Final Clinical Study Report
Protocol B5161004

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc
Investigational Product: PF-06252616 (Domagrozumab)
Clinical Study Report Synopsis: Protocol B5161004
Protocol Title: A Multicenter, Open-Label Extension Study to Evaluate the Long Term
Safety of PF-06252616 in Boys With Duchenne Muscular Dystrophy
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Centers: The study was conducted at 22 sites, including 4 sites in Canada, 2 sites in
Italy, 2 sites in Japan, 2 sites in the United Kingdom and 12 sites in the United States.
Publications Based on the Study: None
Study Initiation Date: 13 October 2016
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Study Completion Date: 22 November 2018
Report Date: 15 May 2019
Previous Report Date(s): Not applicable
Phase of Development: Phase 2
Primary and Secondary Study Objectives and Endpoints: The primary and secondary
study objectives and endpoints are listed in Table S1.
Study B5161004 was designed as a 4-year study, however this study was prematurely
terminated by the sponsor as no significant treatment effect was observed in Parent
Study B5161002. Therefore, there are less long-term data available in Study B5161004. As
planned, both the changes from overall baseline (B5161002 baseline) in Parent
Study B5161002 and B5161004 baseline in this open-label extension (OLE) study were
evaluated whenever possible. Changes from overall baseline provide a long-term analysis on
the safety and efficacy of domagrozumab, which may have not been possible by only
evaluating the changes from B5161004 baseline. See Statistical Methods section for thedefinition of the overall baseline and B5161004 baseline for the efficacy endpoints.

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints

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Primary
SafetyObjective
To evaluate the long-term safety of IV dosing of
domagrozumab in boys with DMD

EndpointSecondary
Efficacy

To evaluate the long-term efficacy ofdomagrozumab using functional assessments
and strengthPK andimmunogenicity

To assess the PK and immunogenicity ofdomagrozumabIncidence and/or rate of intolerability or dose limiting treatment related AEs following up to an
additional 4 years of treatment
Incidence and/or rate, severity and causal relationship of TEAEs and withdrawals due to TEAEs
following up to an additional 4 years of treatment
Incidence and magnitude of abnormal laboratory findings (clinical laboratory tests: hematology,
chemistry, GGT, GLDH, PT, aPTT, creatine kinase, amylase, serum ferritin, serum iron, total
iron binding capacity, % transferrin saturation; hormones: luteinizing hormone, follicle
stimulating hormone, thyroxine, thyroid stimulating hormone; fecal occult blood; cardiac
Troponin I and urinalysis) following up to an additional 4 years of treatment
Abnormal and clinically relevant changes in liver MRI, physical examination (including atargeted nose and throat mucosal examination), Tanner staging and testicular volume, weight,
vitals, ECG, LVEF measured by echocardiogram (or cardiac MRI), bone mineral density by
DXA, x-ray (hand and wrist for bone age evaluation) and C-SSRS
Mean change from baseline following up to an additional 4 years of treatment in the following
functional assessment tests: PFTs (including FVC, FEV1 and PEFR), 4SC, NSAA, PUL, ROM
and 6MWD
Mean change from baseline in muscle strength measured by myometry following up to an
additional 4 years of treatment
Trough serum domagrozumab concentrations for all participants receiving active drug
Incidence of ADA and NAb

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Protocol B5161004

CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design: This was a Phase 2 OLE study to Protocol B5161002 and provided anassessment of the long-term safety, efficacy, pharmacokinetics (PK), immunogenicity andpharmacodynamics (PD) of intravenous (IV) dosing of domagrozumab in boys with
Duchenne muscular dystrophy (DMD).

090177e190ed12ee\Approved\Approved On: 16-May-2019 02:18 (GMT)The individual dose level selected for each participant was based on the maximum tolerated
dose (MTD) from the parent study B5161002. In the parent study B5161002, eligible
participants were randomized to one of 3 sequence groups:

Sequence 1: Period 1 - active treatment (domagrozumab) within participant dose
escalation (5, 20, 40 mg/kg); Period 2 - active treatment (domagrozumab) at the MTD
in Period 1.

Sequence 2: Period 1 - active treatment (domagrozumab) within participant dose
escalation (5, 20, 40 mg/kg); Period 2 - placebo.

Sequence 3: Period 1 - placebo; Period 2 - active treatment (domagrozumab) within
participant dose escalation (5, 20, 40 mg/kg).

All participants who continued into Study B5161004 from the parent study B5161002
tolerated the 40 mg/kg dose, and therefore all participants received 40 mg/kg of
domagrozumab monthly via an infusion in this OLE study.
Diagnosis and Main Criteria for Inclusion: Eligible participants were boys with DMD
who enrolled and completed through Week 97 of Study B5161002 and who had adequate
hepatic function, glutamate dehydrogenase (GLDH) 20 units/liter (2 × upper limit of normal[ULN]), iron content estimate on the liver magnetic resonance imaging (MRI) within thenormal range as determined by R2* value.
Study Treatment: The investigational product (domagrozumab) was infused over a 2-hour
period (-15 or +30 minutes) which included the flush time. Participants received 40 mg/kg
domagrozumab monthly up to Week 93 in Study B5161004. Investigational productdescription is provided in Table S2.

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Protocol B5161004

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Investigational Product Description
Investigational
Product Description

Vendor Lot
Number

Pfizer Lot Number

Strength/Potency

Dosage Form

PF-06252616 Powder
for Solution for
Infusion, 260mg/vial

N58801

16-002923

260 mg/vl

Lyophile

PF-06252616 Powder
for Solution for
Infusion, 260mg/vial

N99971

16-003498

260 mg/vl

Lyophile

PF-06252616 Powder
for Solution for
Infusion, 260mg/vial

N1989716-001457

260 mg/vl

Lyophile

Efficacy Evaluations:
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Refer to Table S1 for the efficacy endpoints evaluated in the study.
All functional assessments were completed in the following order, pulmonary function tests(PFTs), 4 stair climb (4SC), Northstar Ambulatory Assessment (NSAA), range of motion(ROM), muscle strength, performance of upper limb (PUL), 6-minute walk distance(6MWD). If loss of ambulation occurred, the 4SC, NSAA and 6MWD assessments were notcompleted. Loss of ambulation was defined as the inability to walk unassisted and without
braces for at least 10 m, as assessed and reported by the investigator at each study visit, andconfirmed by the inability to walk/run 10 m (as 1 component of the NSAA) evaluated at thenext visit at which timed function tests were performed.
Pharmacokinetic and Immunogenicity Evaluations:Pharmacokinetics
Trough serum domagrozumab concentrations for all participants receiving domagrozumab
was the only parameter analyzed for PK in this study. Trough serum domagrozumab
concentrations were observed directly from data.
Blood samples (2 mL) providing serum for PK analysis were collected at pre-specified times.
PK samples were assayed for domagrozumab using a validated, sensitive and specificenzyme-linked immunosorbent assay (ELISA) method.
Immunogenicity
Blood samples (2 mL) providing serum for analysis of anti- domagrozumab were collected at
pre-specified times. Human serum anti-drug antibody (ADA) samples were analyzed for thepresence or absence of anti-domagrozumab antibodies using a validated, sensitive andspecific electrochemiluminescent (ECL) assay. A tiered approach using screening,
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CLINICAL STUDY REPORT SYNOPSIS
confirmation and titer assays was used for sample analysis. Samples that were determined to
be positive for ADA were to be further tested for the presence of neutralizing antibody(NAb).
Safety Evaluations: Refer to Table S1 for the safety endpoints evaluated in the study.
Statistical Methods:
Efficacy
Overall baseline was defined as the last pre-dose assessment prior to the first day of dosing inStudy B5161002. B5161004 baseline was defined as the last assessment prior to dosing on
Day 1 in Study B5161004. The B5161004 baseline value was the screening visit which may
in some cases, be the same data as the Week 97 visit for Study B5161002.

090177e190ed12ee\Approved\Approved On: 16-May-2019 02:18 (GMT)The efficacy analysis was performed based on the Full Analysis Set (FAS), which included
all participants who received as least 1 dose of domagrozumab in Study B5161004.
The long-term effect on 4SC following treatment with domagrozumab was characterizedcompared to a natural history control group; a sensitivity analysis of 4SC and NSAA were
performed based on the velocity (defined as the reciprocal of time); and a time-to-event
analysis was performed for loss of ambulation.
Pharmacokinetics
The PK concentration analysis set included all participants who received at least 1 dose of
domagrozumab in Study B5161004 and had at least 1 domagrozumab concentration
measured.
In all data presentations (except listings), concentrations below the limit of quantification(BLQ) was set to 0. Summary statistics were provided for trough serum concentrations by
sequence and timepoint.
Immunogenicity
Immunogenicity analysis was performed based on the Safety Analysis Set (SAS), which
included all participants who received at least 1 dose of domagrozumab in Study B5161004.
Categorical endpoints (ie, positive, negative not tested and missing) were reported for the
ADA assays overall and by sequence and timepoint.
SafetySafety analysis was performed based on the SAS. No formal statistical analysis of safety was
undertaken. Descriptive summaries were generated.

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CLINICAL STUDY REPORT SYNOPSISRESULTS
Participant Disposition and Demography:
Table S3 summarizes the participant disposition in the study. Of 61 participants who werescreened, 2 participants failed at screening due to not meeting entrance criteria and study
termination by the sponsor, and 59 participants were assigned to study treatment and weretreated with domagrozumab. No participants completed the study. The most commonly
reported reason for discontinuation was study termination by the sponsor(55/59 [93.2%] participants).

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All 59 participants were males. Most participants were white (53 participants, 89.8%).
Overall, the mean age was 9.9 years (range: 7.0 to 11.0 years), the mean weight was 37.2 kg(range: 18.9 to 92.9 kg), and the mean body mass index (BMI) was 21.4 kg/m2 (range: 14.3
to 39.4 kg/m2). Weight was slightly greater in Sequence 2 and Sequence 3 compared to
Sequence 1, which was driven by a single participant in each sequence, whose weight was
79.1 kg (Sequence 2) and 92.9 kg (Sequence 3). Overall, comparability was observed on all
demographic characteristics across each sequence.

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CLINICAL STUDY REPORT SYNOPSIS
Table S3. Participant Evaluation Groups by Sequence - SAS

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Number (%) of Participants
Screened: 61

Sequence 1

Sequence 2

Sequence 3

Total

Assigned to Study Treatment: 59
TreatedCompleted
Discontinued
Participant diedOther
Did not meet entrance criteria
No longer willing to participate in study
Study terminated by sponsor

19 (100.0)019 (100.0)000
1 (5.3)18 (94.7)

20 (100.0)020 (100.0)0
1 (5.0)0
1 (5.0)18 (90.0)

20 (100.0)020 (100.0)
1 (5.0)00019 (95.0)

59 (100.0)059 (100.0)
1 (1.7)
1 (1.7)0
2 (3.4)55 (93.2)

Analyzed for PD
Whole body DXA

19 (100.0)

20 (100.0)

20 (100.0)

59 (100.0)

Analyzed for Efficacy
4SC
NSAA
FVC
Muscle strength
PUL
6MWD
ROM

17 (89.5)
16 (84.2)
19 (100.0)
19 (100.0)
19 (100.0)
19 (100.0)
19 (100.0)

13 (65.0)
13 (65.0)
20 (100.0)
20 (100.0)
20 (100.0)
20 (100.0)
20 (100.0)

13 (65.0)
12 (60.0)
20 (100.0)
19 (95.0)
19 (95.0)
18 (90.0)
19 (95.0)

43 (72.9)
41 (69.5)
59 (100.0)
58 (98.3)
58 (98.3)
57 (96.6)
58 (98.3)

Analyzed for Safety
Adverse events
19 (100.0)
20 (100.0)
20 (100.0)
59 (100.0)
Laboratory data
19 (100.0)
20 (100.0)
20 (100.0)
59 (100.0)
Adverse event analysis included participants with adverse events evaluation in the database. Laboratory data analysis included participants with at least
1 evaluable lab result.
Efficacy data analysis included participants who were dosed and had at least 1 efficacy assessment in this sequence.
PD data analysis included participants who were dosed and had at least 1 PD assessment in this sequence.

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CLINICAL STUDY REPORT SYNOPSIS
Efficacy Results:
All the efficacy endpoints evaluated in Study B5161004 were secondary endpoints(Table S1).

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All efficacy assessments measured meaningful disease progression while participants wereenrolled in the study. Not all efficacy endpoints were measured in both Studies B5161002
and B5161004. When endpoints were measured in both Studies B5161002 and B5161004,
the changes from baseline in Study B5161004 are listed as Weeks 13, 25, 49 and 73,
reflecting the changes from pre-dose Day 1 of Study B5161004. However, when these same
visits in Study B5161004 were evaluated as the changes from the overall (B5161002)
baseline, they were listed as Weeks 110, 122, 146 and 170, reflecting timepoints startingfrom the pre-dose Day 1 of Study B5161002 (Table S4). As a result of participants enrollingat various timepoints, the follow-up duration for each participant in Study B5161004 waslimited. Less than 10 participants reached Week 73 for the B5161004 baseline (Week 170
for the overall baseline), and therefore data from these visits are not included in thedescription of efficacy results.
Table S4. Timepoint Equivalence of B5161004 Baseline and Overall Baseline
Week Number From Baseline in Study B5161004

Week Number From Overall Baseline in
Study B5161004
13
110
25
122
49
146
73
170
B5161004 baseline was defined as the last assessment prior to dosing on Day 1 in Study B5161004.
Overall baseline was defined as the last pre-dose assessment prior to the first day of dosing inStudy B5161002.

Four Stair Climb (4SC)
There was a mean increase from overall baseline of 6.784 seconds with a 95% confidence
interval (CI) of 0.749 to 12.819 seconds observed in the 4SC time among 15/59 evaluableparticipants at Week 146. There was no statistically significant difference in change fromoverall baseline for the 4SC time between Sequence 1 and the natural history control groupover the course of Studies B5161002 and B5161004, which was confirmed by avelocity-based sensitivity analysis.
Northstar Ambulatory Assessment (NSAA)The NSAA total score decreased over the course of Studies B5161002 and B5161004. At
Week 146, the mean decrease from overall baseline in the NSAA total score was -8.6 with a
95% CI of -11.9 to -5.3 among 19/59 evaluable participants in the study.
Increases from overall baseline were observed in the time to complete 10 m run/walk overthe course of Studies B5161002 and B5161004, which was confirmed by a velocity-based
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CLINICAL STUDY REPORT SYNOPSIS
sensitivity analysis. At Week 146, the mean increase from overall baseline in the time tocomplete 10 m run/walk was 1.785 seconds with a 95% CI of 0.840 to 2.731 seconds among
13/59 evaluable participants in the study.
Increases from overall baseline in the time to stand from supine were observed over thecourse of Studies B5161002 and B5161004, which was confirmed by a velocity-based
sensitivity analysis. At Week 122, the mean increase from overall baseline in the time tostand from supine was 2.573 seconds with a 95% CI of 0.903 to 4.243 seconds among
18/59 evaluable participants in the study.
Pulmonary Function Tests (PFTs)

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Forced vital capacity (FVC) increased over the course of Studies B5161002 and B5161004.
At Week 146, mean increase from overall baseline was 0.3960 L with a 95% CI of 0.2797 to
0.5123 L among 20/59 evaluable participants in the study.
Percent predicted FVC remained stable over the course of Studies B5161002 and B5161004.
At Week 146, the mean change from overall baseline in percent predicted FVC was 1.2100%
with a 95% CI of -4.8019% to 7.2219% among 20/59 evaluable participants in the study.
Forced expiratory volume in 1 second (FEV1) increased over the course of OLE
Study B5161004. At Week 49, the mean increase from B5161004 baseline for FEV1 was
0.2100 L with a 95% CI of 0.0874 to 0.3326 L among 19/59 evaluable participants in the
study. For percent predicted FEV1, there was a mean increase from B5161004 baseline of
6.3889 L with a 95% CI of -2.4989 to 15.2767 L observed among 18/59 evaluableparticipants at Week 49. This increase of percent predicted FEV1 was primarily driven by
Sequence 1.
For peak expiratory flow rate (PEFR), the mean increase from B5161004 baseline was
8.305 L/min with a 95% CI of -24.489 to 41.099 L/min among 19/59 evaluable participantsat Week 49.
There was no summary data for the mean change from overall baseline for the FEV1
(including FEV1 and percent predicted FEV1) and PEFR as they were not collected in Parent
Study B5161002.
Muscle Strength
Knee extension strength decreased over the course of Studies B5161002 and B5161004. The
loss of knee extension strength was similar between Sequences 1 and 2 with less loss of knee
extension strength in Sequence 3 over time.

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Performance of Upper Limb (PUL)
The total PUL score combines all 3 dimension level scores (shoulder, middle and distal).
Decreases from overall baseline in the total PUL score were observed over the course ofStudies B5161002 and B5161004. Changes over time were similar across the 3 sequences.
At Week 146, the mean decrease from overall baseline in shoulder level score was -2.7 with
a 95% CI of -5.0 to -0.5 among 21/59 evaluable participants; the mean decrease from overall
baseline in the middle level score was -1.0 with a 95% CI of -2.3 to 0.4 among
21/59 evaluable participants; the mean decrease from overall baseline in the distal level score
was -0.1 with a 95% CI of -0.9 to 0.6 among 21/59 evaluable participants.
Six-Minute Walk Test (6MWT)

090177e190ed12ee\Approved\Approved On: 16-May-2019 02:18 (GMT)The 6MWD decreased over the course of Studies B5161002 and B5161004. At Week 146,
the mean decrease from overall baseline in the 6MWD was -138.1 m with a 95% CI
of -213.2 to -62.9 m among 19/59 evaluable participants in the study.
Ankle Range of Motion (ROM)
Passive flexion ankle ROM decreased in both the left and right ankles over the course ofStudies B5161002 and B5161004. At Week 146, the mean decrease of degrees of passive
flexion for the left and right ankles from overall baseline were -10.6 (95% CI = -15.7 to -5.4)
and -11.4 (95% CI = -16.8 to -6.0) among 20/59 evaluable participants, respectively.
Pharmacokinetic and Immunogenicity Results:
Pharmacokinetics
For all sequences, trough concentrations increased from the first dose on Day 1, Week 1 andappeared to be at steady state at Week 25 based on similar median serum trough levels byWeeks 25, 49 and 73.
Immunogenicity
No participants tested positive (titer 1.88) for ADA.
Safety Results:
There were 195 all causalities treatment emergent adverse events (TEAEs) reported by
49 (83.1%) participants. Of these, 6 TEAEs were determined by the investigator as treatment
related, and were reported by 6 (10.2%) participants. The majority of all causalities TEAEs
were mild in severity (173/195 events at preferred term level). All 6 treatment related
TEAEs were mild in severity.

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The most commonly reported TEAEs, regardless of causality, were in the SOCs of infections
and infestations (28/59 participants, 47.5%), and injury, poisoning and procedural
complications (23/59 participants, 39.0%). The most frequently reported TEAEs, regardlessof causality, were fall (13/59 participants, 22.0%), headache (11/59 participants, 18.6%), andnasopharyngitis (11/59 participants, 18.6%). Treatment related TEAEs are summarized inTable S5.

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Table S5. Treatment-Emergent Adverse Events by MedDRA Preferred Term
(Treatment Related) by Sequence in Descending Order of Frequency - SAS
MedDRA (version 21.1) Preferred
Sequence 1
Sequence 2
Sequence 3
Total
Term
(N=19)(N=20)(N=20)(N=59)
Epistaxis
1 (5.3)1 (5.0)02 (3.4)
Blood uric acid increased0
1 (5.0)0
1 (1.7)
Hair growth abnormal0
1 (5.0)0
1 (1.7)
Headache00
1 (5.0)1 (1.7)
Nausea00
1 (5.0)1 (1.7)
Treatment-Emergent adverse events were reported under the last treatment received prior to the onset of theadverse event.
Included all data collected since the first dose of study drug.
MedDRA version 21.1 coding dictionary applied.

There were 5 (8.5%) participants who experienced serious adverse events (SAEs), none ofwhich were determined by the investigator as treatment related. There was
1 (1.7%) participant who discontinued from study due to an SAE of fat embolism syndromethat resulted in death. This SAE was due to a left tibial fracture, which was caused by a fallfrom wheelchair.
There were 4 (6.8%) participants who experienced severe AEs, none of which were
determined by the investigator as treatment related. No participants experienced dose
reduction or temporary discontinuation due to AEs. There was no intolerability or dose
limiting treatment related AEs reported over the course of Study B5161004.
No participants met the potential Hy’s Law criteria. One (1) participant from Sequence 3 hada transient abnormal elevation in GLDH (>2 × ULN) during the study; there were no othersigns of hepatic injury observed.
Three (3) participants from Sequence 1 had reported TEAEs of increased cardiac troponin I,
one of which was determined as an SAE. All TEAEs of increased cardiac troponin I were
determined as not treatment related but due to disease under study.
There were no clinically significant findings observed in relation to vital signs orelectrocardiogram (ECG). The majority of physical examination abnormalities were due todisease under study. A mild treatment related TEAE of abnormal pubertal hair growth was
experienced by 1 participant from Sequence 2. Precocious puberty was not observed. No
advanced bone age was identified as assessed by hand and wrist x-rays.

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There was no apparent change observed in bone mineral density (BMD) (including z-scoreand height adjusted z-score) in anteroposterior (AP) spine total L1 to L4 or body withouthead over time.
There was 1 participant from Sequence 1, whose left ventricular ejection fracture (LVEF)
was 50% at both overall and B5161004 baseline, had an LVEF of <50% at earlytermination visit. Overall baseline for LVEF was defined as the last pre-dose assessment
prior to the first day of dosing in Study B5161002; B5161004 baseline was defined as the lastassessment prior to dosing on Day 1 in Study B5161004.
There was no iron accumulation observed above normal or mild overload in the study.
One (1) participant from Sequence 2 had suicidal ideation at Week 13 but did not have any
suicidal behavior.

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Conclusions:

A 40 mg/kg dose of domagrozumab administered every 4 weeks by IV infusion over
97 weeks (B5161004) was generally safe and well tolerated in boys with DMD in thisstudy.



There were no long-term safety issues associated with dosing DMD boys withdomagrozumab in Parent Study B5161002 for 96 weeks following an additional
97-week treatment of domagrozumab in OLE Study B5161004.



In general, the mean changes from baseline for 4SC, NSAA, PFTs, muscle strength,
PUL, 6MWT and ROM appeared to be consistent with the CINRG natural history
dataset. No apparent treatment effect was observed in Study B5161004.



Following domagrozumab IV administration every 4 weeks at 40 mg/kg, troughvalues steadily increased relative to the first dose.

Trough values appeared to be at steady state at approximately Week 25 for all
sequences.



No participants tested positive for ADA in the study.

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