6 minute walk distance (6MWD)
at Weeks 17, 33 and 49. Mean change from baseline as compared to placebo on the
4SC at Weeks 17 and 33.

Mean change from baseline as compared to placebo on muscle strength by myometryat Weeks 17, 33 and 49.

In participants randomized to Sequence 1, mean change from baseline as compared tohistorical control on functional tests including, 4SC, 6MWD, FVC, NSAA at
Week 97.

In a pre-specified subset of participants who may demonstrate a rapid disease decline
and with relatively low variability, the mean change from baseline as compared toplacebo on function tests including, 4SC, FVC, NSAA, PUL, 6MWD at Weeks 17,
33 and 49. The 3 pre-specified subsets of participants were defined as participants
with baseline 4SC <3.5 sec, 3.5 sec to 8 sec, and >8 sec.

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In a pre-specified subset of participants who may demonstrate a rapid disease decline,
the mean change from baseline as compared to placebo on muscle strength at
Weeks 17, 33 and 49.

Pharmacokinetic, Pharmacodynamic and Immunogenicity Evaluations: Blood samples(2 mL) to provide serum for PK analysis were collected into the appropriately labeled tubes(containing no anticoagulant or gel separator). PK samples were assayed for domagrozumab
using a validated, sensitive and specific enzyme-linked immunosorbent assay (ELISA)
method.

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Images of the same thigh by MRI were obtained to measure the percent change in muscle
volume as compared to placebo at Weeks 17, 33, and 49. Thigh MRIs were obtained at
approximately the same time of day (morning) to provide optimal testing conditions andconsistency in endpoint measurements. In addition, whole thigh muscle volume index was
also analyzed. Total GDF-8 levels in human serum samples were assayed using a validated,sensitive and specific immunoprecipitation high-performance liquid chromatography tandem
mass spectrometric method (HPLC-MS/MS).
Whole blood samples were collected at the designated times to provide serum for evaluationof domagrozumab immunogenicity. Immunogenicity blood samples were assayed foranti-domagrozumab antibodies using a validated, sensitive and specificelectrochemiluminescent (ECL) assay.
Safety Evaluations: Safety assessments consisted of the collection of adverse events (AEs),serious adverse events (SAEs), vital signs, physical examination/nose and throat mucosal
examinations, dual energy X-ray absorptiometry (DXA) of the spine for bone mineraldensity, X-ray of the hand and wrist for bone age, Tanner stage and testicular volume,12-lead electrocardiogram (ECG), cardiac MRI/echocardiogram, liver MRI, gamma-glutamyltransferase (GLDH, biomarker of liver injury) data, laboratory assessment, and assessment ofsuicidal ideation and behavior as per the Columbia Suicide Severity Rating Scale (C-SSRS).
Statistical Methods: The primary endpoint, change from baseline in 4SC, was analyzed
based on the Full Analysis Set (FAS) using the mixed effects model. For the primary
efficacy analysis, Per-Protocol Analysis Set (PPAS) was used to assess the sensitivity of theanalysis results. Model assumptions were tested using appropriate statistical or graphicaltechniques. Missing data were handled using mixed effect model for repeated measures(MMRM). This analysis was unbiased under the assumption of missing at random when themodel assumptions held. Participants who lost the ability to complete a functional
assessment and/or ambulate were assumed to be missing not at random. Additional methods
to assess the impact of the missing-not-at-random data were also performed. The methods
included transforming time to complete a functional assessment to velocity, so thatparticipants with a missing time were assumed to have a velocity of 0, and performing acompleter analysis (only participants who completed through Week 49 were analyzed). An
analysis using the natural log transformation of the 4SC data was conducted to address the
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skewness in the results and a Wilcoxon Rank-Sum test was also performed to address the
non-normality of the data.
These analyses were performed based on the data for all participants through 49 weeks. The
primary efficacy analysis was tested at =0.025 (one-sided). The same type I error rate wasused for testing the secondary analyses. This test was performed based on the data in
Period 1 from all participants. Participants assigned to Sequence 1 and Sequence 2 wereanalyzed together in an active treatment group compared to participants in Sequence 3(placebo during Period 1). Secondary endpoints were analyzed using the same longitudinal
mixed model as described for the primary analysis.

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PK parameters for domagrozumab were determined from the serum concentration-time
profiles. Actual PK sampling times were used in the derivation of PK parameters. Serum
concentrations for domagrozumab were listed and summarized descriptively by nominal PK
sampling time and dose.
To assess the PD profile of domagrozumab, total GDF-8 concentrations were listed,summarized and plotted for participants in the PD analysis set. Total GDF-8 parameters
were derived from concentration data.
Safety data were summarized according to Sponsor data standards.
RESULTS
Subject Disposition and Demography: A summary of participant disposition by treatment
sequence is presented in Table S2. A summary of participant disposition by combined active
treatment and placebo in Period 1 is presented in Table S3.
All 120 participants treated were male. The majority (80%) were 6 to 10 years of age, with amean (standard deviation [SD]) age of 8.7 (2.0) years. Most (84.2%) participants wereWhite. The mean (SD) body mass index (BMI) was 19.9 (4.6) kg/m2 (range from 11.7 to39.7 kg/m2). The mean weight (SD) of Sequence 3 (35.3 [14.4] kg) was slightly higher thanthat of Sequence 1 (29.9 [8.5] kg) and Sequence 2 (30.3 [8.8] kg), which was driven by
2 participants with weights of 86.4 kg and 81.8 kg. Other demographic characteristics werecomparable among 3 sequences. Demographic characteristics were comparable between
Sequence 1 and historical control, and between combined domagrozumab and placebo
treatment groups.

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Table S2. Participant Evaluation Groups (ITT Population) by Treatment Sequence
Number (%) of Participants
Sequence 1
Sequence 2
Sequence 3
Total
162
Screened
121
Assigned to Study Treatment
Treated
41
39
40
120
Completed
22 (53.7)
21 (53.8)
22 (55.0)
65 (54.2)
Discontinued - Period 1
3 (7.3)2 (5.1)2 (5.0)7 (5.8)
No longer willing to participate
1 (2.4)1 (2.6)
1 (2.5)3 (2.5)in study
Other0
1 (2.6)
1 (2.5)2 (1.7)
Lost to follow-up
1 (2.4)00
1 (0.8)AE
1 (2.4)00
1 (0.8)Discontinued - Period 2
16 (39.0)
16 (41.0)
16 (40.0)48 (40.0)
Study terminated by Sponsor
16 (39.0)
16 (41.0)
16 (40.0)48 (40.0)
Analyzed for PK:
PK concentration
41 (100.0)
39 (100.0)
38 (95.0)
118 (98.3)
PK parameter
41 (100.0)
39 (100.0)
38 (95.0)
118 (98.3)
Analyzed for PD:
Whole body DXA
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
Thigh MRI
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
GDF-8 concentration
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
GDF-8 parameter
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
Analyzed for efficacy:4SC
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
NSAA
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
FVC
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
Muscle strength
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
PUL
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
6MWD
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
ROM
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
Analyzed for safety:AEs
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
Laboratory data
41 (100.0)
39 (100.0)
40 (100.0)
120 (100.0)
Laboratory data (Analyzed): number of participants who dosed in this sequence with at least 1 evaluable
laboratory result.
Efficacy data (Analyzed): participants who dosed and had conducted at least 1 efficacy assessment in thissequence were included.
PK data (Analyzed): participants who dosed and had conducted at least 1 PK assessment in this sequence
were included.
PD data (Analyzed): participants who dosed and had conducted at least 1 PD assessment in this sequence
were included. A total of 121 participants were enrolled and 41 participants were screening failure among
all screened participants.
Sequence 1: Period 1-Active treatment within participant dose escalation (5, 20, 40 mg/kg); Period 2-Active
treatment at the highest tolerated dose in Period 1.
Sequence 2: Period 1-Active treatment within participant dose escalation (5, 20, 40 mg/kg);
Period 2-Placebo.
Sequence 3: Period 1-Placebo; Period 2-Active treatment within participant dose escalation (5, 20,
40 mg/kg).

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Table S3. Participant Evaluation Groups (ITT Population) by Combined Active
Treatment and Placebo - Period 1
Number (%) of Participants
Domagrozumab
Placebo
Screened
162
Assigned to Study Treatment
121
Treated80
40Completed
75 (93.8)
38 (95.0)
Discontinued
5 (6.3)2 (5.0)No longer willing to participate in study
2 (2.5)
1 (2.5)Other
1 (1.3)1 (2.5)
Lost to follow-up
1 (1.3)0AE
1 (1.3)0Analyzed for PK:
PK concentration
80 (100.0)
1 (2.5)
PK parameter80 (100.0)0
Analyzed for PD:
Whole body DXA
80 (100.0)
40 (100.0)
Thigh MRI
80 (100.0)
40 (100.0)
GDF-8 concentration
80 (100.0)
40 (100.0)
GDF-8 parameter80 (100.0)
40 (100.0)
Analyzed for efficacy:4SC
80 (100.0)
40 (100.0)
NSAA
80 (100.0)
40 (100.0)
FVC
80 (100.0)
40 (100.0)
Muscle strength
80 (100.0)
40 (100.0)
PUL
80 (100.0)
40 (100.0)
6MWD
80 (100.0)
40 (100.0)
ROM
80 (100.0)
40 (100.0)
Analyzed for safety:
AEs
80 (100.0)
40 (100.0)
Laboratory data
80 (100.0)
40 (100.0)
AEs (Analyzed): number of participants who dosed in this treatment with AE evaluation.
Laboratory data (Analyzed): number of participants who dosed in this treatment with at least 1 evaluable
laboratory result.
Efficacy data (Analyzed): participants who dosed and had conducted at least 1 efficacy assessment in thistreatment were included in this analysis.
PK data (Analyzed): participants who dosed and had conducted at least 1 PK assessment in this treatment
were included in this analysis.
PD data (Analyzed): participants who dosed and had conducted at least 1 PD assessment in this treatment
were included in this analysis.
A total of 121 participants were enrolled and 41 participants were screening failure among all screened
participants.

Efficacy Results:
Primary Endpoint: The primary efficacy endpoint was the mean change from baseline on
the 4SC as compared to placebo at Week 49. Primary analysis and sensitivity analyses
showed that there were no statistically significant differences in the mean change frombaseline on 4SC between the domagrozumab and placebo groups at Week 49 (Table S4).

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Table S4. Primary and Sensitivity Analyses of Mean Change from Baseline on the 4 Stair Climb for DomagrozumabCompared to Placebo at Week 49

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MMRM Analysis
4SC, FAS
4SC, PPAS
Velocity of 4SC, FAS
Log transformed 4SC, FAS
4SC Completer, FAS
Wilcoxon Rank-Sum Test

N
Active
63
61
75
63
63

Control
32
31
38
32
32
N

ActiveControl

Adjusted Mean (SE)ActiveControl
8.2835 (2.1507)
8.0122 (3.03)
7.0257 (2.0214)
7.7726 (2.7867)-0.0467 (0.0093)-0.0635 (0.013)
0.3045 (0.0535)
0.4033 (0.0754)
1.8801 (0.7438)
2.7539 (1.0437)
Mean Score
ActiveControl

Difference(Active-Control)
0.2712-0.7469
0.0168-0.0989-0.8738
NormalApproximation
P-value (2 sided)

Two-sided
95% CI(-7.3799, 7.9223)(-7.981, 6.4871)(-0.0149, 0.0485)(-0.2834, 0.0856)(-3.4196, 1.6719)

P-Value
0.94230.83030.297
0.28840.4971t
Approximation
P-value(2 sided)
0.22520.3123

4SC, FAS
63
32
45.53252.8590.2222
Velocity of 4SC, FAS
75
38
59.23352.5920.3101
N=number of participants with data available at this time point.
All 4SC data through Week 49 were included for MMRM analysis and Wilcoxon Rank-Sum Test.
Completer was defined as participant with 4SC data at week 49. Participants with missing 4SC values at Week 49 have been excluded.
Baseline was defined as the last pre-dose assessment which was collected at the baseline visit.
Velocity was defined as the reciprocal of the time to climb 4 stairs. For those 4SC missing values when a participant had the test but didn’t have a value, forwhatever reason (lost of ambulation/could not complete or others), its velocity was to have a 0 value. For those who didn’t have the test, missing was tostay missing.
MMRM with baseline result, treatment, time, and treatment by time interaction as fixed effects, participants as random effect.
Change from baseline for each visit was attributed to the last dose received at the previous visit.
Unscheduled and early termination 4SC assessments have been excluded from the presentation.

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Secondary Endpoints: There were no statistically significant differences in the 4SC at
Week 17 or Week 33 between participants on domagrozumab and participants on placebo.
The MMRM analysis for mean change from baseline on NSAA total score using FAS dataset
showed that there were no statistically significant differences between the domagrozumab
and placebo groups at Week 49, with the mean (95% confidence interval [CI]) difference of
1.6 (-0.5, 3.8; p-value=0.1268). However, there was a statistically significant difference
between the domagrozumab and placebo groups at Week 33, with the mean (95% CI)
differences of 2.5 (0.7, 4.2; p-value=0.0061).

090177e190e5f36a\Approved\Approved On: 13-May-2019 07:24 (GMT)The MMRM analysis showed that there were no statistically significant differences between
the domagrozumab and placebo groups at Week 17, Week 33 and Week 49 in the meanchanges from baseline on FVC, PUL overall score and 6 minute walk test (6MWT). There
were statistically significant differences in the mean change from baseline on
myometry-based muscle strength (right elbow extension and right shoulder abduction)
between the domagrozumab and placebo groups at Week 33; however, the differences
favored placebo.
Subgroup analysis showed that there were no statistically significant differences in the meanchange from baseline on the 4SC, FVC, PUL, and 6MWT between the domagrozumab andplacebo groups in all the 3 pre-specified subgroups at Weeks 17, 33 and 49. There were
statistically significant differences in myometry-based muscle strength at Weeks 17 and 33 inparticipants with a baseline 4SC<3.5 sec, however, the differences favored placebo. There
was a statistically significant difference in the mean change from baseline on the NSAA total
score between the domagrozumab and placebo groups at Week 49 in participant withbaseline 4SC>8 sec and the difference favored domagrozumab.
The historical control group was selected using age, 4SC baseline function,
glucocorticosteroid use, ambulatory status and baseline left ventricular ejection fraction(LVEF) function. While there were no statistically significant differences observed whencomparing the historical control group with the placebo (Sequence 3) group at Week 49 for
4SC, there were some differences in the mean change from baseline on the NSAA total scoreand 6MWD suggesting that they may not have been optimally matched for the functional
tests being analyzed.
Pharmacokinetic, Pharmacodynamic and Immunogenicity Results:
PK Results:
Median serum concentrations increased with increasing dose for participants within eachdose level (Period 1 and Period 2) following IV administration at 5, 20 and 40 mg/kg.
Following repeated IV administration at 40 mg/kg, the MTD observed in Period 1,
Sequence 1, median serum concentrations remained generally constant for those participantsin Period 2, Sequence 1. Pre-dose concentration (Ctrough) values generally increased from the
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first dose through the last dose within each dose escalation and appeared to be at steady stateby the last dose across all Period 1 and Period 2 sequence treatments with the exception of
the repeated MTD in Period 2 Sequence 1 as concentrations were at steady state prior toentry into Period 2.

090177e190e5f36a\Approved\Approved On: 13-May-2019 07:24 (GMT)The elimination of the 6-hour PK time point in Protocol Amendment 2 impacted theestimation of maximum serum concentration (Cmax) and time for Cmax (Tmax), therefore inplace of Cmax and Tmax, the concentration at planned 2 hours (C2), the end of infusion, wasdetermined for all participants irrespective of those participants with a 6-hour PK sample
collected. Following a total of 4 IV doses within each dose level, C2 levels were similar
between the first through the last dose administered. Following the last dose of each doselevel, Ctrough and C2 values were similar for both Process 1 (original manufacturing process)and Process 2 (commercial ready process) material.
Additional summarized PK parameters showed that Cmax were generally observed in samples
collected immediately at the end of infusion (about 2 hours). Serum domagrozumab
exposure (Cmax and area under the curve over the dosing interval [AUCτ]) increased withincreasing dose from 5 mg/kg to 40 mg/kg. Overall, exposures were slightly higher at eachdose level after the last dose relative to the first dose reflecting accumulation of
domagrozumab. Following the last dose, systemic clearance (CL) was similar acrosstreatment sequences.
PD Results:
The MMRM analysis showed that there were no statistically significant differences between
the domagrozumab and placebo groups in the mean percent change from baseline on thightissue volume measures at Weeks 17, 33 and 49. Although there were no statisticallysignificant differences in the mean percent change from baseline for both muscle volume andmuscle volume index, there were directionally favorable differences between thedomagrozumab and placebo groups.
Linear regression analyses were conducted on combined treatment groups to understand therelationship between MRI imaging measures and functional measures (log transformed 4SC
and NSAA). MRI endpoints presented in this synopsis include percent change from baselinein both thigh muscle volume and thigh muscle volume index. When comparing Week 49 logtransformed 4SC versus Week 49 thigh volume, there was no significant relationship. When
comparing Week 97 log transformed 4SC versus Week 49 thigh volume, both muscle volume
and muscle volume index were significantly associated with longer term functional changes
suggesting that imaging changes precede functional changes.
Similar results were obtained when comparing imaging measures with NSAA changes at
Week 49 or Week 97. When comparing Week 49 muscle volume imaging changes to NSAA
measures, muscle volume index was correlated with NSAA changes after 49 weeks.
Comparing Week 49 muscle volume imaging measures to Week 97 NSAA changes, muscle
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volume and muscle volume index were significantly correlated with functional changes at alater time point.
As anticipated total serum GDF-8 was modulated at all dose levels given domagrozumab was
anticipated to bind to GDF-8. After domagrozumab treatment was completed in Period 1,
Sequence 2, total serum GDF-8 gradually declined towards the baseline level in Period 2,
Sequence 2 corresponding to the expected decline in drug concentrations. Total serum
GDF-8 Ctrough levels were slightly higher for all dose levels compared to placebo while Ctroughvalues at the 5 mg/kg dose were similar to placebo at Week 61. There were no apparent dose
specific trends observed for total GDF-8 Ctrough levels. Following the last dose of each doselevel, total serum GDF-8 Ctrough values were similar for both Process 1 (original
manufacturing process) and Process 2 (commercial ready process) material.

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Immunogenicity Results:
Among the participants tested for anti-drug antibody (ADA), only 1 (2.7%) participant in thedomagrozumab 20 mg/kg treatment group in Sequence 3 had a positive ADA (titer1.88) at
Week 65 (Study Day 451) and the subsequent sample timepoint was ADA negative.
Neutralizing antibody (NAb) analysis was not performed on the ADA positive sample.
There were no AEs of hypersensitivity reported for this participant.
Safety Results: The majority of participants experienced at least 1 treatment-emergent
adverse event (TEAE). The incidence of TEAEs was comparable between the placebo anddomagrozumab groups, and among the 3 dose levels of domagrozumab. The majority of the
TEAEs were not treatment related. There were no clinically meaningful differences in theincidence of Tier-1 and Tier-2 TEAEs between the domagrozumab and placebo groups. The
incidence of the TEAE of gait inability, which was due to disease progression, wascomparable between the domagrozumab and placebo groups. The number of combinedvertebral and non-vertebral fractures was comparable between the domagrozumab andplacebo groups. For participants in the domagrozumab treatment group, 2 participants
reported all-causality SAEs in Period 1 and 3 participants reported all-causality SAEs in
Period 2. Three participants had treatment-related SAEs (1 femoral neck fracture, 1 anxiety
and 1 troponin increased). One participant in the domagrozumab 40 mg/kg permanently
discontinued from study due to the SAE of anxiety.
There were no clinically meaningful differences in laboratory abnormalities between thedomagrozumab and placebo groups. No participants with elevated liver enzymes and/or
bilirubin met Hy’s law criteria.
There were no clinically meaningful differences in vital signs, 12-lead ECGs, sexual
development, bone age, bone mineral density, LVEF, and C-SSRS between thedomagrozumab and placebo groups.

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090177e190e5f36a\Approved\Approved On: 13-May-2019 07:24 (GMT)The AE of troponin increased was reported for 2 participants each in the placebo group anddomagrozumab group in Period 1. The AE of troponin increased was reported for
1 participant in the placebo treatment group and 3 participants in the domagrozumab group in
Period 2. All of the AEs of troponin increased were mild in severity. The AE of ejection
fraction decreased was reported for 1 participant in placebo group and 2 participants in thedomagrozumab group in Period 2. All of the AEs were mild or moderate in severity andwere caused by disease under study. Only 1 participant in Sequence 1 had both the AEs of
troponin increased and ejection fraction decreased. Both AEs were not related to study drug.
Overall, there were no safety signals identified. However, a letter of special safety concern
was issued on 14 November 2018 due to the preliminary data of potential greater LVEF
decline with domagrozumab exposure for 24 months than with 12 months. The External Data
Monitoring Committee (E-DMC), whose members included a pediatric cardiologist withexpertise in DMD, reviewed the data. Both Sponsor and the E-DMC agreed that no urgent
intervention was required. The final data did not remove this potential risk observed in
Sequence 1. The quantitative difference in LVEF was neither statistically different nor
clinically meaningful. However, it should remain an important potential risk in a population
at-risk for progressive cardiac dysfunction.
Conclusions:
EfficacyThe study did not achieve the primary endpoint at Week 49: the difference (95% CI) in
the mean change from baseline of 4SC for the domagrozumab group compared to placebousing FAS was 0.2712 sec (95% CI: -7.3799, 7.9223; p-value=0.9423), which favored
placebo, and was not statistically significant. The sensitivity analyses showed smallchanges that favored domagrozumab; however, they were not statistically significant.



The MMRM analysis based on FAS for the secondary functional endpoints including:
NSAA, FVC, myometry-based muscle strength, PUL and 6MWT at Week 49 did notdemonstrate statistically significant changes between the domagrozumab and placebogroups.



Results observed on the primary endpoint and other secondary functional endpoints using
the MMRM analysis methodology are difficult to interpret due to skewness in theobserved data and missing data due to loss of ambulation (LOA) or physical inability.
Sensitivity analyses have been presented to address these limitations of the MMRM
method and did not contradict the findings of the primary analysis.

The historical control group performed similar to the placebo group (Sequence 3) at
Week 49 for the 4SC and therefore it was an appropriate comparator for participants who
received domagrozumab through both Periods 1 and 2. There was no statistically

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significant difference in the mean change from baseline on the 4SC at Week 97 between
the Sequence 1 participants and the historical control group.

090177e190e5f36a\Approved\Approved On: 13-May-2019 07:24 (GMT)

PK, Immunogenicity and PDFollowing a total of 4 IV doses at 5, 20 and 40 mg/kg within a participant dose escalatingfashion, serum domagrozumab C2 and Ctrough levels were similar between the first throughthe last dose in both Periods 1 and 2. Trough values generally increased from the firstdose through the last dose within each dose escalation and appeared to be at steady state
following the last dose across all Period 1 and Period 2 sequence treatments.



Following the last dose of each dose level, serum domagrozumab Ctrough and C2 values
were similar for both Process 1 (original manufacturing process) and Process 2(commercial ready process) material.

Following the first and last dose administration at each dose level for participants withadditional PK sampling timepoints, serum domagrozumab exposure (Cmax and AUCτ)increased with increasing dose from 5 mg/kg to 40 mg/kg. Overall, exposure was slightly
higher for the last dose relative to first dose due to accumulation across all Period 1,
Sequences 1 and 2 treatments.

Domagrozumab demonstrated low immunogenicity potential, with only 1 participant inSequence 3 developing positive ADA (titer1.88). No AEs of hypersensitivity werereported for the participant.

The mean T2 relaxation time in both thigh muscle bundle and thigh muscle demonstrated astatistically significant difference between domagrozumab and placebo treatedparticipants at Week 49.

Muscle volume and fat fraction analysis both trended in favor of domagrozumab treatment
at Week 49. However, statistical significance was not observed as compared to placebo.

Regression analyses of MRI changes at Week 49 vs 4SC and NSAA changes at Week 97
indicated statistically significant regression coefficients for thigh muscle, thigh T2
mapping and thigh fat fraction.

Compared to placebo, there were statistically significant increases in lean tissue mass inboth the appendicular skeleton and arms by whole body DXA in the domagrozumab
group at Week 49.

Increases of total serum GDF-8 post domagrozumab treatment from baseline wereobserved for all the treatment sequences.

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Total serum GDF-8 Ctrough levels were slightly higher for all dose levels compared toplacebo while Ctrough values at the 5 mg/kg dose were similar to placebo in Week 61.
There were no apparent dose specific trends observed for total GDF-8 Ctrough levels.
Following the last dose of each dose level, total serum GDF-8 Ctrough values were similar
for both Process 1 (original manufacturing process) and Process 2 (commercial readyprocess) material.

090177e190e5f36a\Approved\Approved On: 13-May-2019 07:24 (GMT)

Safety

Multiple ascending repeat IV doses of domagrozumab at 5, 20 and 40 mg/kg weregenerally safe and well tolerated.



The majority of participants experienced at least 1 TEAE. The incidence of TEAEs wascomparable between the placebo and domagrozumab groups, and among the 3 dose levelsof domagrozumab. The majority of the TEAEs were not treatment related.



There were no clinically meaningful differences in the incidence of Tier-1 and Tier-2
TEAEs between the domagrozumab and placebo groups.



The incidence of the TEAE of gait inability, which was due to disease progression, wascomparable between the domagrozumab and placebo groups.



The number of combined vertebral and non-vertebral fractures was comparable between
the domagrozumab and placebo groups.



There were no clinically meaningful differences in laboratory abnormalities between thedomagrozumab and placebo groups. No participant with elevated liver enzymes and/or
bilirubin met Hy’s law criteria.



There were no clinically meaningful differences in vital signs, 12-lead ECGs, sexual
development, bone age, bone mineral density, LVEF, and C-SSRS between thedomagrozumab and placebo groups. LVEF was noted as an important potential risk in a
population at-risk for progressive cardiac dysfunction.

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