A Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effects on Heterotopic Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva
Phase: PHASE2
Conditions: Fibrodysplasia Ossificans Progressiva
Sponsor: Regeneron Pharmaceuticals

Clinical Study Protocol 
R2477-FOP-1623 Amendment 6 Global Admin 
EudraCT Number: 2016-005035-33 
IND Number: 130595 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND EFFECTS ON HETEROTOPIC BONE 
FORMATION OF REGN2477 IN PATIENTS WITH FIBRODYSPLASIA OSSIFICANS 
PROGRESSIVA
Compound: 
REGN2477 
Clinical Phase: 
2 
Study Name: 
LUMINA-1 
Protocol Number: 
R2477-FOP-1623 
Protocol Version: 
R2477-FOP-1623 Amendment 6 Global Admin 
Amendment 6 Global  Admin Date of Issue: 
See appended electronic signature page
Amendment 6 Global Date of Issue: 
22 May 2020 
Amendment 5 Global Date of Issue 
25 Oct 2019 
Amendment 4 Global Date of Issue: 
21 Jun 2019 
Amendment 3 Global Date of Issue: 
15 Feb 2019 
Amendment 2 Global Date of Issue: 
29 Nov 2018 
Amendment 1 Global Date of Issue: 
10 Sep 2018 
Original Date of Issue: 
03 Apr 2017 
Scientific/Medical Monitor: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00123469-1.0 Approved - 28 Aug 2020 GMT-5:00
NCT03188666

Clinical Study Protocol 
 
R2477-FOP-1623 Amendment 6 Global Admin 
Regeneron Pharmaceuticals, Inc. 
Page 2 of 126 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 6 Global Admin  
The purpose of this non-substantial amendment is to correct minor errors identified in 
Amendment 6 Global. 
Change 
Rationale for Change 
Section Changed 
This non-substantial amendment seeks to 
correct the following identified minor errors:  
− 
Revised the description of access to 
REGN2477 after Period 3 in the 
synopsis to match correct description in 
the protocol body  
− 
Corrected footnotes #17 and #28 and 
linked #28 to the rows for collection of 
hematology, blood chemistry, and 
urinalysis in Schedule of Events Table 3   
Correction of errors in the 
synopsis and the Schedule 
of Events footnotes for the 
previous Amendment 6 
Global 
Clinical Study Protocol Synopsis, 
Study Duration 
Table 3 Schedule of Events: 
Period 3 (Follow-Up Treatment 
Period), footnote #28 
Section 8.1.1 Footnotes for the 
Schedule of Events Table 1, 
Table 2, Table 3, #17, #28 
 
− 
Revised the description of the change in 
Amendment 6 Global Amendment 
History Table  from ‘every 3 months’ to 
‘every 6 months’ to match the statement 
in the protocol body : 
“Reduced the frequency of blood sample 
collection to every 6 months after week 
56 for assessments of safety and ADA  
Correction of an error in 
the amendment history 
table for the previous 
Amendment 6 Global 
Amendment History Table 
Amendment 6 Global (row 10) 
 
Amendment 6 Global 
The purpose of this amendment is to account for the COVID-19 pandemic and to minimize the 
risks to the patients in the study as well as healthcare providers by allowing flexibility in the visit 
schedule while social distancing suggestions are in place. Allowing for this flexibility does not 
increase the risk of participating in this study as there will be continued contact between the 
patients and study personnel despite postponement of in-person clinic visits.  In addition, this 
amendment seeks to update the planned analysis for Period 2 (open-label treatment period; week 56) based 
on the primary analysis results from Period 1 (double-blind, placebo-controlled period; week 28). These 
data prompted definition of a separate study hypothesis to “treatment with REGN2477 prevents the 
formation of new HO lesion in patients with FOP” and addition of new endpoints to test this separate 
hypothesis for Period 2 (week 56)  
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Page 3 of 126 
CONFIDENTIAL 
Change 
Rationale for Change 
Section Changed 
Added statements to address the impact 
of the COVID-19 pandemic: 
− 
That temporary, alternative 
mechanisms and flexibility in the 
visit schedule that may be used to 
ensure the continuity of clinical 
study conduct and oversight in 
light of the public health 
emergency related to COVID-19. 
 
Defined the COVID-19 modified intent-
to-treat principle that will be used for the 
week 56 primary analysis of efficacy 
endpoints related to imaging 
 
 
To explain the plan for 
ensuring continuity of 
clinical study activities and 
study oversight activities 
during the COVID-19 
public health emergency. 
 
 
 
To address the potential 
impact of the COIVID-19 
pandemic on the collection 
of imaging scans and/or 
missed or delayed study 
drug administration 
Section 3.3.4 Rationale for Efficacy 
Endpoints (Period 2; Week 56) 
Section 3.4 Study-Specific Safety 
Considerations and Monitoring 
Section 5.1 Study Description and 
Duration 
Section 8.1 Schedule of Events 
Section 8.1.1 Footnotes for the 
Schedule of Events Table1, Table 2, 
Table 3, #26 and #27  
Section 8.2.2.1 Positron Emission 
Tomography/Computed Tomography 
Procedures 
Section 10.4.3.2 Analysis of Efficacy 
Endpoints in Period 2 (Week 56) 
Added a summary of the primary 
analysis results for efficacy and safety in 
Period 1 (week 28) 
Added a summary of risks for epistaxis 
and skin and soft tissue infection 
To provide a high-level 
summary of the study 
results for efficacy and 
safety for Period 
1(week 28) 
Section 1 Introduction 
Section 3.4.3 Risk for Epistaxis and 
Monitoring 
Section 3.4.4 Risk for Skin and Soft 
Tissue Infection and Monitoring 
Added a new hypothesis for Period 2 
(week 56; open-label treatment period) 
based on the current understanding of 
the biology of FOP  
Added a rationale for the analyses to 
confirm the new hypothesis (week 56) 
with additional alpha of 0.1 specified for 
control for Type I multiplicity for 
Period 2 (week 56) 
Revised the description of the Clinical 
Endpoint Measures 
To update the planned 
efficacy analysis for Period 
2 (week 56; open-label 
treatment period) based on 
the primary efficacy 
analysis results from 
Period 1 (week 28; double-
blind, placebo- controlled 
period) 
To specify new analyses 
which can handle the 
possibility of patients with 
missing week 56 imaging 
assessment (due to 
COVID-19 disruption for 
the study) and are 
consistent with regulatory 
guidance for analysis for 
rare disease patient 
populations. 
Clinical Study Protocol Synopsis: 
Statistical Plan  
Section 1 Introduction 
Section 3.1 Hypothesis:  Period 1 
Double-Blind, Placebo-Control 
Treatment Period (Week 28)  
Section 3.2 Hypothesis:  Period 2 
Open-Label Period (Week 56) 
Section 3.3.1 Rationale for Clinical 
Development of REGN2477 for FOP  
Section 3.3.3 Rationale for Efficacy 
Endpoint Measures (Period 1; Week 8) 
Section 3.3.4 Rationale for Efficacy 
Endpoints (Period 2; Week 56) 
Section 3.3.6 Clinical Endpoint 
Measures 
Section 10.4.3.2.4 Multiplicity 
Considerations for Period 2 (Week 56) 
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Page 4 of 126 
CONFIDENTIAL 
Change 
Rationale for Change 
Section Changed 
Added new endpoints for Period 2 
(week 56) to confirm the understanding 
of the biology of new HO bone lesions: 
• 
primary efficacy endpoint 
• 
key secondary efficacy 
endpoints 
• 
other secondary efficacy 
endpoints  
 
Added a new primary endpoint 
(week 56) based on low-dose CT 
assessment 
 
 
Reorganized the Study Variables section 
to present endpoints by Period 1 
(week 28), Period 2 (week 56), and 
Period 3 (week 76) 
To describe the added 
endpoints or analysis in 
Period 2 (open-label 
treatment period; Week 56) 
 
 
 
 
To specify a primary 
endpoint using an imaging 
assessment that may be 
easier to perform than the 
PET assessment during the 
COVID-19 
Clinical Study Protocol Synopsis: 
Endpoint(s) for Period 1 (Week 28), 
Endpoint(s) for Period 2 (Week 56)  
Section 3.4.6 Radiation Exposure 
Section 4.2 Primary, Secondary, and 
Exploratory Endpoints (Period 1; Week 
28) 
Section 4.2.4 Other Secondary 
Endpoints  
Section 4.2.5 Other Secondary 
Endpoints related to Clinical 
Pharmacology (Period 1, Period 2, 
Period 3) 
Section 4.2.6 Exploratory Endpoints 
(Period 1; Week 28) 
Section 4.3 Primary, Secondary, and 
Exploratory Endpoints (Period 2; Week 
56) 
Section 4.3.1 Primary Efficacy 
Endpoint (Period 2 [Week 56]) 
Section 4.3.2 Key Secondary Efficacy 
Endpoints (Period 2 [Week 56]) 
Section 4.3.3 Other Secondary Efficacy 
Endpoints (Period 2 [Week 56]) 
Section 4.3.4 Exploratory Endpoints 
(Period 2 [Week 56]) 
Section 4.4 Exploratory Endpoints 
(Period 3 [Week 76]) 
Section 5.1.2 Period 1:  Double-Blind 
Treatment (Week 1 [Day 1] to Week 24 
[Day 169]) and End of Period 1 
Assessments (Week 28 [Day 197]) 
Section 5.1.3 Period 2:  Open-Label 
REGN2477 Treatment (Week 28 [Day 
197]) to Week 52 [Day 365]) and End 
of Period 2 Assessments (Week 56 
[Day 393]) 
 
 
Section 5.1.4 Period 3:  Follow-Up 
Treatment Period Week 56 (Day 393) 
to End of Study 
Section 8.1.1 Footnotes for the 
Schedule of Events Table 1, Table 2, 
and Table 3, #26, #27 
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CONFIDENTIAL 
Change 
Rationale for Change 
Section Changed 
Added description of the new statistical 
analyses for efficacy in Period 2 
(week 56) 
To specify the new 
statistical analyses in 
Period 2 (open-label 
treatment period; week 56) 
based on the primary 
efficacy analysis results 
from Period 1 (week 28; 
double-blind, placebo-
controlled period) 
Clinical Study Protocol Synopsis: 
Statistical Plan  
Section 3.3.4 Rationale for Efficacy 
Endpoints (Period 2; Week 56) 
Section 10 Statistical Plan 
Section 10.1.1 Statistical Hypothesis 
(Period 1 [Week 28]) 
Section 10.1.2 Statistical Hypothesis 
(Period 2 [Week 56]) 
Section 10.4.3.1 Analysis of Efficacy 
Endpoints in Period 1 (Week 28) 
Table 5 Analysis Strategy for Primary 
and Key Secondary Efficacy Endpoints 
Section 0 Primary Endpoints: Total 
Lesion Activity by 18F-NaF PET 
Section 10.4.3.1.2 Primary Endpoints: 
Total HO Volume by CT 
Section 10.4.3.2 Analysis of Efficacy 
Endpoints in Period 2 (Week 56) 
Section 10.4.3.1.4 Multiplicity 
Considerations for Efficacy Analyses 
for Period 1 (Week 28) 
Section 10.4.3.2.1 Primary Efficacy 
Endpoints in Period 2 (Week 56) 
Section 10.4.3.2.2 Key Secondary 
Efficacy Endpoints in Period 2 
(Week 56) 
Section 10.4.3.2.3 Other Secondary 
Efficacy Endpoints in Period 2 
(Week 56) 
Section 10.4.3.2.4 Multiplicity 
Considerations for Period 2 (Week 56) 
Section 10.4.5 Analysis of Drug 
Concentration and Total Activin A 
Concentration Data 
Section 10.5 Primary and Additional 
Analysis 
Updated the description of the analysis 
of efficacy endpoints in Period 1 (Week 
28) was updated (amendment 6) to 
match the final SAP for Period 1 
To be consistent with the 
final SAP for Period 1 
(double-blind treatment 
period; Week 28) issued 
before the database lock 
Clarified the description of drug 
(functional REGN2477) and target (total 
activin A) assessed 
To be consistent with the 
drug and target assays 
Added a description of the criteria for 
continued access to REGN2477 for 
patients who completed Period 3 
(week 76) 
To be consistent with our 
corporate policy governing 
access to investigational 
drugs in confirmatory 
clinical studies. 
Clinical Study Protocol Synopsis: 
Study Design 
Section 5.1 Study Description and 
Duration 
Figure 1 Study Design Schematic 
Screening/Baseline Period (Day -28 to 
Day -1):  Study Visit 1 
Section 5.1.4 Period 3:  Follow-Up 
Treatment Period Week 56 (Day 393) 
to End of Study 
Section 8.1.1 Footnotes for the 
Schedule of Events Table 1, Table 2, 
and Table 3, #17 
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CONFIDENTIAL 
Change 
Rationale for Change 
Section Changed 
Removed the requirement for a safety 
discussion with investigators prior to 
each administration of study drug after 
week 56.  Therefore, after week 56 the 
need for such interactions will be 
decided on a case by case basis.  
The safety results for 
Period 1 (week 28) have 
not identified significant 
safety concerns that require 
continued safety 
discussions or frequent 
safety laboratory 
assessments. 
Clinical Study Protocol Synopsis: 
Study Design 
Section 5.1.2 Period 1:  Double-Blind 
Treatment (Week 1 [Day 1] to Week 24 
[Day 169]) and End of Period 1 
Assessments (Week 28 [Day 197]) 
Section 7.2.1 Dose Modification 
Section 7.2.2 Study Drug 
Discontinuation  
Table 3 Schedule of Events:  Period 3 
(Follow-Up Treatment Period) 
Section 8.1.1 Footnotes for the 
Schedule of Events Table 1, Table 2, 
and Table 3, #11, #17, #28 
Section 8.1.2 Early Termination Visit 
Reduced the frequency of blood sample 
collection to every6 months after 
week 56 for assessments of safety and 
ADA  
The reduction in 
assessments for safety and 
ADA assessment after 
week 28 reduces the 
burden on patient.  
Added assessments for FOP I-ADL, 
EQ-5D-3L, CAJIS and spirometry and 
collection of blood samples for 
measurement of drug and target, and 
ADA every 24 weeks after week 76. 
To support assessment of 
safety, PK, target, and 
ADA. 
Table 3 Schedule of Events:  Period 3 
(Follow-Up Treatment Period) 
Section 8.1.1 Footnotes for the 
Schedule of Events Table 1, Table 2, 
and Table 3, #17 
Will ask patients who permanently 
discontinue study treatment but do not 
withdraw from the study to return to the 
clinic for blood sample collection for  
• 
measurement of serum drug 
and target concentration, at 
4 weeks, 8 weeks, and 
16 weeks, and 28 weeks after 
the patient's last dose. 
• 
assessment of ADA at the 
patients last visit. 
The request will support 
assessment of 
- 
drug elimination 
phase  
- 
safety assessments 
for follow-up of 
patients 
- 
assessment for 
potential disease 
rebound 
- 
assessment of ADA 
at the end of the 
study  
Section 7.2.2 Study Drug 
Discontinuation 
Section 8.1.2 Early Termination Visit 
Updated Pharmacovigilance and Risk 
Management to Global Patient Safety in 
various sections 
Text change reflects the 
new organization name  
Section 7.2.1.1 Individual Level Dose 
Modification 
Section 9.6 Safety Monitoring 
Amendment 5 Global 
Change and Rationale for Change 
Section Changed 
• 
The purpose of this amendment is to revise the 
description of study treatment based on a new 
liquid formulation. The option for subcutaneous 
(SC) administration is removed as the 
concentration of the current formulation is not 
suitable for SC use.  
Section 7.1 Investigational and Reference Treatments 
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CONFIDENTIAL 
Amendment 4 Global 
Change and Rationale for Change 
Section Changed 
This is a non-substantial amendment to change the 
hierarchy order of statistical testing for the primary 
efficacy and key secondary endpoints in response to 
comments from a health authority.  The order of 
statistical testing of the primary efficacy and key 
secondary endpoints is:  Baseline-Active heterotopic 
ossification (AHO) analysis set first and Baseline-Active 
HO Classic ACVR1[R206H] Mutation (AHOC) analysis 
set second. 
Clinical Study Protocol Synopsis: Endpoints, Efficacy 
Analysis Sets, Primary Efficacy and Key Secondary; 
Statistical Plan, Justification of Sample Size, Statistical 
Methods 
Section 4.2.2 Primary Efficacy Endpoints 
Section 4.2.3 Key Secondary Endpoints 
Section 10.1 Statistical Hypothesis 
Table 5 Analysis Strategy for Primary and Key 
Secondary Efficacy Endpoints 
Section 10.4.3.1.1 Primary Endpoints: Total Lesion 
Activity by 18F-NaF PET 
Section 10.4.3.1.2 Primary Endpoints: Total HO 
Volume by CT 
Section 10.4.3.1.3 Key Secondary Endpoints: Pain 
NRS-AUC 
Section 10.2 Justification of Sample Size 
Section 10.3.1 Baseline-Active HO Analysis Set 
Section 10.3.2 Baseline-Active HO Classic 
ACVR1[R206H] Mutation Analysis Set 
Section 10.4.3.1.4 Multiplicity Considerations 
Update in Scientific/Medical Monitor title 
Title Page 
Typographical errors 
Throughout the document 
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CONFIDENTIAL 
Amendment 3 Global 
Change and Rationale for Change 
Section Changed 
The purpose of this amendment is to revise the protocol 
to reflect new safety information relating to a potential 
risk for epistaxis. 
In order to mitigate the potential risk for epistaxis, 
3 exclusion criteria were added: 
• #18 Patients who are on concomitant antiplatelet 
therapy (egg, clopidogrel), anti-coagulants 
(eg, warfarin, heparin, factor Xa inhibitor, or 
thrombin inhibitors) in the last 30 days or within 
5 half-lives of the therapy, whichever is longer.  
Low dose acetylsalicylic acid (aspirin) is 
acceptable. 
• #19 Patients with a history of severe, non-traumatic 
bleeding requiring transfusion or hospitalization for 
hemodynamic compromise 
• #20 Patients with a known pre-existing medical 
history of a bleeding diathesis (eg, hemophilia A, 
von Willebrand’s Factor deficiency, platelet count 
≤20x109/L). 
As an additional mitigation strategy, investigators should 
discourage the use of anti-inflammatory drugs that inhibit 
platelet function or are otherwise associated with an 
increased risk of bleeding, to the extent possible. 
Clarified the Low dose acetylsalicylic acid (aspirin; 
[≤100 mg/day]) 
To aid in the exclusion of patients who may have existing 
propensity for bleeding and to assess the effect of 
REGN2477 administration, baseline and post-treatment 
laboratory measures of coagulation parameters and 
platelet effector function were added.  
Added baseline exploratory research sample to explore 
mechanism of epistaxis and REGN2477 mechanism of 
action  
Added antiplatelet therapy, anticoagulants, and herbal 
supplements (that inhibit platelet function or are 
associated with increased risk of bleeding) to the list of 
prohibited medications  
To increase early detection of epistaxis or bleeding 
events, the following were added as adverse events of 
special interest (AESIs): 
• Moderate to severe episodes of non-traumatic 
bleeding 
• Moderate epistaxis (defined as any episode lasting 
longer than 30 minutes or requiring professional 
medical intervention)  
• Severe epistaxis (based on definition of a severe AE 
as per protocol) 
Clinical Study Protocol Synopsis: Procedures and 
Assessments 
Section 3.3.3 Potential Risk for Epistaxis and 
Monitoring  
Section 5.1.1 Screening/Baseline Period (Day -28 to 
Day -1): Study Visit 1 
Section 5.1.2 Period 1:  Double-Blind Treatment 
(Week 1 [Day 1] to Week 24 [Day 169]) and End of 
Period 1 Assessments (Week 28 [Day 197]) 
Section 6.2.2 Exclusion Criteria, #18, #19, #20 
Section 7.6.1 Prohibited Medications 
Section 7.6.2 Permitted Medications 
Table 1 Schedule of Events:  Screening/Baseline 
through Period 1 (Randomized Double-Blind 
Treatment Period) 
Table 2 Schedule of Events: Period 2 (Open Label 
Treatment Period) 
Table 3 Schedule of Events: Period 3 (Follow-Up 
Treatment Period 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2, and Table 3, #25 
Section 8.2.4.5 Laboratory Testing 
Section 8.2.6 Biomarker Procedures 
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
 
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CONFIDENTIAL 
Amendment 2 Global 
Change and Rationale for Change 
Section Changed 
The purpose of this amendment is to add individual level 
dose modification criteria, clarify the study level dose 
modification, and specify that a pregnancy will be 
tracked until delivery along with a 3-month postnatal 
follow-up period for the infant, in response to a health 
authority requests. 
Clinical Study Protocol Synopsis: Study Design 
Section 3.2.7 Rationale for Dose Selection 
Section 3.3.2 Potential Risk for Teratogenicity/Fetal 
Toxicity and Pregnancy Monitoring and Prevention 
Section 5.1.3 Period 2:  Open-Label REGN2477 
Treatment (Week 28 [Day 197]) to Week 52 [Day 
365]) and End of Period 2 Assessments (Week 56 
[Day 393]) 
Section 7.2.1 Dose Modification 
Section 7.2.1.1 Individual Level Dose Modification 
Section 7.2.1.2 Study Level Dose Modification 
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
Added 3 footnotes that had been inadvertently omitted 
from amendment 1 Global: 
• 
A footnote to indicate that measurement of a 
patient’s height may not be precise or not 
possible to be assessed. 
• 
A footnote clarifying the urinalysis procedure.  
• 
A footnote to provide more detail about the 
clinical endpoint measures.  
Added further detail regarding study assessments. 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2 and Table 3: Footnotes #22, #23, and 
#24.   
Section 8.2.3 Clinical Endpoint Measures 
Section 8.2.4.5 Laboratory Testing 
Minor edits for clarification of study terminology, 
corrections, and minor changes: 
• 
Clarified the description of the sample size  
• 
Correct an error in description of the full 
analysis set in the synopsis 
Clinical Study Protocol Synopsis: Study Design, 
Population, Endpoints, Statistical Plan 
Section 1 Introduction 
Section 3.2.2 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 6.1 Number of Patients Planned 
Section 7.2.1 Dose Modification 
Section 7.2.1.1 Individual Level Dose Modification 
Section 7.2.1.2 Study Level Dose Modifications 
Section 10.2 Justification of Sample Size 
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CONFIDENTIAL 
Amendment 1 Global 
Change and Rationale for Change 
Section Changed 
The purpose of this amendment 1 Global is to remove the 
requirement that patients have the specific classic 
ACVR1[R206H] mutation.  This change is based on in 
vitro studies which demonstrated that different mutations 
in ACVR1 receptors transduced bone morphogenic 
protein signaling when stimulated with Activin A.  These 
results indicate that REGN2477 may be effective for all 
FOP mutations.  This change expands the scope of the 
study to include patients with a clinical diagnosis of FOP 
who may have different ACVR1 mutations.   
To support interpretation of the study results, all patients 
will have their ACVR1 gene sequenced during the study 
(mandatory).   
The primary statistical analyses for the study will be based 
on the original study design, not the expanded study 
population.   
Clinical Study Protocol Synopsis: Study Design, 
Endpoints, Statistical Plan 
Study Design, Target Population, Procedures and 
Assessments, Statistical Plan 
Section 1 Introduction 
Section 3.2.2 Rationale for Study Design 
Section 3.3.1 Potential Risk for Reproductive Organ 
Adverse Events in Male Subjects and Monitoring 
Section 4.1 Demographic and Baseline Characteristics 
Section 5.1.1 Screening/Baseline Period (Day -28 to 
Day -1): Study Visit 1 
Section 6.2.1 Inclusion Criteria: Criterion #3 (deleted)  
Table 1 Schedule of Events:  Screening/Baseline 
through Period 1 (Randomized Double-Blind 
Treatment Period) 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2 and Table 3: Footnotes #5 and #21 
Section 8.2.1 Procedures Performed only at the 
Screening/Baseline visit  
Section 21 References:  Hino, 2015 
The statistical analysis was revised to address feedback 
from regulatory agencies, as well as addressing the 
changes related to inclusion of patients with ACVR1 
mutations: 
Use a hierarchical testing procedure instead of the 
Hochberg procedure. Revised Statistical Plan  
Specify hierarchical testing of the 4 efficacy primary 
endpoints 
Specify that the baseline active HO analysis set includes 
all randomized patients who had active HO lesion at 
baseline  
Specify that patients will be randomized to REGN2477 or 
placebo in a 1:1 ratio by ACVR1 mutation (classic 
[R206H], 
other) 
in 
addition 
to 
gender 
and 
presence/absence of baseline active HO lesions. 
Specify that results are analyzed first in patients with the 
ACVR1[R206H] mutation and secondly in patients with 
any ACVR1 mutation. 
Make minor corrections to descriptions and tables 
Clinical Study Protocol Synopsis: Study Design, 
Endpoints, Statistical Plan 
Section 4.2 Primary, Secondary, and Exploratory 
Endpoints 
Section 4.2.2 Primary Efficacy Endpoints 
Section 4.2.3 Key Secondary Endpoints  
Section 4.2.4 Other Secondary Endpoints 
Section 4.2.6 Exploratory Endpoints 
Section 10.1 Statistical Hypothesis 
Section 10.2 Justification of Sample Size 
Table 4 Sample Size (Total Lesion Activity by 
18F-NaF PET, Total Volume of HO Lesions by CT, 
and SUVmax) at Week 28 for Comparisons between 
REGN2477 and Placebo Treatment Groups 
Section 10.3.1 Baseline Active HO Classic 
ACVR1[R206H] Mutation Analysis Set (new) 
Section 10.3.1 Baseline Active HO Analysis Set 
Section 10.3.3 Full Analysis Set 
Section 10.3.5 Other Analysis Sets 
Section 10.4.3 Efficacy Analyses 
Table 5 Analysis Strategy for Primary and Key 
Secondary Efficacy Endpoints 
Section 10.4.3.1.1 Primary Endpoints: Total Lesion 
Activity by 18F-NaF PET 
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Change and Rationale for Change 
Section Changed 
Section 10.4.3.1.2 Primary Endpoints: Total HO 
Volume by CT  
Section 10.4.3.1.3 Key Secondary Endpoints: Pain 
NRS-AUC 
Section 10.4.3.1.4 Multiplicity Considerations 
The study design was revised to allow patients who 
completed the open label portion of the study through 
week 52, to continue to receive study drug from week 56 
through week 76 or beyond.   
Changed “the 24-week follow-up period” to the “follow-
up treatment period” (Period 3).  Each patient will 
continue to receive REGN2477 every 4 weeks during this 
period until they complete the week 76 visit, and all data 
have been collected and validated through the time when 
the last patient randomized into the study completes the 
week 28 visit (Period 1), and results of the primary 
analyses of safety and efficacy are available to the 
sponsor.  If at the time patients reach the week 76 visit 
but data from the last patient randomized into the study 
through the week 28 visit have not been collected and 
validated, and results of the primary analyses of safety 
and efficacy are not yet available to the sponsor, patients 
will continue to receive REGN2477 every 4 weeks, 
beyond week 76.   
Patients will have the option to discontinue study 
medication before the beginning or at any time during 
Period 3, similarly to what occurs at any time during the 
study after patients have signed the informed consent.   
Treatment with REGN2477 will continue provided that 
no safety signals are identified during continuous 
monitoring of the study by the investigator, medical 
monitor and IDMC.  In addition, all patients will be 
required to maintain contraception during this period. 
Revised footnote #17 in the Schedule of Events, Table 3, 
as this footnote addressed the transition from 
on-treatment to off- treatment which is no longer relevant 
to the study.  
The deletion of this footnote caused footnote #19 for 
Daily Pain NRS and Daily FOP disease activity diary 
from Schedule of Events, Table 1 to be changed to 
footnote#18.  
Removed the post-treatment period as the third 
observation period, because treatment with REGN2477 
will continue during Treatment Follow-up (Period 3) 
through the end of the study.  
Clinical Study Protocol Synopsis: Study Design, Study 
Duration, Statistical Plan 
Section 1 Introduction 
Section 3.2.2 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 5.1.4 Period 3:  Follow-Up Treatment Period 
Week 56 (Day 393) to End of Study (heading only) 
Figure 1 Study Design Schematic 
Section 7.1 Investigational and Reference Treatments 
Table 1 Schedule of Events: Screening/Baseline 
through Period 1 (Randomized Double-Blind 
Treatment Period)  
Table 3 Schedule of Events: Period 3 (Follow-Up 
Treatment Period) 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2, and Table 3: Footnotes #17 and #18  
Section 10.4.4.1 Adverse Events 
Section 10.5 Primary and Additional Analysis 
“End of Treatment” was removed from visit 17 of Period 
2 (Open Label Treatment Period), as the end of study will 
occur after Period 3 (Follow-up Treatment Period). 
Table 2 Schedule of Events: Period 2 (Open Label 
Treatment Period) 
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Change and Rationale for Change 
Section Changed 
Schedule of Events Table 3: Addition of a new column 
entitled: “End of Study/Week 80” to denote the new end 
of study and to indicate the procedures that will be 
conducted during this period in the event that data from 
the last patient randomized into the study through the 
week 28 visit (Period 1) have not been collected and 
validated, and results of the primary analyses of safety 
and efficacy are not yet available to the sponsor.   
Reduced visit windows in Period 3 from ±14 days to 
±7 days, as patients will continue to be treated with 
REGN2477 during this period. 
A new row entitled “Administer REGN2477” was added.  
Table 3 Schedule of Events: Period 3 (Follow-Up 
Treatment Period) 
Removed the sentence regarding patients entering the 
off-drug treatment phase after early termination as the 
off-drug phase was removed and the statement is no 
longer applicable 
Section 8.1.2 Early Termination Visit 
Removed the post-treatment period from the definitions 
of Adverse Events, as the post-treatment period is no 
longer relevant. 
Section 10.4.4.1 Adverse Events, Definitions 
Added the week 76 time point to the additional analyses 
of safety and efficacy data to be performed following the 
open-label treatment period for consistency with the 
planned analyses.  
Section 10.5 Primary and Additional Analysis 
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Change and Rationale for Change 
Section Changed 
Added a secondary objective and secondary endpoints for 
assessment of the effect of REGN2477, between week 28 
and week 56, on the number, activity, and volume of HO 
lesions identified by 18F-NaF PET or by CT in patients 
who switch from placebo to REGN2477 at week 28. 
Clinical Study Protocol Synopsis: Objectives, 
Endpoints 
Section 2.2 Secondary Objectives 
Section 4.2.4 Other Secondary Endpoints 
Added assessment of hs-CRP as a biomarker 
Added assessment of magnesium to the clinical 
chemistry panel 
Added an endpoint for FEV1 of spirometry 
Added measurement of height at baseline 
Section 4.2.6 Exploratory Endpoints 
Section 5.1.2 Period 1:  Double-Blind Treatment 
(Week 1 [Day 1] to Week 24 [Day 169]) and End of 
Period 1 Assessments (Week 28 [Day 197]) 
Section 5.1.4 Period 3:  Follow-Up Treatment Period 
Week 56 (Day 393) to End of Study 
Table 3 Schedule of Events:  Period 3 (Follow-Up 
Treatment Period): Future Biomedical Research 
Sample row. 
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Section 8.2.4.5 Laboratory Testing 
Section 8.2.6 Biomarker Procedures 
Section 8.2.7 Future Biomedical Research 
Provided more detail about the frequency of IDMC 
meetings and clarified the monitoring for potential AEs in 
male patients. 
Section 5.1.5.1 Study Stopping Criteria 
Table 1 Schedule of Events:  Screening/Baseline 
through Period 1 (Randomized Double-Blind 
Treatment Period) 
Section 8.2.1 Procedures Performed only at the 
Screening/Baseline Visit 
To address feedback from a regulatory agency: 
The duration of time for patients to maintain highly 
effective contraception was extended to 30 weeks after the 
last dose of study drug to address feedback from a 
regulatory agency. 
Added an exclusion criterion “Previous history or 
diagnosis of cancer” and updated the SAE definition to 
note that “a new diagnosis or progression of a malignancy 
in patients enrolled in the study will also be considered a 
SAE” to address feedback from a regulatory agency. 
Deleted ‘futility’ as a reason for premature termination of 
the study. 
Section 6.2.2 Exclusion Criteria: Criterion #16 
Section 6.2.2 Exclusion Criteria: Criterion #3 
Section 9.3.2 Serious Adverse Event 
Section 16.1 Premature Termination of the Study 
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Change and Rationale for Change 
Section Changed 
Clarified the rationale for use of SC route of 
administration. 
Provided details on how the safety of each dose will be 
reviewed prior to next dose. 
Clinical Study Protocol Synopsis: Study Design 
Section 5.1.2 Period 1:  Double-Blind Treatment 
(Week 1 [Day 1] to Week 24 [Day 169]) and End of 
Period 1 Assessments (Week 28 [Day 197]) 
Section 7.1 Investigational and Reference Treatments 
Section 7.2.1 Dose Modification 
Clarified the PET/CT procedures and the exploratory 
endpoints assessed by PET/CT. 
Section 4.2.6 Exploratory Endpoints 
Section 8.2.2.1 Positron Emission 
Tomography/Computed Tomography Procedures 
Section 4.2.6 Exploratory Endpoints 
Clarified that PET/CT scans will be read and analyzed 
using a blinded central reading center during the study, 
however at baseline, added the provision that the 
investigator will be allowed to independently read and 
analyze PET/CT images. Baseline PET/CT images will 
be performed before each patient is randomized into the 
study.  As these baseline images do not contain any 
unblinding data, the PI may utilize these images as part 
of standard of care resulting in not having to duplicate the 
imaging assessments and thereby reducing the patients’ 
total annual radiation exposure. 
Section 8.2.2.1 Positron Emission 
Tomography/Computed Tomography Procedures 
Added the requirement that any incidental findings 
identified through PET/CT scans will be reported to the 
investigator and medical monitor, and that the 
investigator will communicate any findings to the patient. 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2, and Table 3: Footnotes #13 
Section 8.2.2.1 Positron Emission 
Tomography/Computed Tomography Procedures 
Added whole body 18F-NaF PET and whole body low 
dose CT imaging at week 76 (day 533 [±7 days]) for a 
total of 5 scans during the study.  This will allow for the 
evaluation of longer term effects of REGN2477 (ie, an 
additional 20 weeks of treatment) in FOP patients.  As a 
result of the additional scan, the total ED range 
approximation was changed from 21 mSv to 25 mSv. 
Clinical Study Protocol Synopsis: Study Design  
Table 3: Schedule of Events: Period 3 (Follow-Up 
Treatment Period) 
Section 3.2.4.1 18F-NaF Positron Emission 
Tomography 
Section 3.3.6 Radiation Exposure 
Section 4.2.6 Exploratory Endpoints 
Section 5.1.4 Period 3 Follow-up Treatment Period 
Week 56 (Day 393) to End of Study 
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Change and Rationale for Change 
Section Changed 
Added that ECG and symptom-directed physical 
examination may be performed during the follow-up 
treatment period (Period 3, after week 56) with 
REGN2477 at the investigator’s discretion, and that urine 
pregnancy testing will be performed prior to each 
REGN2477 dose administration, and a serum pregnancy 
test will be performed at the end of study visit.  PK/ADA 
sampling will continue to be performed at all visits after 
week 56. 
Section 8.1.1 Footnotes for the Schedule of Events: 
Table 1, Table 2, and Table 3: Footnotes #9, #10, and 
#11 
Clarified that treatment with imatinib or isotretinoin is 
also exclusionary and are prohibited medications 
Section 3.2.2 Rationale for Study Design  
Section 6.2.2 Exclusion Criteria: Criterion #12 
Section 7.6.1 Prohibited Medications 
Provide more detail about the clinical endpoint measures 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2 and Table 3: Footnote #14 and #24 
Section 8.2.3.3 FOP Independent Activity of Daily 
Living 
Section 8.2.3.4 EQ-5D-3L Questionnaire 
Added that patients can be rescreened for study 
participation.  
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2 and Table 3: Footnote #20 
Added a footnote to indicate that measurement of a 
patient’s height may not be precise or not possible to be 
assessed 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Table 2 and Table 3: Footnote #22 
Removed futility as a reason for study termination 
Section 16.1 Premature Termination of the Study 
Reorganization of sections for consistency with current 
template, minor corrections for the content 
Section 4.5 Pharmacokinetic Variables 
Updated the Scientific/Medical Monitor  
Protocol Title Page 
Minor edits for clarification of study terminology, 
corrections, and minor changes: 
Period 1, Period 2, and Period 3 instead of “treatment 
period 1”, “treatment period 2”, or “treatment period 3” 
“diary” has been replaced with “e-diary”. 
“FOP disease diary” has been replaced with “FOP 
disease activity diary”.  
“Menstrual History” instead of “Menstrual 
Questionnaire” 
“FOP Independent Activities of Daily Living” instead of 
“Activity of Daily Living” 
“FCV” to “FVC” 
Subjects changed to patients 
Adding “Doppler” to scrotum ultrasound 
Throughout the document  
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................36 
1. 
INTRODUCTION ......................................................................................................39 
2. 
STUDY OBJECTIVES ..............................................................................................41 
2.1. 
Primary Objective .......................................................................................................41 
2.2. 
Secondary Objectives .................................................................................................41 
2.3. 
Exploratory Objectives ...............................................................................................42 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................42 
3.1. 
Hypothesis:  Period 1 Double-Blind, Placebo-Control Treatment Period 
(Week 28) ...................................................................................................................42 
3.2. 
Hypothesis:  Period 2 Open-Label Period (Week 56) ................................................42 
3.3. 
Rationale .....................................................................................................................43 
3.3.1. 
Rationale for Clinical Development of REGN2477 for FOP .....................................43 
3.3.2. 
Rationale for Study Design .........................................................................................45 
3.3.3. 
Rationale for Efficacy Endpoint Measures (Period 1; Week 28) ...............................47 
3.3.3.1. 
18F-NaF Positron Emission Tomography ...................................................................47 
3.3.3.2. 
Quantitative Whole Body CT .....................................................................................48 
3.3.4. 
Rationale for Efficacy Endpoints (Period 2; Week 56) ..............................................48 
3.3.5. 
Biochemical Markers of Bone Formation ..................................................................49 
3.3.6. 
Clinical Endpoint Measures ........................................................................................49 
3.3.7. 
Rationale for Dose Selection ......................................................................................49 
3.4. 
Study-Specific Safety Considerations and Monitoring ..............................................51 
3.4.1. 
Potential Risk for Reproductive Organ Adverse Events in Male Patients and 
Monitoring ..................................................................................................................51 
3.4.2. 
Potential Risk for Teratogenicity/Fetal Toxicity and Pregnancy Monitoring 
and Prevention ............................................................................................................52 
3.4.3. 
Risk for Epistaxis and Monitoring ..............................................................................52 
3.4.4. 
Risk for Skin and Soft Tissue Infection and Monitoring ............................................53 
3.4.5. 
Potential Iatrogenic Injuries ........................................................................................54 
3.4.6. 
Radiation Exposure .....................................................................................................54 
4. 
STUDY VARIABLES................................................................................................54 
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4.1. 
Demographic and Baseline Characteristics ................................................................54 
4.2. 
Primary, Secondary, and Exploratory Endpoints (Period 1; Week 28) ......................55 
4.2.1. 
Primary Safety Endpoint .............................................................................................55 
4.2.2. 
Primary Efficacy Endpoints ........................................................................................55 
4.2.3. 
Key Secondary Endpoints ...........................................................................................55 
4.2.4. 
Other Secondary Endpoints ........................................................................................55 
4.2.5. 
Other Secondary Endpoints Related to Clinical Pharmacology (Period 1, 
Period 2, Period 3) ......................................................................................................56 
4.2.6. 
Exploratory Endpoints (Period 1; Week 28) ..............................................................56 
4.3. 
Primary, Secondary, and Exploratory Endpoints (Period 2; Week 56) ......................57 
4.3.1. 
Primary Efficacy Endpoint (Period 2 [Week 56]) ......................................................57 
4.3.2. 
Key Secondary Efficacy Endpoints (Period 2 [Week 56]) .........................................57 
4.3.3. 
Other Secondary Efficacy Endpoints (Period 2 [Week 56]) ......................................58 
4.3.4. 
Exploratory Endpoints (Period 2 [Week 56]) .............................................................59 
4.4. 
Exploratory Endpoints (Period 3 [Week 76]) .............................................................60 
4.5. 
Biomarker Variables ...................................................................................................61 
4.6. 
Pharmacokinetic Variables .........................................................................................61 
4.7. 
Anti-Drug Antibody Variables ...................................................................................62 
5. 
STUDY DESIGN .......................................................................................................62 
5.1. 
Study Description and Duration .................................................................................62 
5.1.1. 
Screening/Baseline Period (Day -28 to Day -1): Study Visit 1 ..................................63 
5.1.2. 
Period 1:  Double-Blind Treatment (Week 1 [Day 1] to Week 24 [Day 169]) 
and End of Period 1 Assessments (Week 28 [Day 197]) ............................................64 
5.1.3. 
Period 2:  Open-Label REGN2477 Treatment (Week 28 [Day 197]) to Week 
52 [Day 365]) and End of Period 2 Assessments (Week 56 [Day 393]) ....................65 
5.1.4. 
Period 3:  Follow-Up Treatment Period Week 56 (Day 393) to End of Study ..........66 
5.1.5. 
Study Stopping Rules .................................................................................................67 
5.1.5.1. 
Study Stopping Criteria ..............................................................................................67 
5.1.5.2. 
Individual Patient Stopping Rule ................................................................................67 
5.1.6. 
End of Study Definition ..............................................................................................67 
5.2. 
Planned Interim Analysis ............................................................................................67 
5.3. 
Study Committees .......................................................................................................67 
5.3.1. 
Independent Data Monitoring Committee ..................................................................67 
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............68 
6.1. 
Number of Patients Planned .......................................................................................68 
6.2. 
Study Population .........................................................................................................68 
6.2.1. 
Inclusion Criteria ........................................................................................................68 
6.2.2. 
Exclusion Criteria .......................................................................................................68 
6.3. 
Premature Withdrawal from the Study .......................................................................70 
6.4. 
Replacement of Patients .............................................................................................71 
7. 
STUDY TREATMENTS............................................................................................71 
7.1. 
Investigational and Reference Treatments ..................................................................71 
7.2. 
Dose Modification and Study Treatment Discontinuation Rules ...............................71 
7.2.1. 
Dose Modification ......................................................................................................71 
7.2.1.1. 
Individual Level Dose Modification ...........................................................................72 
7.2.1.2. 
Study Level Dose Modification ..................................................................................72 
7.2.2. 
Study Drug Discontinuation .......................................................................................72 
7.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................73 
7.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................73 
7.3. 
Management of Acute Reactions ................................................................................73 
7.3.1. 
Acute Infusion Reactions ............................................................................................73 
7.3.1.1. 
Interruption of the Infusion .........................................................................................73 
7.3.1.2. 
Termination of the Infusion ........................................................................................74 
7.4. 
Method of Treatment Assignment ..............................................................................74 
7.4.1. 
Blinding ......................................................................................................................74 
7.4.2. 
Emergency Unblinding ...............................................................................................74 
7.5. 
Treatment Logistics and Accountability .....................................................................75 
7.5.1. 
Packaging, Labeling, and Storage ..............................................................................75 
7.5.2. 
Supply and Disposition of Treatments .......................................................................75 
7.5.3. 
Treatment Accountability ...........................................................................................75 
7.5.4. 
Treatment Compliance ................................................................................................75 
7.6. 
Concomitant Medications ...........................................................................................76 
7.6.1. 
Prohibited Medications ...............................................................................................76 
7.6.2. 
Permitted Medications ................................................................................................76 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................77 
8.1. 
Schedule of Events .....................................................................................................77 
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8.1.1. 
Footnotes for the Schedule of Events Table 1, Table 2, and Table 3 .........................85 
8.1.2. 
Early Termination Visit ..............................................................................................87 
8.1.3. 
Unscheduled Visits .....................................................................................................87 
8.2. 
Study Procedures ........................................................................................................87 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................87 
8.2.2. 
Imaging Procedures ....................................................................................................88 
8.2.2.1. 
Positron Emission Tomography/Computed Tomography Procedures .......................88 
8.2.3. 
Clinical Endpoint Measures ........................................................................................89 
8.2.3.1. 
Numeric Rating Scale Pain Evaluation .......................................................................89 
8.2.3.2. 
FOP Disease Activity Assessment ..............................................................................89 
8.2.3.3. 
FOP Independent Activities of Daily Living ..............................................................89 
8.2.3.4. 
EQ-5D-3L Questionnaire ............................................................................................89 
8.2.3.5. 
Cumulative Analog Joint Involvement Scale .............................................................90 
8.2.3.6. 
Pulmonary Function by Spirometry............................................................................90 
8.2.4. 
Safety Procedures .......................................................................................................90 
8.2.4.1. 
Vital Signs ..................................................................................................................90 
8.2.4.2. 
Physical Examination .................................................................................................90 
8.2.4.3. 
Menstrual History .......................................................................................................90 
8.2.4.4. 
Electrocardiogram .......................................................................................................91 
8.2.4.5. 
Laboratory Testing ......................................................................................................91 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................93 
8.2.5.1. 
Drug Concentration and Total Activin A Concentration Measurements and 
Samples .......................................................................................................................93 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples ......................................................93 
8.2.6. 
Biomarker Procedures ................................................................................................93 
8.2.7. 
Future Biomedical Research .......................................................................................94 
8.2.7.1. 
Optional Genomic Study: DNA Analysis ...................................................................94 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................94 
9.1. 
Obligations of Investigator .........................................................................................94 
9.2. 
Obligations of Sponsor ...............................................................................................95 
9.3. 
Definitions ..................................................................................................................95 
9.3.1. 
Adverse Event .............................................................................................................95 
9.3.2. 
Serious Adverse Event ................................................................................................95 
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9.3.3. 
Adverse Events of Special Interest .............................................................................96 
9.3.4. 
Infusion Reactions ......................................................................................................96 
9.4. 
Recording and Reporting Adverse Events ..................................................................96 
9.4.1. 
Adverse Events ...........................................................................................................96 
9.4.2. 
Serious Adverse Events ..............................................................................................96 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................97 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................98 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................98 
9.4.6. 
Follow-up ....................................................................................................................98 
9.5. 
Evaluation of Severity and Causality .........................................................................98 
9.5.1. 
Evaluation of Severity ................................................................................................98 
9.5.2. 
Evaluation of Causality ...............................................................................................99 
9.6. 
Safety Monitoring .....................................................................................................100 
9.7. 
Investigator Alert Notification ..................................................................................101 
10. 
STATISTICAL PLAN..............................................................................................101 
10.1. 
Statistical Hypotheses ...............................................................................................101 
10.1.1. 
Statistical Hypothesis (Period 1 [Week 28]) ............................................................101 
10.1.2. 
Statistical Hypothesis (Period 2 [Week 56]) ............................................................102 
10.2. 
Justification of Sample Size......................................................................................103 
10.3. 
Analysis Sets .............................................................................................................104 
10.3.1. 
Baseline-Active HO Analysis Set .............................................................................104 
10.3.2. 
Baseline-Active HO Classic ACVR1[R206H] Mutation Analysis Set ....................105 
10.3.3. 
Full Analysis Set .......................................................................................................105 
10.3.4. 
Safety Analysis Set ...................................................................................................105 
10.3.5. 
Other Analysis Sets ...................................................................................................105 
10.4. 
Statistical Methods ....................................................................................................105 
10.4.1. 
Patient Disposition ....................................................................................................105 
10.4.2. 
Demography and Baseline Characteristics ...............................................................106 
10.4.3. 
Efficacy Analyses .....................................................................................................106 
10.4.3.1. 
Analysis of Efficacy Endpoints in Period 1 (Week 28) ............................................106 
10.4.3.2. 
Analysis of Efficacy Endpoints in Period 2 (Week 56) ............................................109 
10.4.4. 
Safety Analysis .........................................................................................................113 
10.4.4.1. 
Adverse Events .........................................................................................................113 
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10.4.4.2. 
Other Safety ..............................................................................................................114 
10.4.4.3. 
Treatment Exposure ..................................................................................................114 
10.4.4.4. 
Treatment Compliance ..............................................................................................114 
10.4.5. 
Analysis of Drug Concentration and Total Activin A Concentration Data ..............114 
10.4.6. 
Analysis of Anti-Drug Antibody Data ......................................................................115 
10.4.7. 
Analysis of Quality of Life Data ..............................................................................115 
10.4.8. 
Analysis of Biomarker Data .....................................................................................115 
10.5. 
Primary and Additional Analysis ..............................................................................115 
10.6. 
Additional Statistical Data Handling Conventions ...................................................115 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .......116 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................116 
11.1. 
Data Management .....................................................................................................116 
11.2. 
Electronic Systems ....................................................................................................116 
12. 
STUDY MONITORING ..........................................................................................117 
12.1. 
Monitoring of Study Sites .........................................................................................117 
12.2. 
Source Document Requirements ..............................................................................117 
12.3. 
Case Report Form Requirements ..............................................................................117 
13. 
AUDITS AND INSPECTIONS ...............................................................................117 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................118 
14.1. 
Good Clinical Practice Statement .............................................................................118 
14.2. 
Informed Consent .....................................................................................................118 
14.3. 
Patient Confidentiality and Data Protection .............................................................118 
14.4. 
Institutional Review Board/Ethics Committee .........................................................119 
15. 
PROTOCOL AMENDMENTS ................................................................................119 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................119 
16.1. 
Premature Termination of the Study .........................................................................119 
16.2. 
Close-out of a Site ....................................................................................................120 
17. 
STUDY DOCUMENTATION .................................................................................120 
17.1. 
Certification of Accuracy of Data .............................................................................120 
17.2. 
Retention of Records ................................................................................................120 
18. 
CONFIDENTIALITY ..............................................................................................121 
19. 
FINANCING AND INSURANCE ...........................................................................121 
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20. 
PUBLICATION POLICY ........................................................................................121 
21. 
REFERENCES .........................................................................................................122 
22. 
INVESTIGATOR’S AGREEMENT ........................................................................124 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................126 
 
LIST OF TABLES 
Table 1: 
Schedule of Events:  Screening/Baseline through Period 1 (Randomized 
Double-Blind Treatment Period) ................................................................................78 
Table 2: 
Schedule of Events: Period 2 (Open-Label Treatment Period) ..................................81 
Table 3: 
Schedule of Events:  Period 3 (Follow-Up Treatment Period) ...................................83 
Table 4: 
Sample Size (Total Lesion Activity by 18F-NaF PET, Total Volume of HO 
Lesions by CT, and SUVmax) at Week 28 for Comparisons between 
REGN2477 and Placebo Treatment Groups .............................................................104 
Table 5: 
Analysis Strategy for Primary and Key Secondary Efficacy Endpoints ..................107 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic Screening/Baseline Period (Day -28 to Day -1): 
Study Visit 1 ...............................................................................................................63 
 
LIST OF APPENDICES 
APPENDIX 1. FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP 
OF ADVERSE EVENTS TO STUDY DRUG AND STUDY 
CONDUCT .......................................................................................................125 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Effects on Heterotopic Bone Formation of REGN2477 
in Patients with Fibrodysplasia Ossificans Progressiva 
Site Location(s) 
 
Principal Investigator 
The study will be conducted at multiple sites globally 
TBD  
Objective(s) 
Primary Objective: 
The primary safety objective of the study is to assess the safety and tolerability 
of REGN2477 in male and female patients with fibrodysplasia ossificans 
progressiva (FOP). 
The primary efficacy objective of the study is to assess the effect of 
REGN2477 versus placebo on the change from baseline in heterotopic 
ossification (HO) in patients with FOP, as determined by 18-NaF uptake in 
HO lesions by positron emission tomography (PET) and in total volume of 
HO lesions by computed tomography (CT). 
Secondary Objectives: 
The secondary objectives of the study are: 
• To compare the effect of REGN2477 versus placebo on pain due to 
FOP, as measured by the area under the curve (AUC) for pain based 
on daily numeric rating scale (NRS) scores 
• To assess the effect of REGN2477 versus placebo on the change from 
baseline in HO, as determined by the number of new HO lesions 
identified by 18F-NaF PET or by CT 
• To assess the effect of REGN2477 versus placebo on the change from 
baseline in 18F-NaF standardized uptake value maximum (SUVmax) of 
individual active HO site (s) by PET 
• To assess the effect of REGN2477, between week 28 and week 56, on 
the number, activity, and volume of HO lesions identified by 18F-NaF 
PET or by CT in patients who switch from placebo to REGN2477 at 
week 28 versus the same patients between baseline and week 28 
• To assess the effect of REGN2477 versus placebo on the change from 
baseline in biochemical markers of bone formation  
• To characterize the concentrations of total activin A at baseline and 
over time following the first dose of study drug 
• To characterize the concentration-time profile (pharmacokinetics 
[PK]) of REGN2477 in patients with FOP  
• To assess the immunogenicity of REGN2477 
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Study Design 
This is a phase 2, randomized, placebo-controlled, 2-period study designed to 
evaluate the safety, tolerability, PK, and effects on heterotopic bone formation 
of repeated doses of 10 mg/kg REGN2477 administered intravenously (IV), 
every 4 weeks (Q4W) in adult patients with FOP. 
Up to 40 patients with FOP disease activity may be enrolled at multiple sites 
globally to yield approximately 24 or more patients with the classic type I 
activin A receptor with a R206H mutation (ACVR1[R206H]) and active HO 
at baseline as determined by 18F-NaF PET/CT. 
This study consists of a screening/baseline period (day -28 to day -1), 
2 treatment periods and a follow-up treatment period.  The 3 treatment periods 
are: 
• Period 1: a 6-month randomized double-blind placebo-controlled 
treatment period 
• Period 2: a 6-month open-label REGN2477 treatment period  
• Period 3: a follow-up treatment period with REGN2477 continuing until 
patients have completed the week 76 visit, and all data have been 
collected and validated through the time when the last patient randomized 
into the study completes the week 28 visit (Period 1), and results of the 
primary analyses of safety and efficacy are available to the sponsor. 
Patients who meet initial eligibility screening will have baseline procedures 
conducted. 
In light of the public health emergency related to the COVID-19 pandemic, 
the continuity of clinical study conduct and oversight may require 
implementation of temporary or alternative mechanisms.  Examples of 
alternative mechanisms may include, but are not limited to, any of the 
following:  phone contact, virtual visits, telemedicine visits, online meetings, 
non-invasive remote monitoring devices, use of local clinic or laboratory 
locations, and home visits by skilled staff.  All temporary mechanisms 
utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will 
remain in effect only for the duration of the public health emergency and/or 
until the COVID-19 pandemic is deemed manageable and no longer 
interfering with the conduct of trials at individual sites. 
During Period 1, patients will be randomized to receive REGN2477 at 
10 mg/kg dose or matching placebo, administered IV Q4W through week 24, 
for a total of 7 doses.  Randomization will be stratified by gender, by classic 
ACVR1[R206H] 
mutation/different 
ACVR1 
mutations, 
and 
by 
presence/absence of baseline active HO lesions as determined by 18F-NaF 
PET/CT.  Index HO lesion identified at baseline and new HO lesions will be 
assessed by imaging endpoint measures including whole body 18F-NaF PET 
and whole body low dose CT at week 8 (day 57 [±7 days]), and week 28 
(day 197 [±7 days]).  Serum samples for the determination of REGN2477 
concentrations and anti-drug antibody (ADA) will be collected. 
To ensure safety, individual patients will be closely monitored and safety of 
each dose of study drug will be reviewed by the investigator and Regeneron 
medical monitor prior to administering the subsequent repeated dose.  The 
safety review to be conducted by the investigator and Regeneron medical 
monitor prior to study drug infusions on visits 2, 5, 6 and 7 (Period 1) and 
visits 11, 12, 13 and 14 (Period 2) will include evaluation of laboratory test 
(hematology, blood chemistry and urinalysis) results collected as part of these 
visits.  For the remaining study visits, assessment of results of hematology, 
blood chemistry and urinalysis tests planned for these same visits may be 
performed, but will not be required prior to study drug infusion. The decision 
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Regeneron Pharmaceuticals, Inc. 
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not to wait for the results of these exams, processed at the study’s central 
laboratory, should be made on a case-by-case basis, if the patient’s clinical 
condition, adverse event profile, and assessment of vital signs, ECGs and 
previous laboratory test results indicate that the patient is suitable to receive 
the next dose of study drug.  For the study visits after week 56 (Period 3), the 
need for a safety review by the investigator and Regeneron medical monitor 
will be decided on a case-by-case basis. In addition, the Independent Data 
Monitoring Committee (IDMC) will regularly monitor the unblinded safety 
data.  In the event that a significant tolerability issue or safety concern is 
identified, dose modification or study drug discontinuation may be 
implemented.  
All patients who complete the Period 1 double-blind treatment will receive 
REGN2477 open-label in Period 2, administered IV at a dose of 10 mg/kg 
Q4W through week 52, for a total of 7 doses.  For patients previously treated 
with placebo drug, week 28 (day 197) assessments will be considered as 
pretreatment baseline for safety and efficacy analysis of this period of the 
study.  Serum samples for the determination of REGN2477 concentrations 
and ADA will be collected. Index HO lesion identified at baseline and new 
HO lesions will be assessed by imaging endpoint measures including whole 
body 18F-NaF PET and whole body low dose CT at week 56 (day 393 [±7 
days]), and at week 76 (day 533 [±7 days]). 
In light of the public health emergency related to the COVID-19 pandemic, 
Investigators may perform study visit 18 (week 56) imaging exam employing 
only whole body low-dose CT scans.  Assessment of imaging endpoints 
without the PET scan may be implemented to mitigate the delay to acquire 
images due to the inaccessibility to PET/CT imaging centers and/or 
unavailability of the 18F-NaF tracer.  In addition, the timing for study visit 18 
(week 56) is flexible as long as any changes are documented.  This low-dose 
CT scan may be performed by trained staff either at study site or at other 
clinical sites with access to a qualified CT scanner or using a mobile qualified 
CT scanner at a local community healthcare setting close to patient or at a 
home visit, contingent upon prior concurrence and approval from the 
Investigator and Regeneron medical director.  Individual patient dose 
modification will be determined on a case-by-case basis as described in the 
protocol.  Study level dose modification will be determined by the sponsor 
upon recommendation of the IDMC following their review of safety, PK, and 
total activin A (target engagement) data available at the time. 
During the follow-up treatment period with REGN2477 (Period 3), from 
week 56 until the end of study, efficacy and safety procedures will be 
performed, and serum samples for the determination of REGN2477 
concentrations and ADA will be collected.  Each patient will continue to 
receive REGN2477, provided that no safety signals are identified during 
continuous monitoring of the study by the investigator, medical monitor and 
IDMC.  In addition, during this period, all patients will be required to maintain 
contraception. 
Study Duration 
The duration of the double-blind treatment period (Period 1), and open-label 
treatment and assessment period (Period 2) for a patient is approximately 
56 weeks, excluding the screening period.  The follow-up treatment period 
will begin at week 56 and continue until patients have completed the week 76 
visit (Period 3), and all data have been collected and validated through the 
time when the last patient randomized into the study completes the week 28 
visit (Period 1), and results of the primary analyses of safety and efficacy are 
available to the sponsor. 
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After Period 3 (week 76), patients can continue to receive REGN2477 
treatment every 4 weeks until any 1 of the following occurs: clinical 
development of REGN2477 is terminated, the risk-benefit is deemed 
unfavorable in this patient population, other means of access to REGN2477 
(eg, expanded access protocol) becomes available for study patients for whom 
the benefit-risk assessment for REGN2477 treatment remains positive, or, 
approval of the drug by the competent regulatory authority governing each 
respective country (eg, European Commission for EU Member States) with 
commercial availability.  A limited number of assessments for safety, 
efficacy, and clinical pharmacology parameters will be conducted. 
Population 
 
 
Sample Size: 
Up to 40 patients with FOP may be enrolled at multiple sites globally to yield 
approximately 24 or more patients with the classic ACVR1[R206H] mutation 
and active HO at baseline. 
 
Target Population: 
The study population will consist of male and female adult patients aged 18 to 
60 years of age, with a clinical diagnosis of FOP based on findings of 
congenital malformation of the great toes, episodic soft tissue swelling, and/or 
progressive HO, and confirmed with documentation of ACVR1 genotype, 
including the classic [R206H] or different ACVR1 mutations.  If at the time 
of screening, the patient does not have documentation of what ACVR1 
mutation he/she carries or it cannot be retrieved, genotyping will need to be 
performed prior to randomization.  Patients must have had FOP disease 
activity within 1 year of screening visit, defined as pain, swelling, stiffness, 
and other signs and symptoms associated with FOP flare-ups; or worsening 
of joint function, or radiographic progression of HOs (increase in size or 
number of HO lesions) with/without being associated with flare-up episodes. 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
Treatment(s) 
 
 
Study Drug 
 
(Dose/Route/Schedule): 
REGN2477  
10 mg/kg, administered IV Q4W 
 
Placebo (Route/Schedule): 
REGN2477-matching placebo 
administered IV Q4W 
Efficacy Analysis Sets 
• 
Baseline-Active HO (AHO) analysis set:  all randomized patients who 
had active HO lesion at baseline; it is based on the treatment allocated 
(as randomized).  For analyses of change from week 28, baseline will 
be defined as week 28. 
• 
Baseline-Active HO Classic ACVR1[R206H] Mutation (AHOC) 
analysis set:  all randomized patients with the classic ACVR1[R206H] 
mutation and who had active HO lesion at baseline; it is based on the 
treatment allocated (as randomized).  For analyses of change from 
week 28, baseline will be defined as week 28. 
• 
Full Analysis Set (FAS):  all randomized patients; it is based on the 
treatment allocated (as randomized). 
Endpoint(s) for Period 1 (Week 28) 
Primary Safety Endpoint for 
Period 1 (Week 28): 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) 
through the end of the Period 1 at week 28 
Primary Efficacy Endpoints for 
Period 1 (Week 28): 
• 
Time-weighted average (standardized area under the curve [AUC]) 
percent change from baseline in total lesion activity by 18F-NaF PET 
over 28 weeks (AHO) 
• 
Percent change from baseline in the total volume of HO lesions as 
assessed by CT at week 28 (AHO) 
• 
Time-weighted average (standardized area under the curve [AUC]) 
percent change from baseline in total lesion activity by 18F-NaF PET 
over 28 weeks (AHOC) 
• 
Percent change from baseline in the total volume of HO lesions as 
assessed by CT at week 28 (AHOC) 
Secondary Endpoints for Period 
1 (Week 28): 
Key Secondary Endpoints: 
• 
Time-weighted average (standardized AUC) change from baseline in 
daily pain due to FOP, as measured using the daily NRS over 28 weeks 
(AHO) 
• 
Time-weighted average (standardized AUC) change from baseline in 
daily pain due to FOP, as measured using the daily NRS over 28 weeks 
(AHOC) 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
 
Other Secondary Endpoints 
• 
Percent change from baseline in 18F-NaF SUVmax of individual active 
HO site(s) by PET at week 8 (AHOC) 
• 
Percent change from baseline in 18F-NaF SUVmax of individual active 
HO site(s) by PET at week 8 (AHO) 
• 
Change from baseline in number of HO lesions as assessed by 18F-
NaF PET at week 28 (AHOC) 
• 
Change from baseline in number of HO lesions as assessed by 18F-
NaF PET at week 28 (AHO) 
• 
Change from baseline in number of HO lesions as assessed by 18F-
NaF PET at week 28 (FAS) 
• 
Change from baseline in the number of HO lesions detectable by CT 
at week 28 (AHOC) 
• 
Change from baseline in the number of HO lesions detectable by CT 
at week 28 (AHO) 
• 
Change from baseline in the number of HO lesions detectable by CT 
at week 28 (FAS) 
 
• 
Time-weighted average (standardized AUC) change from baseline in 
daily pain due to FOP, as measured using the daily NRS over 28 weeks 
(FAS) 
• 
Time weighted average (standardized AUC) percent change from 
baseline in biomarkers of bone formation levels in serum over 
28 weeks, including Total Procollagen Type 1 N-Terminal Propeptide 
(P1NP), bone specific alkaline phosphatase (BSAP), and total alkaline 
phosphatase (tAP) (FAS) 
• 
Incidence and severity of TEAEs  
Other Secondary Endpoints related to Clinical Pharmacology (Period 1, 
Period 2, Period 3) 
• 
Concentration of total activin A in serum over time 
• 
PK profile of REGN2477, assessed as concentrations of REGN2477 
in serum over time 
• 
Immunogenicity of REGN2477, as determined by the incidence, titer, 
and clinical impact of treatment-emergent ADA to REGN2477 over 
time 
Endpoint(s) for Period 2 (Week 56) 
Primary Efficacy Endpoint for 
Period 2 (Week 56): 
• 
Number of new HO lesions as assessed by CT at week 56 relative to 
week 28 scan (in patients switching from placebo to REGN2477 after 
the double-blind period) (AHO) 
Key Secondary Endpoints for 
Period 2 (Week 56): 
• 
Total volume of new HO lesions as assessed by CT at week 56 relative 
to week 28 scan (in patients switching from placebo to REGN2477 
after the double-blind period) (AHO) 
• 
Number of new HO lesions as assessed by 18F-NaF PET at week 56 
relative to week 28 scan (in patients switching from placebo to 
REGN2477 after the double-blind period) (AHO) 
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• 
Total lesion activity by18F-NaF PET in new HO lesions at week 56 
relative to week 28 scan (in patients switching from placebo to 
REGN2477 after double-blind period) (AHO) 
• 
Percent of patients with new HO lesions as assessed by CT at week 56 
relative to week 28 scan (in patients switching from placebo to 
REGN2477 after the double-blind period) (AHO) 
• 
Percent of patients with new HO lesions as assessed by 18F-NaF PET 
at week 56 relative to week 28 scan (in patients switching from 
placebo to REGN2477 after the double-blind period) (AHO) 
Other Secondary Endpoints for 
Period 2 (week 56): 
 
• 
Number of new HO lesions as assessed by CT only at week 56 relative 
to week 28 scan (in patients switching from placebo to REGN2477 
after the double-blind period) (AHO) 
• 
Percent of patients with investigator-assessed flare-ups in Period 2 (in 
patients switching from placebo to REGN2477 after the double-blind 
period) (AHO) 
• 
Percent of patients with flare-ups assessed by patient e-diary in Period 
2 (in patients switching from placebo to REGN2477 after the 
double-blind period) (AHO) 
• 
Number of new HO lesions as assessed by CT at week 56 relative to 
baseline scan (in patients who continue REGN2477 after the 
double-blind period) (AHO) 
• 
Total volume in new HO lesions as assessed by CT at week 56 relative 
to baseline scan (in patients who continue REGN2477 after the 
double-blind period) (AHO) 
• 
Percent of patients with new HO lesions as assessed by CT at week 56 
relative to baseline scan (in patients who continue REGN2477 after 
the double-blind period) (AHO) 
• 
Number of new HO lesions as assessed by 18F-NaF PET at week 56 
relative to baseline scan (in patients who continue REGN2477 after 
the double-blind period) (AHO) 
• 
Total lesion activity in new HO lesions as assessed by 18F-NaF PET 
at week 56 relative to baseline scan (in patients who continue 
REGN2477 after the double-blind period) (AHO) 
• 
Percent of patients with new HO lesions as assessed by 18F-NaF PET 
at week 56 relative to baseline scan (in patients who continue 
REGN2477 after the double-blind period) (AHO) 
• 
Percent change from week 28 in SUVmax to week 56 (in patients 
switching from placebo to REGN2477 after the double-blind period) 
• 
Percent change from baseline in SUVmax to week 56 (in patients who 
continue REGN2477 after the double-blind period) (AHO) 
• 
Percent change from week 28 in total lesion activity as assessed by 
18F-NaF PET to week 56 (in patients switching from placebo to 
REGN2477 after the double-blind period) versus the same patients 
between baseline and week 28 (AHO) 
• 
Percent change from baseline in total lesion activity as assessed by 
18F-NaF PET to week 56 (in patients who continue REGN2477 after 
the double-blind period) (AHO) 
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Regeneron Pharmaceuticals, Inc. 
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• 
Percent change from week 28 in the total volume of HO lesions as 
assessed by CT to week 56 (in patients switching from placebo to 
REGN2477 after the double-blind period) versus the same patients 
between baseline and week 28 (AHO) 
• 
Percent change from baseline in the total volume of HO lesions as 
assessed by CT to week 56 (in patients who continue REGN2477 after 
the double-blind period) (AHO) 
• 
Change from week 28 in number of HO lesions (target and new lesions 
relative to baseline) as assessed by 18F-NaF PET to week 56 (in 
patients switching from placebo to REGN2477 in double-blind period 
and who have active HO lesions at week 28) versus the same patients 
between baseline and week 28 (AHO) 
• 
Change from week 28 in number of HO lesions (target and new lesions 
relative to baseline) as assessed by CT to week 56 (in patients 
switching from placebo to REGN2477 in double-blind period and who 
have active HO lesions at week 28) versus the same patients between 
baseline and week 28 (AHO) 
Procedures and Assessments 
Safety Assessments 
Safety procedures and assessments will include vital signs assessment, 
physical examination, a menstrual cycle history, electrocardiogram, and 
laboratory testing. 
ACVR1 Gene Sequencing 
A blood sample for future ACVR1 gene sequencing will be preferably 
collected from patients at the screening/baseline visit. However, it can be 
collected at any time during the study period, as the result of this test it is not 
to be used for assessment of study eligibility.  
Imaging Procedures 
Positron emission tomography with 18F-NaF and volumetric CT will be used 
to measure the change in heterotopic bone formation. 
Clinical Endpoint Measures 
Clinical endpoint measures will include the NRS categorical scale of pain, the 
FOP disease activity assessment via patient diary, the patient reported FOP 
Independent Activity of Daily Living (FOP I-ADL) Questionnaire based on 
the Patient Reported Outcomes Measurement Information System 
(PROMIS), the Europol 5 dimensions questionnaire with a 3-level scale (EQ-
5D-3L), the physician assessment of cumulative analog joint involvement 
scale (CAJIS) and spirometry assessment of pulmonary function. 
Biomarker Procedures  
Blood will be collected for the analysis and discovery of biomarkers, 
including but not limited to biochemical bone formation markers (BSAP, tAP 
and P1NP), hs-CRP, as well as mechanism based biomarkers related to the 
activin A and activin receptor pathway including but not limited to Activin 
and BMP ligands or markers that may elucidate the mechanism of action of 
REGN2477, and whole blood RNA analysis.  Blood for a separate optional 
genomics sub-study will also be collected in patients who consent to analysis. 
This analysis will be an exploratory pharmacogenomics analysis that may 
include genome wide analysis that is additional to the mandatory ACVR1 
gene sequencing noted above. 
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Pharmacokinetic and Anti-Drug Antibody Assessments 
Serum samples for measurements of drug concentration, activin A 
concentration, and ADA will be collected.  Any unused serum samples may 
be used for exploratory biomarker research or future biomedical research. 
Statistical Plan 
Justification of Sample Size 
Randomization will be stratified by the presence/absence of active HO lesions 
at baseline, to allow analyses of efficacy endpoint measures defined solely for 
patients with active HO at baseline.  Patients without active HO lesions at 
baseline will contribute to the assessment of safety and other endpoint 
measures.  Randomization will also be stratified by gender and classic 
ACVR1[R206H] mutation/different ACVR1 mutations. 
The sample size estimation for at least 24 patients (12 patients per treatment 
group) with active HO at baseline and classic ACVR1[R206H] mutation is 
based on statistical considerations for the following efficacy endpoints: 
percent change from baseline in (1) total lesion activity by 18F-NaF PET over 
28 weeks, (2) total HO volume by CT at week 28, and (3) 18F-NaF SUVmax at 
week 8.  Accounting for a 20% dropout rate at week 28, the sample size would 
yield approximately 10 patients per treatment group for week-28 analyses.  
This sample size will provide 80% power at a 2-sided 0.05 significance level 
in allowing the detection of an observed treatment difference in the order of 
57%, 65%, and 40% reduction in the total lesion activity by 18F-NaF PET, the 
total HO volume by CT, and the 18F-NaF SUVmax, respectively, if the measure 
variability in FOP patients is similar to that observed in other bone diseases 
and the FOP mouse model.  Recent in vitro studies demonstrated that different 
mutations in the ACVR1 receptor transduced BMP signaling when stimulated 
with activin A.  These results suggest that REGN2477 may provide beneficial 
clinical impact on HO in patients with FOP, irrespective of the underlying 
ACVR1 mutation.   
Statistical Hypotheses 
Hypothesis (Period 1 [Week 28]) 
The following null and alternative hypotheses will be tested sequentially for 
the primary and secondary efficacy endpoints respectively:  
H0: No treatment difference between REGN2477 and placebo  
H1: There is a treatment difference between REGN2477 and placebo  
Hypothesis (Period 2 [Week 56]) 
For the Period 2 (week 56) analyses, the following primary and key secondary 
null hypotheses will be tested:  
H1,1: There is no difference in number of new (relative to week 28 scan) 
HO lesions as assessed by CT per patient at week 56 compared to the 
number of new (relative to baseline scan) HO lesions as assessed by CT 
per patient at week 28 in placebo/REGN2477 group in AHO (primary) 
H2,1: There is no difference in total volume of new (relative to week 28 
scan) HO lesions per patient as assessed by CT at week 56 compared to 
the total volume of new (relative to baseline scan) HO lesions per patient 
as assessed by CT at week 28 in placebo/REGN2477 group in AHO (key 
secondary) 
H2,2: There is no difference in number of new (relative to week 28 scan) 
HO lesions per patient as assessed by 18F-NaF PET at week 56 compared 
to the number of new (relative to baseline scan) HO lesions per patient by 
18F-NaF PET at week 28 in placebo/REGN2477 group in AHO (key 
secondary) 
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CONFIDENTIAL 
H2,3: There is no difference in total lesion activity per patient by 18F-NaF 
PET in new (relative to week 28 scan) lesions at week 56 compared to the 
total lesion activity per patient by 18F-NaF PET in new (relative to baseline 
scan) lesions at week 28 in placebo/REGN2477 group in AHO (key 
secondary) 
H2,4: There is no difference in percent of patients with new HO lesions as 
assessed by CT at week 56 relative to week 28 scan in placebo/REGN2477 
group in AHO (key secondary) 
H2,5: There is no difference in percent of patients with new HO lesions as 
assessed by 18F-NaF PET at week 56 relative to week 28 scan in 
placebo/REGN2477 group in AHO (key secondary) 
Statistical Methods 
Efficacy Analysis for Period 1 (Week 28) 
Percent change from baseline in targeted total lesion activity 18F-NaF PET at 
week 8 and 28 weeks will be analyzed in AHO or AHOC using a mixed-effect 
model with repeated measures (MMRM) model.  The model will include 
treatment, gender, ACVR1 mutation type (AHO analysis set only) as fixed 
effects, time point, and treatment-by-time point interaction, as well as, the 
continuous fixed covariates of baseline value and baseline value-by-time 
point interaction. An unstructured covariance matrix can be used in this model 
to account for within-patient correlation.  Time weighted average over 28 
weeks will be estimated from the model.  Different parameterization of 
MMRM model will be utilized if at least 1 patient is missing all post-baseline 
values. Because all the patients in AHO or AHOC have active HO at baseline, 
the stratification factor for baseline HO status will not be included in the 
model. 
Percent change from baseline in the total volume of HO lesions as assessed 
by CT at week 28 will be analyzed in AHO or AHOC using MMRM model. 
The model will include treatment, gender, ACVR1 mutation type as fixed 
effects, time point, and treatment-by-time point interaction, as well as, the 
continuous fixed covariates of baseline value and baseline value-by-time 
point interaction.  An unstructured covariance matrix can be used in this 
model to account for within-patient correlation.  Different parameterization 
of MMRM model will be utilized if at least 1 patient is missing all post-
baseline values. 
Analysis of Time-weighted average (standardized AUC) change from 
baseline in daily pain due to FOP by the daily NRS over 28 weeks will be 
performed in AHO or AHOC using the ANCOVA with treatment, gender, 
ACVR1 mutation type (AHO analysis set only) as factors, and the baseline 
value as continuous covariate.  
In order to handle multiple testing of the 4 primary and 2 key secondary 
efficacy endpoints, hierarchical testing procedure will be applied at a 2-sided 
5% significance level.  Hypothesis for the primary and key secondary efficacy 
endpoint will be formally tested only if hypothesis for the preceding endpoint 
is significant at the 2-sided 5% level.  The order of testing sequence for 
primary and key secondary efficacy endpoints is as follows: 
Time-weighted average (standardized AUC) of the percent 
change from baseline in total lesion activity by18F-NaF PET 
over 28 weeks in AHO 
 
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Percent change from baseline in the total volume of HO 
lesions as assessed by CT at week 28 in AHO 
 
Time-weighted average (standardized AUC) of the percent 
change from baseline in total lesion activity 18F-NaF PET 
over 28 weeks in AHOC 
 
Percent change from baseline in the total volume of HO 
lesions as assessed by CT at week 28 in AHOC 
 
Time-weighted average (standardized AUC) of the change 
from baseline in daily pain due to FOP, as measured using 
the daily NRS over 28 weeks in AHO 
 
Time-weighted average (standardized AUC) of the change 
from baseline in daily pain due to FOP, as measured using 
the daily NRS over 28 weeks in AHOC 
 
No further multiplicity adjustments will be made for testing other secondary 
efficacy endpoints and exploratory endpoints where nominal p-values will be 
provided for descriptive purpose. 
Efficacy Analysis for Period 2 (Week 56) 
These analyses are new and independent from that of Period 1 and warrant 
their own overall 2-sided type I error rate of 10% (alpha of 0.1) which is 
consistent with regulatory guidance for studies in rare diseases.  The small 
inflation of alpha is also necessary to handle the possibility of patients with 
missing week 56 imaging assessment due to COVID-19.  
The type-I error rate will be controlled at 0.10 for the primary and key 
secondary null hypotheses in Period 2 (week 56).  To control the type-I error 
rate for the primary and key secondary endpoints in Period 2 (week 56), a 
hierarchical testing procedure will be applied at a 2-sided 10% significant 
level to test the above hypotheses in the specified order.  The key secondary 
efficacy endpoints will be tested only if statistical significance is established 
for the primary endpoint.  No further adjustments will be made for other 
secondary and exploratory endpoints in Period 2 (week 56), for which 
estimates, 95% CI, and/or nominal p-values will be provided for descriptive 
purpose. 
The COVID-19 pandemic has affected the conduct of the study mainly by 
causing delay in dose administration, delay in the collection of the PET/CT 
scans due to site closure, and unavailability of 18F-NaF due to interruption of 
tracer production. Some patients may not be able to complete their week 56 
scans within the protocol-specified visit window and may only be able 
complete their scans using CT-only modality.  
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The week 56 efficacy analyses  of imaging endpoints will be conducted using 
COVID-19 modified Intent-To-Treat (COVID-19 mITT) principle which will 
analyze only those patients for whom:  
• 
at least 1 post-week 28 scan is collected and, 
• 
the time period between any 2 consecutive doses is less than 
9 weeks (63 days) in Period 2 and, 
• 
no more than 1 dose was missed in Period 2 
This will ensure that primary analyses for imaging endpoints will include 
patients with continuous saturating levels of REGN2477.  For patients whose 
week 56 scans are delayed, the first delayed scan available after the week 28 
scan will be used to impute the week 56 data in the primary analyses. In the 
absence of a PET/CT scan, data from available CT-only scans will be used to 
analyze the primary endpoint and other secondary imaging endpoints, if 
applicable. This imputation ensures that the estimation of the treatment effect 
will not be biased by the COVID-19 pandemic. 
The number of new HO lesions as assessed by CT at week 56 relative to 
week 28 scan will be summarized for the placebo/REGN2477 group. 
Wilcoxon signed rank test will be used for the within group comparison in the 
placebo/REGN2477 group to compare the number of new HO lesions by CT 
at week 56 relative to week 28 scan with the number of new HO lesions by 
CT at week 28 relative to baseline scan. 
The total volume associated with new HO lesions as assessed by CT at 
week 56 relative to week 28 scan will be summarized for the 
placebo/REGN2477 group. Wilcoxon signed rank test will be used for the 
within group comparison in the placebo/REGN2477 group to compare the 
total volume at week 56 associated with new HO lesions by CT relative to 
week 28 scan with the total volume associated with new HO lesions by CT at 
week 28 relative to baseline scan.  
The number of new HO lesions by 18F-NaF PET at week 56 relative to week 
28 scan will be summarized for the placebo/REGN2477 group. Wilcoxon 
signed rank test will be used for the within group comparison in the 
placebo/REGN2477 group to compare the number of new HO lesions as 
assesses by PET at week 56 relative to week 28 scan with the number of new 
HO lesions by PET at week 28 relative to baseline scan.  
The total lesion activity associated with new HO lesions by PET at week 56 
relative to week 28 scan will be summarized for the placebo/REGN2477 
group. Wilcoxon signed rank test will be used for the within group 
comparison in the placebo/REGN2477 group to compare the total lesion 
activity associated with new HO lesions by PET at week 56 relative to 
week 28 scan with the total lesion activity associated with new HO lesions by 
PET at week 28 relative to baseline scan.  
Number and percent of patients with new HO lesions by CT at week 56 
relative to week 28 will be provided for the placebo/REGN2477 group. The 
within group comparison to compare the percent of patients with new HO 
lesions by CT at week 56 relative to week 28 scan with the percent of patients 
with new HO lesions by CT at week 28 relative to baseline scan will be 
performed using McNemar’s test in placebo/REGN2477 group. 
Number and percent of patients with new HO lesions by PET at week 56 
relative to week 28 scan will be provided for the placebo/REGN2477 group. 
The within group comparison to compare the percent of patients with new HO 
lesions by PET at week 56 relative to week 28 scan with the percent of patients 
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with new HO lesions by PET at week 28 relative to baseline scan will be 
performed using McNemar’s test in placebo/REGN2477 group. 
The type-I error rate will be controlled at 0.10 for the primary and key 
secondary null hypotheses in Period 2 (week 56). 
To control the type-I error rate for the primary and key secondary endpoints 
in Period 2 (week 56), a hierarchical testing procedure will be applied at a 
2-sided 10% significant level to test the above hypotheses in the specified 
order.  The key secondary efficacy endpoints will be tested only if statistical 
significance is established for the primary endpoint. 
No further adjustments will be made for other secondary and exploratory 
endpoints in Period 2 (week 56), for which estimates, 95% CI, and/or nominal 
p-values will be provided for descriptive purpose. 
The results obtained for the REGN2477/REGN2477 group (patients who 
continue receiving REGN2477 beyond week 28) will be analyzed for 
persistence of efficacy. 
In the REGN2477/REGN2477 group, the estimates of treatment effects at 
week 56 will be provided with 95% confidence interval on the endpoints 
related to new HO lesions (new relative to baseline scan). 
Estimates of the treatment effects with 95% confidence interval on the 
endpoints related to new HO lesions from Period 1 (new relative to baseline 
scan) in the REGN2477/REGN2477 group patients will be descriptively 
compared with the estimates from Period 2 (new relative to week 28) in the 
placebo/REGN2477 group. 
Primary and Additional Analysis 
No interim analysis is planned for this study. 
Primary analysis of safety and efficacy data of the randomized double-blind 
placebo-controlled period (Period 1) of the study will be performed once all 
data have been collected and validated through the end of this period 
(Period 1, week 28; database lock [DBL] 1).  Additional analyses of safety 
and efficacy data will be performed following the open-label REGN2477 
period (Period 2; week 56; DBL 2), and at the end of the follow-up treatment 
period at week 76 (Period 3, Week 76; DBL 3).  Since the key efficacy 
measure data collection for Period 1 will have been concluded at the time of 
the first analysis (Period 1, week 28; DBL 1) and the radiographic data for 
subsequent periods had not been read nor entered into the database, the final 
analysis for Period 1 is not considered an interim analysis for subsequent 
periods and no multiplicity adjustments are needed. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
Adrenocorticotropic hormone 
ACVR1 
Type I activin A receptor 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AHOC 
Baseline active HO classic ACVR1[R206H] mutation analysis set 
AHO 
Baseline active HO analysis set (AHO) 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMP 
Bone morphogenic protein 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CAJIS 
Cumulative Analog Joint Involvement Scale 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CT 
Computed tomography 
DBL 
Database lock 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ED 
Effective dose 
EDC 
Electronic data capture 
EQ-5D-3L 
EuroQol 5 dimensions questionnaire with a 3-level scale 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FIH 
First in human 
18F-NaF 
Fluorine-18-labelled sodium fluoride  
FOP 
Fibrodysplasia ossificans progressiva 
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FOP I-ADL 
FOP Independent Activities of Daily Living 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GH 
Growth hormone 
GLP 
Good Laboratory Practice 
HbA1c 
Hemoglobin A1c  
hCG 
Human chorionic gonadotropin 
hs-CRP 
High sensitivity C-reactive protein 
HO 
Heterotopic ossification 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IV 
Intravenous 
Ki 
Incorporation rate 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LLOQ 
Lower limit of quantification  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
NOAEL 
No-observed-adverse-effect-level 
NRS 
Numeric rating scale 
P1NP 
Total Procollagen Type 1 N-Terminal Propeptide 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Preferred term 
Q4W 
Every 4 weeks 
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RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUVmax 
Standardized uptake value (maximum) 
T4 
Thyroxine 
tAP 
Total alkaline phosphatase 
99mTc 
Technetium-99 methylene diphosphonate 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
WBC 
White blood cell 
WoCBP 
Woman of child bearing potential 
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1. 
INTRODUCTION 
REGN2477 is a fully human monoclonal antibody that specifically binds to and blocks signaling 
of activin A.  REGN2477 is being developed for the treatment of fibrodysplasia ossificans 
progressiva (FOP), an ultra-rare genetic disorder affecting approximately 800 patients worldwide.  
Characteristics of FOP include progressive heterotopic ossification (HO) of skeletal muscle, 
ligaments, tendons, and fascia, which leads to joint immobility, significant disability, pain and 
premature death (Kaplan 2010, Aleman-Meunch 2012, Hüning 2014).  There is no approved 
treatment for the prevention or reversal of HO associated with FOP.  Fibrodysplasia ossificans 
progressiva appears to be caused by mutations in the region encoding for the intracellular domain 
of type I activin A receptor (ACVR1) with the most common mutation observed in patients being 
ACVR1[R206H] (Hüning 2014).  Recent studies in a conditional-inducible mouse model of FOP 
have demonstrated that the ACVR1[R206H] variant drives HO by conferring to the receptor the 
abnormal ability to recognize activin A as an agonistic ligand resulting in abnormal bone formation 
similar to the clinical condition (Hatsell 2015).  In this model, exogenous activin A drives 
exuberant HO activity and REGN2477 administration dramatically halts heterotopic bone 
formation.  In vitro studies demonstrated that different mutations in the ACVR1 receptor 
transduced bone morphogenic protein (BMP) signaling when stimulated with activin A 
(Hino 2015).  These results indicate that REGN2477 may suppress HO for patients with FOP who 
have ACVR1 mutations other than ACVR1[R206H].  Taken together, these data suggest that 
REGN2477 may be an effective treatment for FOP irrespective of the underlying ACVR1 
mutation. 
This study (R2477-FOP-1623 LUMINA-1) is designed to test the hypotheses that 1) REGN2477 
is generally well tolerated and 2) REGN2477 inhibits HO in patients with FOP. Positron emission 
tomography (PET) with 18F-NaF and volumetric computed tomography (CT) will be used to 
measure the change in heterotopic bone formation.  18F-NaF PET has been shown in several other 
disease settings to provide a sensitive, specific, and whole body quantitative measure of bone 
mineralization activity.  The use of 18F-NaF PET and other imaging modalities, such as 
Technetium-99 (99mTc) bone scan, are able to detect HO lesions in FOP patients (Eekhoff 2016, 
Fang 1986, Herford 2003, Trikha 2005, Tulchinsky 2007).  In the Regeneron mouse model of 
inducible FOP, HO lesions have been shown to be detectable by 18F-NaF PET and HO activities 
in these lesions are markedly diminished following treatment with REGN2477 (see the 
Investigator’s Brochure [IB]).  It is hypothesized that use of 18F-NaF PET may allow an assessment 
of treatment effect in a relatively small number of patients as early as 8 weeks after treatment 
initiation and may be the most sensitive modality to quantify total change in HO activity during 
the 6-month treatment time planned for Period 1 of this study.  Because this modality has not been 
previously studied in patients with FOP, this study also plans an assessment of change in the total 
volume of HO (as assessed by quantitative CT) over the 6 month treatment interval as well as a 
change in the number of new lesions during this period (as assessed by 18F-NaF PET and CT).  
Additional endpoints captured in this study will include changes in biochemical biomarkers of 
bone turnover and changes in clinical measures for joint function and patient reported disease 
activity and activities of daily living. Patients with FOP describe pain associated with their disease, 
at times refractory to analgesic treatments.  Pain severity will be assessed daily in this study 
through the Pain Numeric Rating Scale (NRS).  
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This study plans to enroll up to 40 adult male and female FOP patients to ensure inclusion of 
approximately 24 or more patients with the classic [R206H] ACVR1 mutation and active HO 
lesion detectable by 18F-NaF PET at baseline to allow the assessment of change from baseline 
treatment effects on key efficacy endpoints of heterotopic bone formation.  The protocol 
amendment 1 expands the scope of patient eligibility by opening enrollment to patients with a FOP 
diagnosis and documentation of any ACVR1 mutation.  During the study, all patients will have 
their ACVR1 gene sequenced as part of the study.  The study will consist of 3 treatment periods.  
The first period (Period 1) will be a 6-month randomized, double-blind, placebo-controlled 
treatment period evaluating changes from baseline in HO by 18F-NaF PET and CT at 8 weeks and 
6 months.  The second period (Period 2) will be a 6-month open-label treatment period, during 
which all patients in the study will be treated with REGN2477.  Patients previously treated with 
placebo will be crossed over to REGN2477 to allow for an assessment of a 6-month treatment 
effect; patients previously on REGN2477 will be treated with REGN2477 for an additional 
6 months to allow for an assessment of a 12-month treatment effect.  The third period (Period 3) 
will be a follow-up treatment period during which all patients in the study will continue to be 
treated with REGN2477 at monthly visits until the patients have completed the week 76 visit, and 
all data have been collected and validated through the time when the last patient randomized into 
the study completes the week 28 visit (Period 1), and results of the primary analyses of safety and 
efficacy are available to the sponsor.  The patients who reach the week 76 visit will continue 
REGN2477 treatment consistent with Regeneron corporate policy governing access to 
investigational drugs in confirmatory clinical studies (Section 5.1.4).  Patients will have the option 
to discontinue study medication before the beginning or at any time during Period 3, similarly to 
what occurs at any time during the study.  The proposed dose regimen is 10 mg/kg, given 
intravenously (IV) every 4 weeks (Q4W). 
The LUMINA-1 study is currently ongoing, and all patients have completed Period 1 
(double-blind, placebo-controlled period; see the IB).  The results from the primary analysis of 
efficacy in Period 1 of the LUMINA-1 study demonstrated clinical benefit of REGN2477 for the 
treatment of FOP by markedly reducing the number of new heterotopic bone lesions as assessed 
by both18F-NaF PET and CT (see Section 3.3.1).  These results refined our understanding of the 
pathophysiology of FOP and the role of activin A in the disease.  Together with the understanding 
of the genetics of this disease and with the complementary preclinical animal model data, the 
clinical data from the primary analysis of LUMINA-1 indicate that activin A is required for the 
formation of new lesions in patients with FOP but does not seem to play a major role in the 
progression of existing lesions by PET or CT.  Moreover, these data demonstrate that REGN2477 
provides improvement on clinically meaningful endpoints, ie, formation of new HO bone lesions 
and inhibition of flare-up episodes for this disease. 
Treatment with REGN2477 demonstrated an acceptable safety profile (see the IB).  During 
Period 1 (the 28-week double-blind treatment period), the majority of treatment-emergent adverse 
events (TEAEs) were mild to moderate in severity.  Notable imbalances in TEAEs for the 
REGN2477 group included Epistaxis, Acne, Madarosis, and a composite of skin and soft tissue 
infections including Abscess, Folliculitis, and Cellulitis.  A pathophysiologic explanation for these 
adverse events (AEs) has not been identified, although with respect to epistaxis, data to date 
suggest that REGN2477 does not inhibit platelet number, function, or clotting activity 
(see Section 3.4.3 and Section 3.4.4). 
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The results from the 2 first-in-human (FIH) studies (R2477-HV-1525 and R2477-1033-HV-1621) 
which evaluated REGN2477 showed that REGN2477 doses up to 10 mg/kg (single-dose) and 
10 mg/kg Q4W for 4 doses were generally well-tolerated (see the IB). 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary safety objective of the study is to assess the safety and tolerability of REGN2477 in 
male and female patients with FOP. 
The primary efficacy objective of the study is to assess the effect of REGN2477 versus placebo on 
the change from baseline in HO in patients with FOP, as determined by 18F-NaF uptake in HO 
lesions by PET and in total volume of HO lesions by CT. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are:  
• To compare the effect of REGN2477 versus placebo on pain due to FOP, as measured 
by the area under the curve (AUC) for pain based on daily pain NRS scores 
• To assess the effect of REGN2477 versus placebo on the change from baseline in HO, 
as determined by the number of new HO lesions identified by 18F-NaF PET or by CT 
• To assess the effect of REGN2477 versus placebo on the change from baseline in 
18F-NaF standardized uptake value maximum (SUVmax) of individual active HO site(s) 
by PET 
• To assess the effect of REGN2477, between week 28 and week 56, on the number, 
activity, and volume of HO lesions identified by 18F-NaF PET or by CT in patients who 
switch from placebo to REGN2477 at week 28 versus the same patients between 
baseline and week 28  
• To assess the effect of REGN2477 versus placebo on the change from baseline in 
biochemical markers of bone formation  
• To characterize the concentrations of total activin A at baseline and over time following 
the first dose of study drug  
• To characterize the concentration-time profile (pharmacokinetic [PK]) profile of 
REGN2477 in patients with FOP  
• To assess the immunogenicity of REGN2477 
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2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore the effects of REGN2477 versus placebo on change from baseline on 
clinical endpoints such as the following: FOP disease activity, joint function, and 
patient reported activities of daily living, and glucocorticoids and pain medication use 
• To explore the effect of REGN2477 versus placebo on normal bone metabolic activity 
as determined by change from baseline in 18F-NaF PET uptake in skeletal bone 
• To explore the effect of REGN2477 on the plasma concentration profile of 18F-NaF 
• To explore the effect of REGN2477 vs. placebo on the total dose of corticosteroids 
used over the treatment phase of the study  
• To explore the correlation between change from baseline in 18F-NaF PET signal of 
SUVmax at 8 weeks with change from baseline in volumetric CT evaluation of HO at 
28 weeks  
• To explore the effects of REGN2477 on lesion progression from PET detectable lesions 
to CT detectable lesions 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis:  Period 1 Double-Blind, Placebo-Control Treatment 
Period (Week 28) 
Prior to the conduct of this LUMINA-1 study, the hypothesis was that activin A is required for the 
formation and progression of new and existing active HO.  By blocking activin A, there was an 
expectation that compared to placebo, REGN2477 would show a marked reduction of HO (on both 
existing target lesions identified at baseline and new lesions that might develop after baseline). 
This effect would be evidenced by decreases in 18F-NaF PET uptake into existing active lesions 
and inhibition of the growth of heterotopic bone lesions by volumetric CT. 
The hypotheses were:  
1. REGN2477 is generally well-tolerated in patients with FOP 
2. Treatment with REGN2477 reduces HO in patients with FOP  
3.2. 
Hypothesis:  Period 2 Open-Label Period (Week 56) 
Results from the prespecified primary efficacy analysis from Period 1 (28-week, double-blind 
period) have indicated that REGN2477 prevents occurrence of new HO lesions (see the IB).   
Upon analysis of the results of time weighted average of percent change from baseline in total 
lesion activity by PET through week 28 and percent change from baseline in total volume of HO 
by CT at week 28, it became clear that the overall reduction of these measures observed in patients 
treated with the REGN2477 compared to those treated with placebo was mainly driven by an 
approximately 90% decrease in the number of new lesions, as detected by both PET and CT.  The 
quantification of new lesions by each modality was highly concordant with one another.   
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These results support a new hypothesis:  
1. Treatment with REGN2477 prevents the formation of new HO in patients with FOP  
3.3. 
Rationale  
3.3.1. 
Rationale for Clinical Development of REGN2477 for FOP  
Fibrodysplasia ossificans progressiva is a devastating ultra-rare autosomal dominant genetic 
disease for which there is no effective treatment currently.  It is caused by mutations in the ACVR1 
gene (also known as ALK2, Shore 2006).  Preclinical data generated at Regeneron 
Pharmaceuticals, Inc. (Regeneron) provide strong rationale for evaluating REGN2477, an anti-
activin A antibody, for the treatment of this disease. 
The FOP disease is characterized by childhood onset and life-long episodic and progressive HO 
in soft tissues, which can lead to joint immobility, skeletal deformity, and severe disability.  Early 
mortality is common, often in the fifth decade, principally due to cardiorespiratory failure from 
thoracic insufficiency syndrome.  Disease flare-up episodes, often reported by patients as acute 
onset of painful or non-painful soft tissue swelling, joint stiffness, or loss of joint mobility, are not 
predictable in their occurrence, are variable in severity and duration (from days to many months), 
and do not always result in HO (Pignolo 2016, Kaplan 2016).  Pain associated with FOP disease 
activity may be severe and even refractory to opioid analgesics.  Heterotopic bone formation and 
disability may develop insidiously without acute flare-up symptoms (Pignolo 2016).  Bone 
scintigraphy and the more sensitive and specific 18F-NaF PET method readily detect multiple focal 
HO lesions with abnormally high uptake of bone homing tracers in body regions where patients 
with FOP report experiencing flare-up symptoms and in regions without symptoms (Fang 1986, 
Herford 2003, Trikha 2005, Tulchinsky 2007, Eekhoff 2016).  There are currently no effective 
treatments to prevent or inhibit HO in patients with FOP.  Surgical attempts to remove the 
heterotopic bone in patients with FOP result in more aggressive episodes of HO and are rarely 
conducted.  Disease flare-ups are typically treated with high doses of glucocorticoids or non-
steroidal anti-inflammatory medications; however, these agents have not been shown to affect the 
course of HO. 
Regeneron has developed a murine model of FOP that conditionally expresses the most common 
mutation variant of ACVR1, ACVR1[R206H], which is seen in patients with FOP, and recreates 
key features of the human disease.  This animal model displays heterotopic bone formation in soft 
tissues, spontaneously or following tissue injury, and exacerbation following surgical resection of 
bony lesions.  In this model, blockade of activin A by REGN2477 not only prevented the onset of 
HO if given prophylactically prior to induction of HO, but also halted the progression of pre-
existing HO if given as a treatment after HO has been induced (Hatsell 2015, see IB).  Recent in 
vitro studies demonstrated that different mutations in the ACVR1 receptor transduced BMP 
signaling when stimulated with activin A (Hino 2015).  These data indicate that REGN2477 may 
suppress HO for patients with FOP who have ACVR1 mutations other than ACVR1[R206H].  
Taken together, these results suggest that REGN2477 may provide beneficial clinical impact on 
HO in patients with FOP, irrespective of the underlying ACVR1 mutation.  Preclinical imaging 
data support the use of both 18F-NaF PET and CT to follow disease progression and treatment.  
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The LUMINA-1 study is currently ongoing, and all patients have completed Period 1 
(double-blind, placebo-controlled period).  The study database for the analysis of Period 1 was 
locked (19 Nov 2019 for clinical results and 13 Dec 2019 for imaging results).  The results of the 
primary efficacy and safety analysis for Period 1, after adult patients received 7 monthly infusions 
of either REGN2477 or placebo with at least 28 weeks of follow-up, showed that REGN2477 
reduced average total lesion activity (by 18F-NaF PET) from baseline over 28 weeks by 
approximately 25% (LS mean difference) compared to placebo (p=0.0741; see IB for details).  
Correspondingly, there was an approximate 25% (LS mean difference) decrease in bone lesion 
volume (both new and existing lesions) compared to placebo as measured by CT (p=0.373).  These 
results were largely driven by marked decreases of nearly 90% in the incidence of new lesions 
irrespective of imaging modality (p<0.01).  The percent of patients who developed 1 or more new 
HO lesions as assessed by PET was lower in the REGN2477 treatment group (3 of 20 patients 
[15%]) as compared to placebo (11 of 24 patients [45.8%]) through week 28 (prespecified 
p=0.050).  Similarly, the percent of patients who developed new HO lesions as assessed by CT 
was again lower in the REGN2477 treatment group (3 of 20 patients [15%]) compared to placebo 
(11 of 24 patients [45.8%]) through week 28 (post-hoc p=0.050).  The identification of lesions as 
"new" versus "existing" at baseline was specified in the imaging charter.  Taken together, these 
results indicate that while REGN2477 has a relatively modest treatment effect on the attenuation 
of existing lesions, there was a large effect preventing the occurrence of new lesions.  
In addition, an analysis to compare low-dose CT-only and PET/CT reads on new HO lesions from 
the LUMINA-1 study was performed by the Sponsor.  Low-dose CT-only reads (ie, in the absence 
of PET scan) were performed by 2 new independent blind readers and a new blinded adjudicator.  
The readers and adjudicator assessments were entered into a separate electronic data capture 
(EDC) system.  The CT-only reads and lesion quantification were carried out following the same 
procedures described in the Imaging Review Charter.  
This analysis to compare the performance between PET/CT and low-dose CT-only showed there 
was no marked difference detected in the performance between PET/CT and CT reads (p=0.75). 
Specifically, the CT-only reading methodology reconfirmed the REGN2477 treatment effects on 
number or percentage of patients with new lesions, total number of new lesions, and volume of 
new lesions seen by the primary PET/CT reading methodology.  Thirty-eight new lesions were 
identified by the CT-only reads and 30 new lesions were identified by the PET/CT reads.  Only 
1 lesion out of 38 new lesions identified by the CT-only reads was in REGN2477 group, and 3 out 
of 30 new lesions identified by the PET/CT reads were in REGN2477 group. 
Additional to the data indicating that activin A mostly serves to initiate the biologic events that 
ultimate result in heterotopic bone formation, the incidence of patient-reported flare ups was also 
reduced by 50% (prespecified p=0.032), while investigator-reported AEs of flare ups were 10% 
for REGN2477 and 42% for placebo (post-hoc p=0.039).  A favorable trend for reduced daily 
average pain as measured by NRS was seen in the REGN2477 groups compared to placebo.  
These data have prompted the definition of separate study hypotheses for the open-label treatment 
period (week 28 to week 56; Section 3.2) and addition of endpoints consistent with these 
hypotheses to confirm the efficacy of REGN2477 in preventing the formation of new HO and 
reducing flare-ups (Section 4.3).  
Further details of REGN2477 clinical data and preclinical data to support clinical development 
may be found in the IB. 
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3.3.2. 
Rationale for Study Design 
The study population will consist of adult male and female patients with FOP who are 18 to 
60 years old with documentation of any ACVR1 mutation and a recent history of active disease or 
HO progression as assessed by their treating physician within the last year.  All patients with FOP 
who enroll in the study will have a blood sample collected for sequencing of their ACVR1 gene 
during the study.  This information will support interpretation of the study results.   
Up to 40 FOP patients with or without current flare-up activities may be enrolled and randomized 
1:1 to REGN2477 or placebo treatment initially.  We estimate that at least 60% of FOP patients 
will have at least 1 active HO lesion, detected by 18F-NaF PET/CT at baseline.  Enrollment of up 
to 40 patients is expected to yield approximately 24 or more patients with the classic 
ACVR1[R206H] mutation and active HO at baseline.  Randomization will be stratified by 
presence/absence of baseline active HO lesions, to allow change from baseline analyses of key 
efficacy endpoint measures such as 18F-NaF uptake in HO lesions.  Patients without baseline active 
HO lesions will contribute to the assessment of safety and other endpoint measures such as 
development of new HO lesions.  Randomization will also be stratified by gender and classic 
ACVR1[R206H] mutation/different ACVR1 mutations. 
As there is no effective treatment for this severe rare disease, which often has a variable and 
insidious course, a placebo-controlled study is appropriate and will allow longitudinal 
documentation of disease activity and progression in both treatment groups in a blinded fashion to 
rigorously assess efficacy and safety of REGN2477.  The 1:1 randomization ratio serves to 
minimize potential erroneous conclusions due to imbalance between the 2 treatment groups, and 
limits the number of patients exposed to REGN2477 until initial safety is established.  
No active comparator is being considered because there is no effective therapy for this disease.  
Patients in both groups will be allowed to receive standard of care therapies, including 
glucocorticoids and analgesics as needed for symptomatic management of the disease.  Treatment 
difference in use of glucocorticoids and analgesics will be exploratory endpoints in this study.  
Bisphosphonates, which are sometime prescribed to patients with FOP, will not be allowed during 
the study, as these drugs are known to affect bone biomarkers and 18F-NaF uptake by the normal 
skeleton.  Also, denosumab, imatinib and isotretinoin should not be prescribed to study patients as 
these drugs may affect skeletal bone turnover.   
This study is designed as a 3-period study, with an initial 6-month randomized double-blind 
placebo-controlled treatment period (Period 1), a subsequent 6-month open-label REGN2477 
treatment period (Period 2) for all patients in the study, and a follow-up treatment period (Period 3) 
with continued use of REGN2477. 
The 6-month duration of Period 1 was chosen based on our current knowledge of HO progression 
in FOP as assessed by the co-primary and key secondary imaging endpoints measures.  Cross-
Sectional and longitudinal 18F-NaF PET data in a small number of FOP patients showed 
abnormally high levels of 18F-NaF uptake at multiple heterotopic locations and that detection of 
new HO lesions by PET was highly sensitive and preceded that by CT.  In these patients, PET 
detectable lesions progressed to CT detectable calcified bony lesions in approximately 6 months, 
and often resulted in functional limitations (Eekhoff 2016; for more details see Section 3.3.3.1).  
Based upon observation of 99mTc bone scans as well as18F-NaF PET from FOP patients, it is 
anticipated that a majority of the patients (more than 60%) in this planned study will have at least 
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1 active lesion which will demonstrate increased 18F-NaF uptake (as measured by maximum 
SUVmax) at baseline.  Without treatment, 18F-NaF uptake in an individual lesion decreases within 
6 months, as bone fully calcifies and becomes visible on CT.  Therefore, to observe a change from 
baseline treatment effect of lesions active by PET at baseline, we chose an early time point of 
8 weeks post-treatment.  This early time point is expected to allow sufficient time for drug action 
in tissue, while permitting a distinction of the effect of the drug from that of the natural HO bone 
maturation process.  It is expected, however, that HO is a dynamic process in these patients and 
that without treatment, patients would have a number of lesions which would wax and wane during 
a 6-month period of time whereas an effective therapy which inhibits HO activity would decrease 
this activity.  For this reason, a co-primary endpoint measure in this study will be the Total Lesion 
Activity (sum of 18F-NaF uptake in all active HO lesions by PET) from baseline through 6 months 
to allow for detection of treatment effects on both existing lesions and new lesions.  Volumetric 
assessment of HO lesions by CT over 6 months will also allow assessment of growth of HO lesions 
and transition of PET detectable lesions to CT detectable mature HO lesions. 
Based on patient reports, FOP patients experience an average of 2 flare-ups per year, with a sub-
set of flare-ups leading to HO. However, HO has also been reported without being preceded by 
flare-ups (Pignolo 2016). Therefore, we anticipate that, in the absence of treatment, a number of 
new HO lesions will develop over the 6-month treatment period. The Total Lesion Activity (sum 
of 18F-NaF uptake in all active HO lesions by PET) from baseline through 6 months allows 
detection of treatment effects on both existing lesions and new lesions.  
After completion of Period 1 (the 6-month double-blind placebo controlled period), patients will 
enter Period 2, during which all patients will be treated open-label for 6 months with REGN2477 
but will remain blinded to their previous treatment assignment.  Those patients who had been in 
the placebo group in Period 1 will be crossed over to REGN2477 treatment in Period 2, thereby 
allowing all patients participating in this study to contribute to the evaluation of REGN2477 safety 
and efficacy.  Patients who had been in the REGN2477 group in Period 1 will be treated with 
REGN2477 for an additional 6 months in Period 2 to provide an assessment of a 12-month 
treatment effect. 
At the end of the Period 2, patients will continue to be treated with REGN2477 monthly during 
the follow-up treatment period (Period 3) until patients have completed the week 76 visit, and all 
data have been collected and validated through the time when the last patient randomized into the 
study completes the week 28 visit (Period 1), and results of the primary analyses of safety and 
efficacy are available to the sponsor.  If at the time patients reach the week 76 visit data from the 
last patient randomized into the study through the week 28 visit have not been collected and 
validated, and results of the primary analyses of safety and efficacy are not yet available to the 
sponsor, patients will continue to receive REGN2477 Q4W beyond week 76.  During this follow-
up treatment period (Period 3), each patient will continue to receive REGN 2477 provided that no 
safety signals are identified during continuous monitoring of the study by the investigator, medical 
monitor and Independent Data Monitoring Committee (IDMC).  In addition, during this period, all 
patients will be required to maintain contraception use.  Patients will have the option to discontinue 
study medication at any time during Period 3, similarly to what occurs at any time during the study 
after patients have signed the informed consent. 
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3.3.3. 
Rationale for Efficacy Endpoint Measures (Period 1; Week 28) 
Heterotopic ossification is the key clinical feature of FOP and the primary cause of immobility, 
disability, pain, and early mortality. Therefore, our choices of efficacy endpoint measures are 
aimed at allowing a rapid and sensitive assessment of the potential drug effect of inhibiting activin 
A on heterotopic bone formation. 
3.3.3.1. 
18F-NaF Positron Emission Tomography 
The 18F-NaF PET imaging will be utilized in this study to assess active HO lesions (lesions with 
rapid mineralization in a period of active growth compared to normotopic skeleton and HO lesions 
that have matured and no longer grow) at baseline, week 8, week 28, week 56, and week 76.  The 
inherent quantitative nature of this imaging modality and our understanding of the biology of HO 
progression in FOP provide the rationale and we intend to qualify this endpoint measure during 
this study. 
18F-NaF is a Food and Drug Administration (FDA)-approved PET tracer widely used to detect 
abnormal osteogenic activity in several bone pathologies such as Paget’s disease, ankylosing 
spondylitis, and osteoblastic bone metastases (Grant 2008).  When combined with CT, 18F-NaF 
PET has a sensitivity and specificity of >90% for the detection of osteoblastic metastases 
(Even-Sapir 2006).  Following IV administration, 18F-NaF is rapidly cleared from the plasma into 
the skeleton and binds to bone at a high rate, leading to an elevated target-to-background ratio 
signal (Blake 2012, Even-Sapir 2006).  Uptake of 18F-NaF is concentrated at sites of high 
osteoblastic activity where the 18F ions bind to the newly mineralizing bone in a manner 
proportional to the apposition rate of bone, as shown by double tetracycline labeling studies in a 
porcine model (Piert 2001).  Due to the inherent quantitative capability of PET, 18F-NaF imaging 
provides an objective, non-invasive measure that is proportional to the rate of bone formation.  
18F-NaF PET/CT has been used in monitoring treatment effects on bone in other diseases. For 
example, in a study of 14 patients with Paget’s disease, the SUVmax and tracer bone incorporation 
rate (Ki) were found to be significantly higher in Pagetic bone than in normal bone 
(35.07±23.86 vs. 7.15±4.76 and 0.114±0.115 vs. 0.014±0.008 mL/min/mL, respectively, 
mean ± standard deviation [SD], p<0.05 for both measures). Following treatment with 
bisphosphonates under various regiments from single IV injection to daily oral administration 
significant reduction of PET signal in Pagetic bone was observed compared to baseline 
(-27.84±24.59 at 1 month and -44.64±23.61% at 6 months, p<0.05 at both time points) 
(Installe 2005). 
Pilot studies (Eekhoff 2016) in a small number (N=4) of FOP patients evaluated by whole body 
18F-NaF PET scan showed all patients had metabolically active HO lesions, with elevated 18F-NaF 
uptake above the background levels of surrounding soft tissue and normal mature bone 
(Win 2014). Though there is limited data with this specific imaging modality, other bone scan data 
using 99mTc, which also detects bone mineralization, have demonstrated uptake in areas of HO in 
patients with FOP (Fang 1986, Herford 2003, Trikha 2005, Tulchinsky 2007). Collectively, these 
results are consistent with those observed in the FOP mouse model with the ACVR1[R206H] 
mutation, which showed that the areas of active HO demonstrate abnormally high uptake of 18F-
NaF on PET. In these mice, administration of REGN2477 inhibits heterotopic bone formation and 
markedly decreases 18F-NaF PET uptake in HO lesions (see IB). It is thus hypothesized that 
normalization in 18F-NaF uptake in pre-existing active HO lesions or a reduction in the number of 
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new active HO lesions in patients treated with REGN2477, compared with those treated with 
placebo, can provide evidence of a “proof of concept” for the treatment effect of REGN2477 on 
HO activity and that eventually this effect will translate into a reduction in HO lesions as detected 
by CT.  Time-weighted percent change (AUC analysis) from baseline in Total Lesion Activity 
by18F-NaF PET to week 28 compared to placebo is chosen as 1 of the co-primary efficacy 
endpoints to assess the drug effect on heterotopic bone formation activity in existing and new 
lesions. 
3.3.3.2. 
Quantitative Whole Body CT 
Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28 
compared to placebo is chosen as another of the co-primary efficacy endpoints, to allow 
assessment of growth of HO lesions. 
In the FOP mouse model, microCT was also used to demonstrate the treatment effects of 
REGN2477.  In this model, REGN2477 prevented new HO lesion development and halted 
progression of existing HO lesions (see the IB for more detail).  Although there are no published 
longitudinal natural history data on the change of HO lesion volume, it is known that new areas of 
HO in patients with FOP are detectable by CT in 3 to 6 months following tissue trauma, flare-up, 
or surgical procedures (Eekhoff 2016, Kaplan 2016, Kitoh 2013).  Thus, it is anticipated that a 
treatment effect may be observed by CT in a 6-month time-frame.  This study will also assess the 
treatment effect of REGN2477, as compared with placebo, on number of new HO lesions, in 
addition to changes in HO lesion volume by CT at 28 weeks.  Without treatment, active HO lesions 
that are detectable by the very sensitive 18F-NaF PET measure at baseline are expected to coalesce 
over time into mature HO lesions that will be detectable by CT.  Therefore, a treatment effect may 
be discernable by comparing the number of new CT detectable HO lesions in REGN2477-treated 
patients versus placebo-treated patients. 
3.3.4. 
Rationale for Efficacy Endpoints (Period 2; Week 56) 
All patients remaining in the study have transitioned to the open-label REGN2477 treatment 
periods, Periods 2 (Section 5.1.3) and Period 3 (Section 5.1.4).   
The switch of patients in the placebo group to REGN2477 treatment will allow the confirmation 
of the study hypothesis for Period 2 (Section 3.2) that REGN2477 treatment leads to the prevention 
of new heterotopic bone formation compared to control.  The "control" is the experience of these 
same patients during the preceding placebo treatment period (Period 1).  New HO related primary 
endpoint and key secondary endpoints will be evaluated in Period 2 (week 56; Section 4.3).  These 
analyses are new and independent from that of Period 1 and warrant their own overall type I error 
rate of 10% (alpha of 0.1) which is consistent with regulatory guidance for studies in rare diseases.  
The small inflation of alpha is also necessary to handle the possibility of patients with missing 
week 56 imaging assessment due to COVID-19 (Section 10.4.3.2.4).  The previously specified HO 
related secondary endpoints will also be assessed in Period 2 (week 56).  Additionally, assessment 
of the patients who continue REGN2477 treatment from Period 1 (double-blind period) will allow 
the confirmation of the persistence of effect of REGN2477 in reducing new heterotopic bone 
formation with the continued REGN2477 treatment.   
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In light of the public health emergency related to the COVID-19 pandemic, announced by the 
World Health Organization on 11 March 2020, Investigators may perform study visit 18 (week 56) 
and/or visit 23 (week 76) imaging exams employing only whole-body low-dose CT scans. 
Assessment of the imaging endpoints without the PET scan may be implemented to mitigate the 
delay to acquire images due to the inaccessibility to PET/CT imaging centers and/or unavailability 
of the 18F-NaF tracer.  The analysis to compare the performance between PET/CT and CT in Period 
1 (week 28) showed there was no marked difference detected in the performance between PET/CT 
and CT reads (details in Section 3.3.1).  Specifically, the CT-only reading method reconfirmed the 
REGN2477 treatment effects on number or percentage of patients with new lesions, total number 
of new lesions, and volume of new lesions seen by PET/CT method primary read.  Based on this 
finding, the CT-only reading method will also be used to analyse all week 56 endpoints.   
The effect of REGN2477 on ‘flare-up’ will be evaluated in Period 2 with a new endpoint based on 
investigator-assessed flare-ups’ and the previously specified endpoint based on patient-assessed 
flare-up (by patient e-diary; Section 4.3.3) which will be analyzed in patients who switch from 
placebo in Period 1 to REGN2477 in Period 2 (Section 10.4.3.2.3). 
3.3.5. 
Biochemical Markers of Bone Formation 
Biochemical markers of bone formation, bone specific alkaline phosphatase (BSAP) and total 
alkaline phosphatase (tAP), are elevated in some patients with FOP at levels 2- to 6-fold above 
those found in healthy subjects (Al Kaissi 2016, Kitoh 2013).  Elevations in these markers of bone 
formation are thought to be due to HO activity.  REGN2477 may depress the levels of these 
markers if they are elevated, compared with the levels in patients who receive placebo.  Therefore, 
the effect of REGN2477 on these biomarkers as well as on other biochemical markers of bone 
formation and resorption will also be assessed. 
3.3.6. 
Clinical Endpoint Measures 
We plan to measure clinical aspects of FOP disease activity (number and duration of flare-ups, 
location and severity of FOP disease signs and symptoms) via a daily diary completed by patients, 
physician assessment of joint involvement using the Cumulative Analog Joint Involvement Scale 
(CAJIS; Kaplan 2017), investigator-assessed flare-ups, patient reported quality of life assessments 
using the EuroQol 5 dimensions questionnaire with a 3-level scale (EQ-5D-3L), additional 
questions relevant to Independent Activities of Daily Living for FOP patients from the Patient 
Reported Outcomes Measurement Information System (PROMIS) (collectively called the FOP I-
ADL Questionnaire), and spirometry assessment of pulmonary function. These measures will 
allow us to explore the correlation between the longitudinal change in disease activities and the 
change in HO activities detected by imaging and biochemical measures of heterotopic bone 
formation. Patients with FOP describe pain associated with their disease, at times refractory to 
analgesic treatments. Pain severity will be assessed daily in this study using a NRS, via the e-diary. 
3.3.7. 
Rationale for Dose Selection 
The dose and dose regimen proposed for this study is 10 mg/kg IV Q4W.  In the FIH single-dose 
study, 10 mg/kg of REGN2477 was generally well-tolerated and demonstrated saturation of target 
over the proposed dosing interval.  Therefore, it was chosen to initiate this proof of concept study 
in FOP.  The rationale for this dose and dose regimen is further discussed below. 
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The clinical data from the FIH study of REGN2477 have demonstrated that single doses of 
10 mg/kg IV appear to be generally well-tolerated. In this study, single doses of REGN 2477 were 
administered IV and subcutaneous (SC) in healthy women not of child bearing potential.  This 
study has been completed and database lock (DBL) occurred on 14 February 2017. A total of 
40 healthy subjects have received placebo or REGN2477 in a 1:3 ratio, with REGN2477 
administered at 0.3, 1, 3, or 10 mg/kg IV and 300 mg SC doses.  Top line analysis of the final 
unblinded safety data indicates that all dose levels have been well-tolerated, and no safety signals 
have been identified. Top line PK and total activin A (a measure of target engagement) data from 
the FIH study demonstrate that 10 mg/kg dose will likely saturate the target over the Q4W dosing 
interval selected for this study, but that 3 mg/kg and lower doses may be subsaturating (see more 
detail in the IB).  
Preclinical efficacy data in FOP mice indicate that, in a prophylactic prevention model, significant 
reduction in heterotopic bone formation was observed following 1 mg/kg given IV every week, 
and maximal effects were seen with 10 mg/kg and 25 mg/kg doses given SC every week.  At the 
1 mg/kg dose, the trough concentration of REGN2477 in these mice was approximately 5 mg/L.  
Preliminary pharmacokinetics and activin A target engagement data from the FIH study suggest 
that a 10 mg/kg dose level, when administered Q4W, is likely to saturate the activin A target and 
to achieve, at 1 month, trough drug levels above the pharmacologically active drug level observed 
in the FOP mouse model.  It is unknown, however, what concentrations of REGN2477 will be 
required to demonstrate a treatment effect in FOP patients with active HO.  Given the severity of 
the disease and rarity of FOP patient, it is proposed that the 10 mg/kg dose given Q4W is likely to 
provide target coverage and is justified with appropriate close monitoring (see Section 3.4.1 and 
Section 3.4.2).  
Results from a chronic non-human primate preclinical toxicology study support this planned study 
in patients with FOP.  A 26-week good laboratory practice (GLP) -compliant toxicology study was 
conducted in cynomolgus monkeys.  This study had a 12-week recovery period.  There have been 
no adverse effects seen after 26 weeks of dosing in this study at dosages up to and including 
50 mg/kg/week.  Therefore, the no-observed-adverse-event-level (NOAEL) in this study was 
50 mg/kg, the highest dose tested.  Based on systemic drug exposures in this toxicology study, the 
selected human dose of 10 mg/kg Q4W provides sufficient safety margin (exposure multiple) of 
approximately 5-fold for the current study design. 
In 5-week GLP studies in rats, a 50 mg/kg NOAEL was established in female rats.  In male rats, 
however, REGN2477 related severe inflammation was observed histologically in the epididymis 
and efferent ducts, resulting in a NOAEL of 0.2 mg/kg/week.  At dose levels above 0.2 mg/kg, 
decreases in sperm motility and counts were observed, which recovered after drug washout.  
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Though the rat has been identified as the most sensitive species for the epididymal/testicular 
toxicity, 2 additional GLP 5-week toxicity studies were conducted in 2 additional non- human 
primate species, green monkeys and marmoset monkeys, in order to better understand the potential 
effect of REGN2477 in humans.  Animals in these studies received REGN2477 once weekly for 
5 weeks.  Preliminary results of these ongoing studies have identified minimal inflammation and 
sperm stasis within a portion of the efferent ducts, with no findings in the epididymis.  The severe 
effects on sperm quality (decreases in sperm motility and counts) observed in the rat studies were 
not observed in the short-term or long-term primate studies.  Marked differences in the magnitude 
of inflammation seen in rats versus nonhuman primates are considered to reflect species 
differences in the respective anatomy of the epididymis and efferent ducts (Foley 2001, La 2012).  
Nevertheless, epididymal toxicity will be considered a potential risk for anti-activin A treatment 
pending further clinical experience. 
Patients in this proof of concept study will be closely monitored and safety data will be carefully 
reviewed by an IDMC (see Section 5.3.1) for any tolerability issues or safety signals.  In the event 
that significant tolerability issues or safety signals were to be identified, the dose level may be 
adjusted downward.  Dose modification and study drug treatment discontinuations rules are 
described in detail in Section 7.2). 
3.4. 
Study-Specific Safety Considerations and Monitoring 
A benefit versus risk assessment of REGN2477 is described in the IB. 
Study Conduct in Response to COVID-19 
Included in this amendment are measures to account for the COVID-19 pandemic and to minimize 
the risks to the patients in the study as well as healthcare providers by allowing flexibility in the 
visit schedule while social distancing suggestions are in place.  Allowing for this flexibility does 
not increase the risk of participating in this study as there will be continued contact between the 
patients and study personnel despite postponement of in-person clinic visits. 
3.4.1. 
Potential Risk for Reproductive Organ Adverse Events in Male Patients and 
Monitoring 
As stated above, it is unclear whether the male reproductive organ findings from the rat will 
translate into clinically meaningful changes in the humans.  Because patients with FOP suffer from 
a severe, debilitating, and ultimately fatal autosomal dominant genetic disease and because there 
is no approved treatment available, it is proposed that the potential benefit of REGN2477 in 
reducing HO activity may outweigh the potential risk of male reproductive changes. 
Male patients in this study will be informed of the potential risk of developing AEs of pain and/or 
discomfort, and swelling of the scrotum region, and decreased sperm counts, motility, and fertility.  
Sperm banking as a mitigating strategy for the potential risk of reduced fertility following 
treatment should be discussed with male patients.  If requested, sperm banking procedures may be 
conducted as directed by the patient’s own physician before the start of study drug treatment and 
will not be a study procedure.  Baseline urogenital exams, including scrotum ultrasound with 
Doppler, will be conducted prior to initiation of treatment and patients will be followed for relevant 
AEs.  Specifically, complaints of epididymitis, orchitis, hydrocele, scrotum pain, or scrotum 
swelling will be followed as adverse events of special interest (AESIs, see Section 9.4.3).  Patients 
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who experience any of these AEs will be evaluated by a study urologist, and will be referred for 
clinical care by an appropriate specialist.  Scrotum ultrasound may be performed, if clinically 
warranted, during follow-up of the AE.  Biomarkers of testicular injury (serum concentrations of 
testosterone, follicle stimulating hormone [FSH], and luteinizing hormone [LH]) will be monitored 
throughout the study.   
3.4.2. 
Potential Risk for Teratogenicity/Fetal Toxicity and Pregnancy Monitoring and 
Prevention 
Results in an ongoing enhanced pre/postnatal development study of REGN2477 in cynomolgus 
monkeys showed a potential risk for teratogenicity/fetal toxicity.  REGN2477 has had no 
abortifacient effects thus far, nor has it resulted in any maternal toxicity.  However, treatment with 
REGN2477 resulted in some early births, infant malformations, a stillbirth, and infant mortality 
(for detailed description of the study, see IB).  In the 50 mg/kg group, none of the pregnancies 
resulted in a normal birth; all had severe total body alopecia, and died shortly after birth or were 
stillborn.  The cause of death has not yet been established.  Exposure to 5 mg/kg did not result in 
severe alopecia or mortality; however, some of these animals had adverse findings of teeth 
abnormalities and neurological deficiencies during their functional observation battery.  Data 
collection from this study’s remaining in-life phase is still incomplete. 
Strict measures will be taken to avoid giving REGN2477 to pregnant women.  Women of child 
bearing potential (WoCBP) will only be enrolled in this study after the results of a pregnancy test 
are negative.  Pregnancy testing will be performed and a negative pregnancy result will be 
confirmed prior to each subsequent dose administration.  Monthly menstrual history will be 
collected, and pregnancy testing and reminders for contraception use will be conducted during the 
study and during the follow-up period.  In addition, WoCBP and male patients with WoCBP 
partners will be instructed to use highly effective methods of contraception throughout the study.  
While the level of antibody drugs in the semen are normally found at extremely low levels, the 
levels of REGN2477 that may cross into the semen is unknown, given the potential for 
inflammation of the efferent duct associated with REGN2477 treatment.  Therefore, a more 
conservative approach to contraception requirements will be applied to male patients enrolled in 
this study.  Male patients with WoCBP partners will be asked to use condom to prevent fetal 
exposure and to inform and ensure their female partners to use highly effective contraception 
measures to prevent pregnancy. In case pregnancy occurs, the investigator will follow the 
pregnancy until delivery (Section 9.4.3). If the pregnancy continues to term (delivery), the health 
of the infant will be followed-up for a period of 3-months postnatally. 
3.4.3. 
Risk for Epistaxis and Monitoring 
Due to AEs of epistaxis reported during the conduct of the R2477-FOP-1623 study through 
30 Jan 2019, epistaxis was considered a potential risk with REGN2477.  Results from 
R2477-FOP-1623 safety analysis during the 28-week double blind treatment period (Period 1) and 
up to data cut-off date of 17 Sep 2019 showed imbalances in TEAEs, with higher incidence of 
epistaxis in the REGN2477group (50.0%) compared to placebo (16.7%).  When patients in the 
placebo group transitioned to REGN2477in the ongoing open-label period (Period 2), epistaxis 
was reported in a total of 9 (20.9%) patients, including 5 (20.8%) patients who received placebo 
during the double-blind treatment period and 4 (21.1%) patients who received REGN2477during 
the double-blind treatment period.  Although epistaxis has been a frequently reported TEAE, the 
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reported events have been predominantly mild in severity with no effect on patients’ ability to 
receive REGN2477.  Only 1 patient experienced a serious event of epistaxis.  The study is ongoing, 
and patients are in the open-label period (Period 2) or the follow-up treatment period (Period 3). 
In toxicology studies with monkey and rats, REGN2477 50 mg/kg/week treatment (26-weeks for 
monkeys, 5-weeks for rats) did not result in epistaxis findings, other bleeding events, or 
abnormalities in coagulation test results in either species.  
In the completed R2477-HV-1525 study which evaluated a single-dose administration of 
REGN2477 10 mg/kg IV, there were no episodes of epistaxis or other bleeding episodes.  In the 
completed R2477-1033-HV-1621, 6 subjects received REGN2477 alone (10 mg/kg IV) and 
24 subjects received REGN2477 (1 mg/kg, 3 mg/kg, or 10 mg/kg) in combination with REGN1033 
(6 mg/kg REGN1033).  One 1 episode of mild epistaxis occurred in 1 subject who received the 
10 mg/kg REGN2477 + 6 mg/kg REGN1033 combination (high dose).  This epistaxis AE occurred 
3 days after administration of study drug, was considered mild, and was assessed by the 
investigator as related to the study drug. 
In order to mitigate the potential risk for patients, 3 exclusion criteria were added to this protocol: 
1) concomitant antiplatelet therapy (other than low dose acetylsalicylic acid) or anticoagulants, 
2) any history of severe, non-traumatic bleeding requiring transfusion or hospitalization for 
hemodynamic compromise, 3) known preexisting medical history of a bleeding diathesis 
(Section 6.2.2).  In addition, investigators should discourage the use of anti-inflammatory drugs, 
to the extent possible.   
In order to monitor the occurrence of epistaxis or other important bleeding episodes, moderate 
epistaxis (defined as any episode lasting longer than 30 minutes or requiring professional medical 
intervention), severe epistaxis (based on definition of a severe AE as described in Section 9.5.1), 
and other AEs of moderate to severe non-traumatic bleeding will be followed as adverse events of 
special interest (AESIs, see Section 9.4.3). 
Baseline and post-treatment assessment of coagulation parameters (activated partial 
thromboplastin time, prothrombin time, international normalization ratio [INR], thrombin time), 
fibrinogen, and platelet effector function will be performed.  For all patients who are currently 
enrolled in the study, the assessment of coagulation parameters (including, but not limited to 
activated partial thromboplastin time, prothrombin time, INR) and platelet effector function will 
be performed at their next evaluation, unless these tests have been performed in the past year.  If 
possible, for patients with a moderate or severe AESI of epistaxis or other non-traumatic bleeding, 
the investigator should attempt to obtain an unscheduled assessments of coagulation parameters 
and platelet effector function as close as possible to the time of this AESI. 
3.4.4. 
Risk for Skin and Soft Tissue Infection and Monitoring 
During the double-blind treatment period (Period 1) of the ongoing R2477-FOP-1623 study, skin 
infection TEAEs (including folliculitis, abscesses, cellulitis, and pustular rash) were reported in 
patients treated with REGN2477 and none of the patients treated with placebo.  None of these 
events were serious, severe, or led to discontinuation of study treatment. 
During the open-label treatment period (Period 2/3) of R2477-FOP-1623 study, skin and soft tissue 
infection TEAEs (including folliculitis, furuncles, abscess, carbuncle, and cellulitis) were reported 
in patients treated with REGN2477, including patients treated with placebo and patients treated 
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with REGN2477during Period 1.  Two patients experienced serious abscesses which required 
admission to the hospital for incision and drainage.  The events resolved, and the patients continued 
to receive REGN2477 after a temporary treatment interruption. 
In the completed R2477-HV-1525 study, no TEAEs involving skin and soft tissue infections were 
reported.  In the completed R2477-1033-HV-1621 study, acne was reported in 1 (12.5%) patient 
and skin infection in 1 patient (12.5%). 
Special attention should be directed towards early detection of skin and soft tissue infections.  
Good hygiene and early and proactive monitoring for potential lesions is recommended.  Particular 
attention should be paid to areas with poor ventilation, such as the perigenital and underarm areas. 
3.4.5. 
Potential Iatrogenic Injuries 
Soft tissue injuries, especially those involving muscle, may induce flare-ups and HO in patients 
with FOP.  There have been anecdotal reports of flare-ups induced by phlebotomy procedures and 
blood pressure cuff pressure.  Study personnel will be trained to minimize the risk of iatrogenic 
soft tissue injuries. 
3.4.6. 
Radiation Exposure 
Positron emission tomography/CT is an imaging procedure that involves ionizing radiation 
exposure to the patient.  The ionizing radiation deposited in tissue is expressed in units of mSv.  
The effective dose (ED) is a single figure that refers to the tissue-weighted radiation dose to the 
subject, accounting for stochastic risk effects associated with the radiation exposure.  In the US, 
the maximum recommended allowed ED for an adult research subject in a single year is 50 mSv 
(CFR 21, vol. 5, 2015).  In the European Union, the guidelines for studies intended to gain 
knowledge directly aimed at the prevention or cure of disease establish an ED limit of up to 20 mSv 
per year for adult subjects.  In the present study, for an adult patient each dose of 18F-NaF will 
result in an annual ED of approximately 2.4 mSv to 8.9 mSv, while a CT scan will result in an ED 
of approximately 2.9 mSv to 5.1 mSv, for a cumulative ED range of 16 mSv to 42 mSv.  For all 5 
scans planned for the study, the total ED range is approximately 25 mSv to 56 mSv.  In selected 
cases, a single low-dose CT scan may change the total ED range to 29 mSv to 60 mSv.  The total 
radiation exposure during the entire study could be up to the equivalent of 3 diagnostic CT scans 
of the chest, abdomen, and pelvis.  Radiation risk information will be included in the informed 
consent form. 
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will include standard demographic and disease 
characteristics including detailed FOP disease (HO status, ACVR1 mutation type), medical history 
and comorbidities, and medication/surgical history for each patient. 
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4.2. 
Primary, Secondary, and Exploratory Endpoints (Period 1; 
Week 28) 
There are 3 analysis sets defined for analysis of efficacy in this study:  Baseline-Active HO Classic 
ACVR1[R206H] Mutation (AHOC) analysis set, Baseline-Active HO (AHO) analysis set, and full 
analysis set (FAS) (for a complete description, see Section 10.3). 
4.2.1. 
Primary Safety Endpoint  
• Incidence and severity of TEAEs through the end of the Period 1 at week 28 
4.2.2. 
Primary Efficacy Endpoints  
• Time-weighted average (standardized AUC) of the percent change from baseline in 
total lesion activity by18F-NaF PET over 28 weeks (AHO) 
• Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 (AHO) 
• Time-weighted average (standardized AUC) of the percent change from baseline in 
total lesion activity by18F-NaF PET over 28 weeks (AHOC) 
• Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 (AHOC) 
4.2.3. 
Key Secondary Endpoints  
• Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks (AHO) 
• Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks (AHOC) 
4.2.4. 
Other Secondary Endpoints  
• Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by 
PET at week 8 (AHOC) 
• Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by 
PET at week 8 (AHO) 
• Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 
(AHOC) 
• Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 
(AHO) 
• Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 
(FAS) 
• Change from baseline in number of HO lesions detectable by CT at week 28 (AHOC) 
• Change from baseline in number of HO lesions detectable by CT at week 28 (AHO) 
• Change from baseline in number of HO lesions detectable by CT at week 28 (FAS) 
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• Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks (FAS) 
• Time weighted average (standardized AUC) of the percent change from baseline in 
biomarkers of bone formation levels in serum over 28 weeks, including Total 
Procollagen Type 1 N-Terminal Propeptide (P1NP), bone specific alkaline phosphatase 
(BSAP), and total alkaline phosphatase (tAP) (FAS) 
• Incidence and severity of TEAEs 
4.2.5. 
Other Secondary Endpoints Related to Clinical Pharmacology (Period 1, 
Period 2, Period 3) 
These secondary endpoints will be analyzed for all 3 study periods:  Period 1 (week 28), Period 2 
(week 56) and Period 3 (week 76).   
• Concentration of total activin A in serum over time 
• PK profile of REGN2477, assessed as concentrations of REGN2477 in serum over time 
• Immunogenicity of REGN2477, as determined by the incidence, titer, and clinical 
impact of treatment-emergent ADA to REGN2477 over time 
4.2.6. 
Exploratory Endpoints (Period 1; Week 28) 
These exploratory endpoints may be analyzed for any of the defined analysis sets (AHOC, AHO, 
FAS).  This will be described in the SAP.   
The exploratory endpoints are: 
• Joint function assessment by physician at baseline and week 28 by the CAJIS 
• Patient-reported quality of life by EQ-5D-3L at baseline and week 28 
• Patient-reported assessment of activities of daily living by FOP I-ADL at baseline and 
week 28 
• FOP disease activity assessed by patient e-diary over time during Period 1 
− Number and duration of flare-ups (defined in this study as experiencing at least 2 of 
the following: new onset of pain, swelling, joint stiffness, decrease in movement, 
or detection of HO) 
− Location and severity of FOP disease signs and symptoms including 1) pain, 
2) swelling, 3) joint stiffness, 4) decreased movement, each scored using a 4-point 
scale (0: no symptom; 1: mild; 2: moderate; 3: severe) 
• Total dosage of glucocorticoids use over time during Period 1 
• Number of patients with new HO lesions as assessed by 18F-NaF PET through week 28 
• Percent change from baseline of mean SUVmean of selected normal bones (eg, lumbar 
spine and femoral heads) as assessed by PET/CT at week 8 and week 28 
• Change in number of lesions that are only 18F-NaF PET detectable at baseline to CT 
detectable lesions at week 28 
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• Change from baseline in the FEV1 of spirometry at week 28 
• Time-weighted average (standardized AUC) change from baseline in the levels of 
hs-CRP over 28 weeks 
4.3. 
Primary, Secondary, and Exploratory Endpoints (Period 2; 
Week 56) 
All patients in the placebo treatment group who completed Period 1 (double-blind treatment 
period; week 28) were switched to receive REGN2477 10 mg/kg Q4W through week 56 
(placebo/REGN2477 treatment group) in the Period 2 (open-label treatment period) 
(Section 5.1.3).  The imaging and clinical assessments at week 28 serve as the baseline for the 
week 56 efficacy endpoints.  
The primary, key secondary, other secondary, and exploratory endpoints will be assessed in the 
AHO population (Section 10.3) and also in the AHOC population.  A separate analysis of the FAS 
will not be performed as the FAS is the same as the AHO set because all patients in the study had 
active HO lesions at baseline. 
4.3.1. 
Primary Efficacy Endpoint (Period 2 [Week 56]) 
The primary efficacy endpoint in Period 2 is: 
• Number of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in 
patients switching from placebo to REGN2477 after the double-blind period) (AHO) 
4.3.2. 
Key Secondary Efficacy Endpoints (Period 2 [Week 56]) 
The key secondary efficacy endpoints for Period 2 analyses (in AHO) are:  
• Total volume of new HO lesions as assessed by CT at week 56 relative to week 28 scan 
(in patients switching from placebo to REGN2477 after the double-blind period) 
(AHO) 
• Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 
(in patients switching from placebo to REGN2477 after the double-blind period) 
(AHO) 
• Total lesion activity by18F-NaF PET in new HO lesions at week 56 relative to week 28 
scan (in patients switching from placebo to REGN2477 after double-blind period) 
(AHO) 
• Percent of patients with new HO lesions as assessed by CT at week 56 relative to week 
28 scan (in patients switching from placebo to REGN2477 after the double-blind 
period) (AHO) 
• Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 
relative to week 28 scan (in patients switching from placebo to REGN2477 after the 
double-blind period) (AHO) 
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4.3.3. 
Other Secondary Efficacy Endpoints (Period 2 [Week 56]) 
The other secondary efficacy variables for Period 2 analyses (all in AHO) are: 
• Number of new HO lesions as assessed by CT only at week 56 relative to week 28 scan 
(in patients switching from placebo to REGN2477 after the double-blind period) 
(AHO) 
• Percent of patients with investigator-assessed flare-ups in Period 2 (in patients 
switching from placebo to REGN2477 after the double-blind period) (AHO) 
• Percent of patients with flare-ups assessed by patient e-diary in Period 2 (in patients 
switching from placebo to REGN2477 after the double-blind period) (AHO) 
• Number of new HO lesions as assessed by CT at week 56 relative to baseline scan (in 
patients who continue REGN2477 after the double-blind period) (AHO) 
• Total volume in new HO lesions as assessed by CT at week 56 relative to baseline scan 
(in patients who continue REGN2477 after the double-blind period) (AHO) 
• Percent of patients with new HO lesions as assessed by CT at week 56 relative to 
baseline scan (in patients who continue REGN2477 after the double-blind period) 
(AHO) 
• Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline 
scan (in patients who continue REGN2477 after the double-blind period) (AHO) 
• Total lesion activity in new HO lesions as assessed by 18F-NaF PET at week 56 relative 
to baseline scan (in patients who continue REGN2477 after the double-blind period) 
(AHO) 
• Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 
relative to baseline scan (in patients who continue REGN2477 after the double-blind 
period) (AHO) 
• Percent change from week 28 in SUVmax to week 56 (in patients switching from placebo 
to REGN2477 after the double-blind period) (AHO) 
• Percent change from baseline in SUVmax to week 56 (in patients who continue 
REGN2477 after the double-blind period) (AHO) 
• Percent change from week 28 in total lesion activity as assessed by 18F-NaF PET to 
week 56 (in patients switching from placebo to REGN2477 after the double-blind 
period) versus the same patients between baseline and week 28 (AHO) 
• Percent change from baseline in total lesion activity as assessed by 18F-NaF PET to 
week 56 (in patients who continue REGN2477 after the double-blind period) (AHO) 
• Percent change from week 28 in the total volume of HO lesions as assessed by CT to 
week 56 (in patients switching from placebo to REGN2477 after the double-blind 
period) versus the same patients between baseline and week 28 (AHO) 
• Percent change from baseline in the total volume of HO lesions as assessed by CT to 
week 56 (in patients who continue REGN2477 after the double-blind period) (AHO) 
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• Change from week 28 in number of HO lesions (target and new lesions relative to 
baseline) as assessed by 18F-NaF PET to week 56 (in patients switching from placebo 
to REGN2477 in double-blind period) versus the same patients between baseline and 
week 28 (AHO) 
• Change from week 28 in number of HO lesions (target and new lesions relative to 
baseline) as assessed by CT to week 56 (in patients switching from placebo to 
REGN2477 in double-blind period) versus the same patients between baseline and 
week 28 (AHO) 
4.3.4. 
Exploratory Endpoints (Period 2 [Week 56]) 
The exploratory endpoints are (all in AHO): 
• Joint function assessment by physician at week 56 by the CAJIS 
• Patient-reported quality of life by EQ-5D-3L at week 56 
• Patient-reported assessment of activities of daily living by FOP I-ADL at week 56 
• FOP disease activity assessed by patient e-diary during Period 2 
− Number and duration of flare-ups (defined in this study as experiencing at least 
2 of the following: new onset of pain, swelling, joint stiffness, decrease in 
movement, or detection of HO) 
− Location and severity of FOP disease signs and symptoms including 1) pain, 
2) swelling, 3) joint stiffness, 4) decreased movement, each scored using a 4-point 
scale (0: no symptom; 1: mild; 2: moderate; 3: severe) 
• Total dosage of glucocorticoids use during Period 2 
• Change from baseline in number of HO lesions (target and new lesions relative to 
baseline) as assessed by 18F-NaF PET at week 56 
• Change from baseline in number of HO lesions (target and new lesions relative to 
baseline) detectable by CT at week 56 
• Number of patients with new HO lesions as assessed by 18F-NaF PET through week 56 
relative to baseline scan 
• Percent change from baseline of mean SUVmean of selected normal bones (eg, lumbar 
spine and femoral heads) as assessed by PET/CT at week 56 
• Percent change from baseline of ratio of mean SUVmean of selected normal bones 
(eg, lumbar spine and femoral heads) to venous plasma SUV during PET as assessed 
by PET/CT at week 56  
• Percent change from baseline in venous plasma clearance 18F-NaF SUV at week 56 
• Percent change from baseline in 18F-NaF incorporation rate (Ki) in individual active 
HO lesion(s) at week 56 
• Percent change from baseline of ratio of SUVmax of individual active HO lesion(s) to 
venous plasma SUV during PET scan at week 56  
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• Change from baseline in the FEV1 of spirometry at week 56 
• Change from week 28 in the FEV1 of spirometry at week 56 
4.4. 
Exploratory Endpoints (Period 3 [Week 76]) 
The exploratory endpoints for Period 3 analyses are: 
• Number of new HO lesions as assessed by CT at week 76 relative to week 28 (in 
patients switching from placebo to REGN2477 after the double-blind period) (AHO) 
• Total volume of new HO lesions as assessed by CT at week 76 relative to week 28 (in 
patients switching from placebo to REGN2477 after the double-blind period) (AHO) 
• Number of new HO lesions as assessed by 18F-NaF PET at week 76 relative to week 28 
(in patients switching from placebo to REGN2477 after the double-blind period) 
(AHO) 
• Total lesion activity by 18F-NaF PET in new lesions at week 76 relative to week 28 (in 
patients switching from placebo to REGN2477 after double-blind period) (AHO) 
• Percent of patients with new HO lesions as assessed by CT at week 76 relative to week 
28 scan (in patients switching from placebo to REGN2477 after the double-blind 
period) (AHO) 
• Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 76 
relative to week 28 scan (in patients switching from placebo to REGN2477 after the 
double-blind period) (AHO) 
• Percent of patients with investigator-assessed flare-ups in Period 3 (in patients 
switching from placebo to REGN2477 after the double-blind period) (AHO) 
• Percent of patients with flare-ups assessed by patient e-diary in Period 3 (in patients 
switching from placebo to REGN2477 after the double-blind period) (AHO) 
• Number of new HO lesions as assessed by CT at week 76 relative to baseline scan (in 
patients who continue REGN2477 after the double-blind period) (AHO) 
• Total volume in new HO lesions as assessed by CT at week 76 relative to baseline scan 
(in patients who continue REGN2477 after the double-blind period) (AHO) 
• Percent of patients with new HO lesions as assessed by CT at week 76 relative to 
baseline scan (in patients who continue REGN2477 after the double-blind period) 
(AHO) 
• Number of new HO lesions as assessed by 18F-NaF PET at week 76 relative to baseline 
scan (in patients who continue REGN2477 after the double-blind period) (AHO) 
• Total lesion activity in new HO lesions by 18F-NaF PET at week 76 relative to baseline 
scan (in patients who continue REGN2477 after the double-blind period) (AHO) 
• Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 76 
relative to baseline scan (in patients who continue REGN2477 after the double-blind 
period) (AHO) 
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• Percent change from week 28 in SUVmax to week 76 (in patients switching from placebo 
to REGN2477 after the double-blind period) (AHO) 
• Percent change from baseline in SUVmax to week 76 (in patients who continue 
REGN2477 after the double-blind period) (AHO) 
• Percent change from baseline in total lesion activity by 18F-NaF PET to week 76 (in 
patients who continue REGN2477 after the double-blind period) (AHO) 
• Percent change from baseline in the total volume of HO lesions as assessed by CT to 
week 76 (in patients who continue REGN2477 after the double-blind period) 
• Joint function assessment by physician at week 76 by the CAJIS 
• Patient-reported quality of life by EQ-5D-3L at week 76 
• Patient-reported assessment of activities of daily living by FOP I-ADL at week 76 
• FOP disease activity assessed by patient e-diary during Period 3 
− Number and duration of flare-ups (defined in this study as experiencing at least 2 of 
the following: new onset of pain, swelling, joint stiffness, decrease in movement, 
or detection of HO) 
− Location and severity of FOP disease signs and symptoms including 1) pain, 
2) swelling, 3) joint stiffness, 4) decreased movement, each scored using a 4-point 
scale (0: no symptom; 1: mild; 2: moderate; 3: severe) 
• Total dosage of glucocorticoids use during Period 3 
• Change from baseline in the FEV1 of spirometry at week 76 
• Change from week 28 in the FEV1 of spirometry at week 76 
4.5. 
Biomarker Variables 
• Research biomarker outcome measures are:  to explore transcription changes in whole 
blood that may be related to activin pathway modulation or FOP disease activity 
• Change in blood levels of additional bone and cartilage biomarkers, which may include 
osteocalcin, Total Procollagen Type 1 C-Terminal Propeptide (P1CP), matrix 
metalloproteinase 13, Procollagen type II, C-terminal telopeptide and cartilage-derived 
retinoic acid-sensitive protein 
• Change in circulating levels of Activin pathway regulatory molecules, such as 
follistatin, inhibin A, and inhibin B 
4.6. 
Pharmacokinetic Variables 
The PK variable is the concentration of functional REGN2477 at each time point.   
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4.7. 
Anti-Drug Antibody Variables 
Anti-drug antibody variables include status (positive or negative) and titer as follows:  
• Total number of patients whose response in the ADA assay is negative at all time points 
analyzed 
• Pre-existing immunoreactivity: defined either as a positive ADA assay response at 
baseline with all post-dose ADA assay results negative, or a positive assay response at 
baseline with all post-dose ADA assay responses less than 9-fold over baseline titer 
levels 
• Treatment-emergent: defined as any positive ADA assay response when baseline 
results are negative or missing.  Treatment-emergent responses are further classified 
as: 
− Persistent: treatment-emergent 
positive ADA response detected in 
at 
least 2 consecutive post baseline samples separated by at least a 12-week post 
baseline period (based on actual sampling time), with no ADA-negative samples 
in-between, regardless of any missing samples or a positive response at the last 
ADA sampling time point, 
− Indeterminate: a positive response at the last collection time point only, regardless 
of any missing samples, or  
− Transient: not persistent or indeterminate, regardless of any missing samples, 
ie, may be positive over less than a 12-week post baseline period, and not positive 
on the last ADA sampling time point. 
• Treatment-boosted: defined as any post-dose positive ADA assay response that has titer 
≥9-fold over the baseline titer when baseline results are positive 
• Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration  
This is a phase 2, randomized, placebo-controlled, study designed to evaluate the safety, 
tolerability, PK, and effects on heterotopic bone formation of repeated doses of 10 mg/kg IV 
REGN2477 Q4W in adult patients with FOP.  Patients may be enrolled at multiple sites globally.  
Up to 40 FOP patients may be enrolled to yield approximately 24 or more patients with the classic 
ACVR1[R206H] mutation and with active HO at baseline as determined by 18F-NaF PET/CT. 
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As depicted in the study design schematics (Figure 1), this study consists of a screening/baseline 
period (day -28 to day -1), two 6-month treatment periods, and a follow-up treatment period 
(Period 3).  The 3 treatment periods are: 
• Period 1: a 6-month randomized double-blind placebo-controlled treatment period 
• Period 2: a 6-month open-label REGN2477 treatment period 
• Period 3: a follow-up treatment period with REGN2477 continuing until patients have 
completed the week 76 visit, and all data have been collected and validated through the 
time when the last patient randomized into the study completes the week 28 visit 
(Period 1) 
After Period 3 (week 76), patients can continue to receive REGN2477 treatment Q4W based on 
details described in Section 5.1.4.  A limited number of assessments for safety, efficacy, and 
clinical pharmacology parameters will be conducted.   
In light of the public health emergency related to COVID-19, study procedures, including study 
drug administration, may be conducted by trained staff at or near patients’ residences (ie, at home 
visits) or at alternative sites established to minimize study patient to exposure to the SARS-CoV-2.  
Figure 1: 
Study Design Schematic Screening/Baseline Period (Day -28 to Day -1): 
Study Visit 1  
 
Note:  The patients who completed through study week 76 may continue REGN2477 treatment beyond week 80 
(described in Section 5.1.4). 
5.1.1. 
Screening/Baseline Period (Day -28 to Day -1): Study Visit 1 
During the screening/baseline period, all patients will undergo the informed consent process and 
screening/baseline procedures.  Procedures during this visit may be conducted on different days 
(Table 1). 
The following screening procedures will be conducted: review of medical/surgical history and 
prior/concomitant medications, physical exams, confirmation of clinical diagnosis of FOP and 
documentation of ACVR1 genotype, including the classic [R206H] or different ACVR1 mutations, 
laboratory assessments, vital signs, ECG, and the study physician’s assessment of a patient’s 
ability to undergo imaging and other procedures described in the study protocol.  If at the time of 
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screening, the patient doesn’t have documentation of what ACVR1 mutation he/she carries or it 
cannot be retrieved, then the study site staff should collect a blood sample for determination of the 
ACVR1 mutation prior to randomization.  Laboratory assessments and other procedures used to 
determine eligibility may be repeated once during the screening period.  Patients and their primary 
caregiver(s), if assistance is needed, will be given instructions on how to complete the FOP disease 
activity diary and the pain NRS.  For male patients, baseline urogenital exams will be conducted 
by the study urologist and scrotum ultrasound will be performed to aid detection of existing 
abnormality and to capture pretreatment baseline image.  For all patients, an assessment of 
coagulation parameters (including, but not limited to activated partial thromboplastin time, 
prothrombin time, INR, thrombin time), fibrinogen, and platelet effector function will be 
performed at baseline visit for newly enrolled patients and prior to next administration of study 
drug for enrolled patients. In addition, assessment of coagulation parameters and platelet effector 
function will be performed at several visits during Period 1 and Period 2 to explore mechanism of 
epistaxis  and REGN2477 mechanism of action (Table 1 and Table 2).  If possible, for patients 
with a moderate or severe AESI of epistaxis or other non-traumatic bleeding, the investigator 
should attempt to obtain an unscheduled assessment of coagulation parameters and platelet effector 
function as close as possible to the time of this AESI. 
Patients who meet initial eligibility screening will have baseline procedures conducted.  Baseline 
imaging procedures (whole body 18F-PET, low dose CT) will be performed within 1 week of study 
drug administration (study day 1), ie, within study day -7 to day -1, to identify and characterize 
index HO lesions.  Patients must be physically able and willing to undergo both PET and CT 
measures to be eligible for this study.  Pre-dose baseline PK, anti-drug antibody, activin A, and 
other biomarker samples will be collected.  Pretreatment CAJIS, daily pain NRS, patient reported 
FOP disease activity diary, and other patient reported outcome questionnaires will be completed.  
The baseline entry for both the daily pain NRS and the daily FOP disease diary will be on day -1.  
A blood sample will be collected from all patients for future ACVR1 gene sequencing.   
Women of child bearing potential and male patients with WoCBP partners will be reminded at all 
visits to adhere to highly effective contraception (defined in exclusion criteria 16 and 17).  
Pregnancy status and menstrual cycle history of WoCBP will be monitored through the end of the 
study.  
5.1.2. 
Period 1:  Double-Blind Treatment (Week 1 [Day 1] to Week 24 [Day 169]) and 
End of Period 1 Assessments (Week 28 [Day 197]) 
Patients will be randomized to receive REGN2477 at 10 mg/kg dose or matching placebo, 
administered IV Q4W through week 24, for a total of 7 doses, as outlined in the schedule of events 
(Table 1).  Randomization will be stratified by gender, classic ACVR1[R206H] mutation/different 
ACVR1 mutations, and by presence/absence of baseline active HO lesions as determined by 
18F-NaF PET/CT.  Baseline imaging data will be reviewed by a central imaging analysis vendor 
and Regeneron Clinical Imaging Director prior to randomization. 
Patients will be closely monitored for a minimum of 120 minutes after administration of study 
drug. 
To ensure safety of this approach, individual patients will be closely monitored and safety of each 
dose will be reviewed by the investigator and the Regeneron medical monitor prior to 
administering the subsequent repeated dose.  The safety review to be conducted by the investigator 
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and Regeneron medical monitor prior to study drug infusions on visits 2, 5, 6 and 7 (Period 1) and 
visits 11, 12, 13 and 14 (Period 2) will include evaluation of laboratory test (hematology, blood 
chemistry and urinalysis) results collected as part of these visits (see Section 8.1).  For the 
remaining study visits, assessment of results of hematology, blood chemistry and urinalysis tests 
planned for these same visits may be performed, but will not be required prior to study drug 
infusion.  The decision not to wait for the results of these exams, processed at the study’s central 
laboratory, should be made on a case-by-case basis, if the patient’s clinical condition, TEAE 
profile, and assessment of vital signs, ECGs and previous laboratory test results indicate that the 
patient is suitable to receive the next dose of study drug.  For the study visits after week 56 
(Period 3), the need for a safety review by the investigator and Regeneron medical monitor will be 
decided on a case-by-case basis.  In addition, the IDMC (see Section 5.3.1) will regularly monitor 
the unblinded study-level safety data. 
In the event that a significant tolerability issue or safety concern is identified, dose modification 
or study drug discontinuation may be implemented according to Section 7.2. 
Efficacy and safety procedures will be performed as outlined in the schedule of events (Table 1).  
Adverse events will be assessed as described in Section 9.4.  Index HO lesion identified at baseline 
and new HO lesions will be assessed by imaging endpoint measures including whole body 18F-NaF 
PET and whole body low dose CT at week 8 (day 57 [±7 days]), and week 28 (day 197 [±7 days]).  
Clinical endpoints will be assessed by investigator or patient reported outcome measures at week 
28 (day 197 [±7 days]).  The daily pain NRS and FOP disease activity diary will be checked at 
every visit for completeness. 
Serum samples for the determination of REGN2477 concentration and ADA will be collected. 
Serum samples for the determination of bone formation and mechanism of action biomarkers, 
BSAP, tAP, and P1NP, inflammation biomarker, hs-CRP, as well as markers related to the Activin 
A and Activin receptor pathway including but not limited to Activin and BMP ligands or markers 
that may elucidate the mechanism of action of REGN2477 will be collected. 
Additional biomarker samples will be collected as described in the schedule of events (Table 1). 
5.1.3. 
Period 2:  Open-Label REGN2477 Treatment (Week 28 [Day 197]) to Week 52 
[Day 365]) and End of Period 2 Assessments (Week 56 [Day 393]) 
All patients who complete the double-blind treatment period will receive REGN2477 administered 
IV at a dose of 10 mg/kg Q4W through week 52, for a total of 7 doses as outlined in the schedule 
of events (Table 2). 
Efficacy and safety procedures will be performed as outlined in the schedule of events (Table 2).  
For patients previously treated with placebo drug, week 28 (day 197) assessments will be 
considered as pretreatment baseline for safety and efficacy analysis of this period of the study. 
Index HO lesion identified at baseline and new HO lesions will be assessed by imaging endpoint 
measures including whole body 18F-NaF PET and whole body low dose CT at week 56 
(day 393 [±14 days]).  Clinical endpoints will be assessed by investigator or patient reported 
outcome measures at week 56 (day 393 [±14 days]).  The daily pain NRS and FOP disease activity 
diary will be checked at every visit for completeness. 
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In light of the public health emergency related to the COVID-19 pandemic, Investigators may 
perform study visit 18 (week 56) imaging exam employing only whole body low-dose CT scans.  
Assessment of imaging endpoints without the PET scan may be implemented to mitigate the delay 
to acquire images due to the inaccessibility to PET/CT imaging centers and/or unavailability of 
the 18F-NaF tracer.  In addition, the timing for study visit 18 (week 56) is flexible as long as any 
changes are documented.  This low-dose CT scan may be performed by trained staff either at study 
site or at other clinical sites with access to a qualified CT scanner or using a mobile qualified CT 
scanner at a local community healthcare setting close to patient or at a home visit, contingent upon 
prior concurrence and approval from the Investigator and Regeneron medical director 
(Section 3.3.4). 
Serum samples for the determination of REGN2477 concentrations and ADA will be collected.  
Additional biomarker samples will be collected as described in the schedule of events (Table 2). 
5.1.4. 
Period 3:  Follow-Up Treatment Period Week 56 (Day 393) to End of Study 
The patients who completed the open-label portion of the study, through week 52, will continue to 
receive study drug from week 56 through week 76 or beyond.   
REGN2477 treatment will continue after week 76 until any 1 of the following occurs: 
• Clinical development of REGN2477 for the indication described in this study protocol 
is discontinued 
• Clinical development of REGN2477 is terminated 
• Risk/benefit of REGN2477 in this patient population is deemed unfavorable 
• 3 years of REGN2477 treatment from the start of Period 3 
• Other means of access to REGN2477 (eg, expanded access protocol) becomes available 
for study patients for whom the benefit-risk assessment for REGN2477 treatment 
remains positive   
• Approval of the drug by the competent regulatory authority governing each respective 
country (eg, European Commission for EU Member States) with commercial 
availability 
Efficacy and safety procedures will be performed as outlined in the schedule of events (Table 3). 
Index HO lesion identified at baseline and new HO lesions will be assessed by imaging endpoint 
measures including whole body 18F-NaF PET and whole body low dose CT at week 76 
(day 533 [±7 days]).   
In light of the public health emergency related to the COVID-19 pandemic, Investigators may 
perform study visit 23 (week 76) imaging exam employing only whole body low-dose CT scans. 
Assessment of imaging endpoints without the PET scan may be implemented to mitigate the delay 
to acquire images due to the inaccessibility to PET/CT imaging centers and/or unavailability of 
the 18F-NaF tracer.  In addition, the timing for study visit 23 (week 76) is flexible as long as any 
changes are documented.  This low-dose CT scan may be performed by trained staff either at study 
site or at other clinical sites with access to a qualified CT scanner or using a mobile qualified CT 
scanner at a local community healthcare setting close to patient or at a home visit, contingent upon 
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prior concurrence and approval from the Investigator and Regeneron medical director 
(Section 3.3.4). 
The daily pain NRS and FOP disease activity diary will be checked at every visit for completeness. 
Additional biomarker samples will be collected as described in the schedule of events (Table 3). 
Serum samples for the determination of REGN2477 concentrations and ADA will be collected.  
5.1.5. 
Study Stopping Rules 
5.1.5.1. 
Study Stopping Criteria 
The emerging benefit-risk profile of REGN2477 treatment will be closely monitored by an IDMC.  
The IDMC (defined in Section 5.3.1) will monitor unblinded data on an ongoing basis to assess 
the risk/benefit profile of REGN2477.  The IDMC will meet to review the unblinded safety data 
after 6 patients have completed 4 weeks of study drug treatment and safety data has become 
available, and monthly thereafter.  As the study progresses, based upon the enrollment rate, the 
cumulative review of safety data, and at the discretion of the IDMC members, the IDMC may 
choose to meet on a quarterly basis. 
If at any time the IDMC has significant concerns regarding a meaningful imbalance in SAEs and 
AESIs, the IDMC may make a recommendation to the sponsor to temporarily halt the study 
(screening, randomization, or dosing of study drug) for additional review.  Based on the outcome 
of the review and discussions with investigators and if appropriate, regulatory authorities, the study 
may be suspended, restarted, or terminated.  In the event of a study restart after a temporary halt, 
dose modification, if needed, will be determined as described in Section 7.2.1. 
The IDMC will not conduct any formal efficacy analyses, other than in their oversight of safety 
and evaluation of risk benefit profile.  There are no formal early stopping criteria for efficacy.  
5.1.5.2. 
Individual Patient Stopping Rule 
Dosing in an individual patient may be temporarily or permanently stopped according to 
Section 7.2.2. 
5.1.6. 
End of Study Definition 
The end of study for this study is defined as the last visit of the last patient. 
5.2. 
Planned Interim Analysis 
No interim analysis is planned. 
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of cumulative unblinded 
safety data.  If requested, the IDMC may have access to any other data for the purposes of a 
risk-benefit assessment. 
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The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study.  The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the study execution. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Up to 40 patients with FOP may be enrolled at multiple sites globally to yield approximately 24 or 
more patients with the classic ACVR1[R206H] mutation and active HO at baseline. 
6.2. 
Study Population 
Male and female adult patients with a clinical diagnosis of FOP aged 18 to 60 years of age and 
with documentation of ACVR1 mutation.  
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female 18 to 60 years of age at screening 
2. Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, 
episodic soft tissue swelling, and/or progressive HO)  
3. Confirmation of FOP diagnosis with documentation of any ACVR1 mutation 
4. FOP disease activity within 1 year of screening visit.  FOP disease activity is defined as 
pain, swelling, stiffness, and other signs and symptoms associated with FOP flare-ups; or 
worsening of joint function, or radiographic progression of HOs (increase in size or number 
of HO lesions) with/without being associated with flare-up episodes 
5. Provide signed informed consent 
6. Willing and able to attend and comply with study visits and study related activities 
7. Willing and able to undergo PET and CT imaging procedures and other procedures as 
defined in this study 
8. Able to understand and complete study-related questionnaires and diaries (assistance from 
caregivers are allowed) 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Patient has significant concomitant illness or history of significant illness such as, but not 
limited to cardiac, renal, rheumatologic, neurologic, psychiatric, endocrine, metabolic or 
lymphatic disease, that in the opinion of the study investigator might confound the results 
of the study or pose additional risk to the patient by their participation in the study 
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2. Previous history or diagnosis of cancer 
3. Severely impaired renal function defined as estimated glomerular filtration rate 
<30 mL/min/1.73 m2 calculated by the Modification of Diet in Renal Disease equation 
(1 retest is allowed) 
4. Uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >9% at screening (1 retest 
allowed) 
5. Cardiovascular conditions such as New York Heart Association class III or IV heart failure, 
cardiomyopathy, intermittent claudication, myocardial infarction, or acute coronary 
syndrome within 6 months prior to screening; symptomatic ventricular cardiac arrhythmia 
(note: sinus dysrhythmia, asymptomatic block or well controlled atrial fibrillation with 
normal resting ventricular rate are not exclusion criteria) 
6. Ongoing significant viral illness or pneumonia within 2 weeks of screening 
7. Severe anemia requiring transfusion 
8. History of severe respiratory compromise requiring oxygen, respiratory support (example 
bilevel positive airway pressure [biPAP] or continuous positive airway pressure [CPAP]) 
or a history of aspiration pneumonia requiring hospitalization 
9. Known history of recent epididymitis (within 6 months of screening), TB, or sexually 
transmitted diseases affecting urogenital organs  
10. Use of bisphosphonate within 1 year of screening 
11. Concurrent participation in another interventional clinical study or a non-interventional 
study with radiographic measures or invasive procedures (eg, collection of blood or tissue 
samples).  Participation in the FOP Connection Registry or other studies in which patients 
complete study questionnaires are allowed 
12. Treatment with another investigational drug, denosumab, imatinib or isotretinoin in the last 
30 days or within 5 half-lives of the investigational drug, whichever is longer 
13. History of hypersensitivity to doxycycline or other tetracycline antibiotics, vaccines, or 
other biologics 
14. Positive serum human chorionic gonadotropin (hCG)/urine pregnancy test at the 
screening/baseline visit 
15. Pregnant or breastfeeding women 
16. Women of child bearing potential* who are unwilling to practice highly effective 
contraception** or undergo pregnancy tests prior to the initial dose, during the study, and 
for 30 weeks after the last dose.   
* Pregnancy testing and contraception are not required for women not of child bearing 
potential, including postmenopausal women or those with documented hysterectomy or 
bilateral oophorectomy. 
Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of child bearing potential.  Postmenopausal status will be confirmed by 
measurement of FSH. 
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** Highly effective contraceptive measures include stable use of combined (estrogen and 
progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or 
progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; 
intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal 
ligation; vasectomized partner; and or sexual abstinence***. 
*** Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient. 
17. Male patients with WoCBP partners* who are not willing to use condoms with WoCBP 
partners to prevent potential fetal exposure, during the study, and for 24 weeks after the 
last dose.  Sperm donation is prohibited during the study and for 24 weeks after the last 
dose of study drug. 
* Male patients with WoCBP partners will be asked to inform and ensure their female 
partners to use highly effective contraception measures** to prevent pregnancy. 
** Vasectomy with medical assessment of surgical success and sexual abstinence*** are 
considered highly effective contraception measures. 
*** Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient. 
18. Patients who are on concomitant antiplatelet therapy (eg, clopidogrel), anti-coagulants 
(eg, warfarin, heparin, factor Xa inhibitor, or thrombin inhibitors) in the last 30 days or 
within 5 half-lives of the therapy, whichever is longer.  Low dose (≤100 mg/day) 
acetylsalicylic acid (aspirin) is acceptable.   
19. Patients with a history of severe, non-traumatic bleeding requiring transfusion or 
hospitalization for hemodynamic compromise 
20. Patients with a known pre-existing medical history of a bleeding diathesis (eg, 
hemophilia A, von Willebrand’s Factor deficiency, platelet count ≤20x109/L). 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete the study 
assessments, as described in Section 8.1.2. 
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Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.2.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
REGN2477 is supplied as a liquid drug product and will be administered IV in this study.  
Instructions on dose preparation are provided in the pharmacy manual.  
Placebo matching REGN2477 is prepared in the same formulation as REGN2477, without the 
addition of protein. 
During the randomized double-blind placebo-controlled treatment period (Period 1), each patient 
will receive REGN2477 or placebo IV in a double-blinded fashion. 
During the open-label REGN2477 treatment period (Period 2), each patient will receive 
REGN2477. 
During the follow-up treatment period (Period 3), each patient will continue to receive open label 
REGN2477. 
7.2. 
Dose Modification and Study Treatment Discontinuation Rules 
7.2.1. 
Dose Modification 
Dose modification will be allowed if emerging safety signals indicates the need for a reduction of 
dose level according to the criteria set out below.  Dose modification will imply a reduction from 
10 mg/kg to 3 mg/kg IV Q4W in patients with FOP.  
To ensure safety of this approach, individual patients will be closely monitored and safety of each 
dose will be reviewed by the investigator and Regeneron medical monitor prior to administering 
the subsequent repeated dose. The blinded safety review to be conducted by the investigator and 
Regeneron medical monitor prior to study drug infusions on visits 2, 5, 6 and 7 (Period 1) and 
visits 11, 12, 13 and 14 (Period 2) will include evaluation of laboratory test (hematology, blood 
chemistry and urinalysis) results collected as part of these visits (see Section 8.1). For the 
remaining study visits, assessment of results of hematology, blood chemistry and urinalysis tests 
planned for these same visits may be performed, b performed, but will not be required prior to 
study drug infusion.  The decision not to wait for the results of these exams, processed at the 
study’s central laboratory, should be made on a case-by-case basis, if the patient’s clinical 
condition, TEAE profile, and assessment of vital signs, ECGs and previous laboratory test results 
indicate that the patient is suitable to receive the next dose of study drug.  For the study visits after 
week 56 (Period 3), the need for a safety review by the investigator and Regeneron medical 
monitor prior to infusion of REGN2477 will be decided on a case-by-case basis. 
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7.2.1.1. 
Individual Level Dose Modification  
Individual patient dose modification will be determined on a case-by-case basis based on the 
discussion between the investigator and Regeneron medical monitor, Regeneron Global Patient 
Safety, and approved by the Vice President Early Clinical Development or his/her designee.   
If 1 of the following occurs, individual dose modification will be considered; 
• Occurrence of 1 severe AE deemed to be related to the study drug. 
• Moderate to severe scrotum pain or swelling not otherwise justified by an alternate 
etiology after urology follow up assessment. 
The following AEs will not be considered as meeting the dosing modification rule: 
• Any AE that has a clear alternative causation 
• Episodes of flare-up or worsening of signs and symptoms of FOP 
After individual level dose reduction and depending upon the patient’s clinical evolution following 
1 or more infusions of 3 mg/kg IV of Q4W study drug, the investigator may consider resuming the 
original 10 mg/kg IV Q4W dosing regimen.  The investigator will communicate with Regeneron 
medical monitor before resuming the original dose.  Prior to resuming the original dose, the 
Regeneron medical monitor will discuss with Regeneron Global Patient Safety and obtain approval 
by the Vice President Early Clinical Development or his/her designee. 
Any individual level dose modification that occurs will be communicated by Regeneron medical 
monitor to the IDMC in a timely manner.  
7.2.1.2. 
Study Level Dose Modification 
The IDMC (see Section 5.3.1) will regularly monitor the unblinded safety data and, based on 
significant concerns regarding a meaningful imbalance in the frequency and/or severity of AEs or 
altered laboratory results, may make recommendations to the sponsor to consider dose 
modification. 
Study level dose modification will be determined by the sponsor upon recommendation of the 
IDMC following their review of safety, PK, and total activin A (target engagement) data available 
at the time. 
7.2.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits per the visit schedule and for 
blood sample collection for measurement of serum drug and target, and ADA:  at 4 weeks, 8 weeks, 
16 weeks, and 28 weeks after the last dose of study drug.  Safety lab exams (ie, hematology, blood 
chemistry and urinalysis) may also be collected during these visits at the investigator's discretion.  
A blood sample collection for assessment of ADA will occur at the patient’s last visit. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 8.1.2. 
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7.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Diagnosis of a malignancy during the study  
• Evidence of pregnancy 
• Severe acute infusion reactions as described in Section 9.5.1 
• Serious or severe hypersensitivity reaction deemed related to study drug 
7.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• Moderate to severe scrotum pain or swelling requiring urology follow-up assessment 
• Surgical procedure  
• Hospitalization  
7.3. 
Management of Acute Reactions  
7.3.1. 
Acute Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use.  All infusion reactions must be reported as AEs (as defined in Section 9.4.1) and 
graded using the grading scales as instructed in Section 9.5.1. 
7.3.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs occur: 
• cough 
• rigors/chills 
• rash, pruritus (itching) 
• urticaria (hives, welts, wheals) 
• diaphoresis (sweating) 
• hypotension 
• dyspnea (shortness of breath) 
• vomiting 
• flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate provided that the symptoms are adequately managed. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
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7.3.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• anaphylaxis 
• laryngeal/pharyngeal edema 
• severe bronchospasm 
• chest pain 
• seizure 
• severe hypotension 
• other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis etc) 
• any other symptom or sign that, in the opinion of the investigator, warrants 
discontinuation of the infusion 
7.4. 
Method of Treatment Assignment 
Patients will be randomly assigned to receive REGN2477 or placebo in a 1:1 ratio (REGN2477: 
placebo) on study day 1.  Patients will be randomized according to a central randomization scheme, 
using an interactive response technology (IRT) provided to the designated study pharmacist or 
qualified designee.  
7.4.1. 
Blinding 
Study patients, investigators, Regeneron Study Director, medical monitor, study monitor, and any 
other Regeneron or contract research organization (CRO) personnel who are in regular contact 
with the study site will be blinded to treatment assignment during the double-blind treatment 
period of the study. 
The PET and CT imaging and bone biomarker data collected after randomization will not be 
communicated to the sites or the sponsor’s study team members who may have regular interactions 
with the sites, until the study data is locked for primary analysis or subsequent analysis in the 
study. 
Drug kits coded with a medication numbering system will be used.  In order to maintain the blind, 
lists linking these codes with product lot numbers will not be accessible to individuals involved in 
study conduct.  An unblinded pharmacist or qualified designee at the site will prepare the drug 
product prior to transferring it to study personnel involved in other study conduct.  The person 
preparing the drug will not participate in other aspects of study conduct. 
7.4.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
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− Only the affected patient will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator.  If there is no study pharmacist, the 
investigator for the site will unblind the patient. 
− The investigator will notify Regeneron and/or designee before unblinding the 
patient, whenever possible. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist/designee (when applicable), at any time during the conduct of the study, except in the 
case of a true emergency.  In the event that there is no study pharmacist, the individual at the site 
fulfilling that role will be the only unblinded member of the site personnel. 
7.5. 
Treatment Logistics and Accountability 
7.5.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label the investigational study drug.  Lists linking 
medication numbers with product lot numbers will be maintained by the groups (or companies) 
responsible for study drug packaging.  In order to maintain the blind, these lists will not be 
accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2oC to 8oC; storage instructions will be 
provided in the pharmacy manual. 
7.5.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2oC to 8oC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be returned to the sponsor or designee. 
7.5.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
• dispensed to each patient, 
• returned from each patient (if applicable), and 
• disposed of at the site (if approved by sponsor) or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.5.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
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7.6. 
Concomitant Medications 
Any treatment administered from the time of informed consent to final study visit will be 
considered concomitant medication.  This includes medications that were started before the study 
and are ongoing during the study. 
7.6.1. 
Prohibited Medications 
Prohibited medications are: 
• Amiodarone 
• Those that may have effects on skeletal bone turnover, such as bisphosphonates (eg, 
etidronate, pamidronate), denosumab, imatinib, or isotretinoin 
• Immunosuppressants (eg, methotrexate) 
• Chemotherapies 
• Radiotherapy 
• Bone marrow transplantation 
• Antiplatelet therapy (eg, clopidogrel) 
• Anticoagulants (eg, warfarin, heparin, factor Xa inhibitor, thrombin inhibitors)  
• Herbal supplements that inhibit platelet function or are associated with increased risk 
of bleeding 
7.6.2. 
Permitted Medications 
Patients will be allowed to continue concomitant medications commonly prescribed for 
management of signs and symptoms of FOP disease activity and other acute or chronic disease.  
These may include  
• Oral or systemic corticosteroids* 
• Muscle relaxants 
• NSAIDs*   
• Opioid and other analgesics 
• Antidepressants 
• Vitamins and calcium supplements 
• Over-the-counter antihistamines and decongestants 
• Paracetamol 
• Antibiotics 
• Vaccinations 
• Anti-hypertensives  
• Proton pump inhibitors 
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• Statins at stable dose levels (for at least 3 months) that are well tolerated and do not 
cause myalgia 
• Oral hypoglycemic drugs  
• Laxatives 
• Antacids 
• Low dose acetylsalicylic acid (aspirin; [≤100 mg/day]) 
*To mitigate the potential risk for epistaxis, investigators should discourage the use of 
anti-inflammatory drugs that inhibit platelet function or are otherwise associated with an increased 
risk of bleeding, to the extent possible. 
As this is not a comprehensive list of all potential concomitant medications, use of concomitant 
medications that are not listed above will be reviewed by the principal investigator and Regeneron 
medical monitor to gain agreement. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
In light of the public health emergency related to the COVID-19 pandemic, the continuity of 
clinical study conduct and oversight may require implementation of temporary or alternative 
mechanisms.  Examples of alternative mechanisms may include, but are not limited to, any of the 
following:  phone contact, virtual visits, telemedicine visits, online meetings, noninvasive remote 
monitoring devices, use of local clinic or laboratory locations, and home visits by skilled staff.  All 
temporary mechanisms utilized and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency and/or until the COVID-19 pandemic is deemed 
manageable and no longer interfering with the conduct of trials at individual sites. 
Study assessments and procedures are presented by study period and visit in Table 1, Table 2, and 
Table 3). 
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Table 1: 
Schedule of Events:  Screening/Baseline through Period 1 (Randomized Double-Blind Treatment Period) 
 
Screening/ 
Baseline Period 
Period 1 (Randomized Double-Blind Treatment) 
Visit1 
Visit 
2 
Visit 
32 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Day  
± visit window (d) 
-28 to -1 
1 
2 
7  
±1d 
29  
±3d 
57  
±7d 
85  
±7d 
113  
±7d 
141 
±7d 
169  
±7d 
Week 
 
1 
1 
1 
4 
8 
12 
16 
20 
24 
Screening/Baseline3, 20: 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Informed consent (optional genomic sub-study) 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical/Prior Medication/Surgical history4 
X 
 
 
 
 
 
 
 
 
 
Urogenital exam (male patients only) 
X 
 
 
 
 
 
 
 
 
 
Scrotum ultrasound with Doppler (male patients only) 
X 
 
 
 
 
 
 
 
 
 
Blood sample for HbA1c measurement 
X 
 
 
 
 
 
 
 
 
 
Confirm clinical FOP diagnosis, including documentation of ACVR1 mutation5 
X 
 
 
 
 
 
 
 
 
 
Whole blood DNA sample for ACVR1 gene sequencing21 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
Study enrollment randomization 
 
X 
 
 
 
 
 
 
 
 
Administer Study Drug (REGN2477 or placebo)6, 8, 9 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (if feasible)22 
X 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Vital signs7, 8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram7, 9 
X 
X9 
X 
 
X 
X 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
Menstrual history, pregnancy status reporting and confirmation of 
contraception use10 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Laboratory Testing3: 
 
 
Hematology7, 11 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Blood chemistry7, 11 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis7, 23 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
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Screening/ 
Baseline Period 
Period 1 (Randomized Double-Blind Treatment) 
Visit1 
Visit 
2 
Visit 
32 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Day  
± visit window (d) 
-28 to -1 
1 
2 
7  
±1d 
29  
±3d 
57  
±7d 
85  
±7d 
113  
±7d 
141 
±7d 
169  
±7d 
Week 
 
1 
1 
1 
4 
8 
12 
16 
20 
24 
Blood samples for FSH7, 11 
X 
X 
 
 
X 
X 
 
 
 
 
Blood samples for ACTH, GH, cortisol, TSH, free T4, testosterone (total and 
free; male patients only), estradiol, LH, amylase, and lipase7, 11 
 
X 
 
 
X 
X 
 
 
 
 
Blood sample for coagulation parameters (activated partial thromboplastin 
time, prothrombin time, INR, thrombin time), fibrinogen, and platelet effector 
function 
X25 
 
 
 
X 
 
X 
 
 
 
Pregnancy test (WoCBP)7, 10, 11  
serum 
urine 
 
 
urine 
urine 
urine 
urine 
urine 
urine 
Imaging Assessments: 
 
 
18F-NaF PET7, 12, 13 
X 
 
 
 
 
X 
 
 
 
 
Blood sample for 18F-NaF tracer concentration (optional)7, 11, 12, 13 
X 
 
 
 
 
 
 
 
 
 
Low dose CT7, 12 
X 
 
 
 
 
X 
 
 
 
 
Clinical Endpoint Measures24 
 
 
Daily Pain NRS14, 18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily FOP disease activity e-diary14, 18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FOP I-ADL 
X 
 
 
 
 
 
 
 
 
 
EQ-5D-3L 
X 
 
 
 
 
 
 
 
 
 
Joint function (CAJIS) 
X 
 
 
 
 
 
 
 
 
 
Pulmonary function by spirometry (FVC, FEV1) 
X 
 
 
 
 
 
 
 
 
 
Biochemical Bone Formation and Mechanism based Biomarkers 
 
 
Blood samples for BSAP and P1NP7, 11 
X 
X 
 
X 
X 
X 
 
X 
 
 
Blood samples for mechanism of action or safety 
X 
 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samples: 
 
 
PK/Drug conc. and activin A sample7, 11 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ADA sample7, 11 
 
X 
 
 
 
 
 
X 
 
 
Biomarker Procedures: 
 
 
Whole blood for RNA gene expression7, 11 
 
X 
X 
X 
X 
 
 
 
 
 
Future Biomedical Research Samples 
 
 
Research biomarker serum and biomarker plasma7, 11 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Optional Genomic Study: DNA Analysis 
 
 
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Screening/ 
Baseline Period 
Period 1 (Randomized Double-Blind Treatment) 
Visit1 
Visit 
2 
Visit 
32 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Day  
± visit window (d) 
-28 to -1 
1 
2 
7  
±1d 
29  
±3d 
57  
±7d 
85  
±7d 
113  
±7d 
141 
±7d 
169  
±7d 
Week 
 
1 
1 
1 
4 
8 
12 
16 
20 
24 
Whole blood DNA sample (optional)7, 15 
 
X 
 
 
 
 
 
 
 
 
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Table 2: 
Schedule of Events: Period 2 (Open-Label Treatment Period) 
 
Period 2 (Open-Label REGN2477 Treatment) 
Visit1 
Visit 1116 
Visit 12 
Visit 13 
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Day  
± visit window (d) 
197 
-7d/+15d 
225 
±7d 
253 
±7d 
281 
±7d 
309 
±7d 
337 
±7d 
365 
±7d 
Week 
28 
32 
36 
40 
44 
48 
52 
Treatment: 
 
Administer REGN24776, 8, 9 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
Vital signs7, 8 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram7, 9 
X9 
 
 
X 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
Menstrual history, pregnancy status reporting and confirmation of 
contraception use10 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
Hematology7, 11 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry7, 11 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7, 23 
X 
X 
X 
X 
X 
X 
X 
Blood samples for ACTH, GH, cortisol TSH, free T4, testosterone (total 
and free; male patients only), FSH, estradiol, LH, amylase, and lipase7, 11 
X 
X 
 
X 
 
 
 
Blood sample for coagulation parameters (activated partial thromboplastin 
time, prothrombin time, INR, thrombin time), fibrinogen, and platelet 
effector function 
X 
X 
 
X 
 
 
 
Pregnancy test (WoCBP)7, 10 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
Imaging and Other Assessments:  
 
18F-NaF PET7, 13 
X 
 
 
 
 
 
 
Low dose CT7, 13 
X 
 
 
 
 
 
 
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Period 2 (Open-Label REGN2477 Treatment) 
Visit1 
Visit 1116 
Visit 12 
Visit 13 
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Day  
± visit window (d) 
197 
-7d/+15d 
225 
±7d 
253 
±7d 
281 
±7d 
309 
±7d 
337 
±7d 
365 
±7d 
Week 
28 
32 
36 
40 
44 
48 
52 
Clinical Endpoint Measures24 
 
Daily Pain NRS14 
X 
X 
X 
X 
X 
X 
X 
Daily FOP disease activity e-diary14 
X 
X 
X 
X 
X 
X 
X 
FOP I-ADL 
X 
 
 
 
 
 
 
EQ-5D-3L 
X 
 
 
 
 
 
 
Joint function (CAJIS) 
X 
 
 
 
 
 
 
Pulmonary function by spirometry (FVC, FEV1) 
X 
 
 
 
 
 
 
Biochemical Bone Formation and Mechanism based Biomarkers 
 
Blood samples for BSAP and P1NP7, 11 
X 
X 
X 
 
X 
 
X 
Blood samples for mechanism of action or safety  
X  
 
 
 
 
 
 
PK/Drug Concentration and ADA Samples: 
 
PK/Drug conc. and activin A sample7, 11 
X 
X 
X 
X 
X 
X 
X 
ADA sample7, 11 
X 
 
 
X 
 
 
X 
Future Biomedical Research Samples 
 
Research biomarker serum and biomarker plasma7, 11 
X 
X 
 
 
X 
 
X 
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Table 3: 
Schedule of Events:  Period 3 (Follow-Up Treatment Period) 
 
Period 3 (Follow-Up Treatment Period) 
End of Study17 
Visit1 
Visit 1819/ 
Early Termination Visit 
Visit 19 
Visit 20 
Visit 21 
Visit 22 
Visit 23 
≥Visit 24 
Day  
± visit window (d) 
393 
±14d 
421 
±7d 
449 
±7d 
477 
±7d 
505 
±7d 
533 
±7d 
561 
±7d 
Week 
56 
60 
64 
68 
72 
76 
8017 
Treatment: 
 
 
 
 
 
 
 
Administer REGN24776, 8, 9, 26 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Vital signs7, 8 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram7, 9 
X 
X 
X 
X 
X 
X 
X 
Physical examination9 
X 
X 
X 
X 
X 
X 
X 
Menstrual history, pregnancy status 
reporting and confirmation of 
contraception use10 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
Hematology7, 11, 
X 
 
 
 
 
 
X17,28 
Blood chemistry7, 11 
X 
 
 
 
 
 
X17,28 
Urinalysis7, 23 
X 
 
 
 
 
 
X17,28 
Blood samples for ACTH, GH, cortisol 
TSH, free T4, testosterone (total and free; 
male patients only), FSH, estradiol, LH, 
amylase, and lipase7, 11 
X 
 
 
 
 
X 
 
Pregnancy test (WoCBP)7, 10, 11 
urine 
urine 
urine 
urine 
urine 
serum 
urine/serum17 
Imaging and Other Assessments:  
 
 
 
 
 
 
 
18F-NaF PET7, 13 
X27 
 
 
 
 
X27 
 
Blood sample for 18F-NaF tracer 
concentration (optional)7, 11, 13 
X 
 
 
 
 
 
 
Low dose CT7, 13 
X 
 
 
 
 
X 
 
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Period 3 (Follow-Up Treatment Period) 
End of Study17 
Visit1 
Visit 1819/ 
Early Termination Visit 
Visit 19 
Visit 20 
Visit 21 
Visit 22 
Visit 23 
≥Visit 24 
Day  
± visit window (d) 
393 
±14d 
421 
±7d 
449 
±7d 
477 
±7d 
505 
±7d 
533 
±7d 
561 
±7d 
Week 
56 
60 
64 
68 
72 
76 
8017 
Clinical Endpoint Measures24 
 
 
 
 
 
 
 
Daily Pain NRS14 
X 
X 
X 
X 
X 
X 
 
Daily FOP disease activity e-diary14 
X 
X 
X 
X 
X 
X 
 
FOP I-ADL 
X 
 
 
 
 
X 
X17 
EQ-5D-3L 
X 
 
 
 
 
X 
X17 
Joint function (CAJIS) 
X 
 
 
 
 
X 
X17 
Pulmonary function by spirometry (FVC, 
FEV1) 
X 
 
 
 
 
X 
X17 
Biochemical Mechanism based Biomarkers 
 
 
 
 
 
 
Blood samples for mechanism of action or 
safety 
X 
 
 
 
 
 
 
Future Biomedical Research Samples 
 
 
 
 
 
 
Research biomarker serum and biomarker 
plasma7, 11 
X 
 
 
 
 
X 
 
PK/Drug Concentration and ADA 
Samples: 
 
 
 
 
 
 
 
PK/Drug conc. and activin A sample7, 11 
X 
X 
X 
X 
X 
X 
X17 
ADA sample7, 11 
X 
 
 
X 
 
 
X17 
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8.1.1. 
Footnotes for the Schedule of Events Table 1, Table 2, and Table 3 
1. Procedures other than those associated with drug administration and imaging procedures 
may be conducted by trained study staff at or near patients’ residences (ie, at home visits). 
2. Study visit 3 (day 2) will be conducted in the clinic following the first dose of study drug, 
although no study drug administration or imaging procedure is conducted at this visit. 
3. Procedures may be conducted on different days during the screening/baseline period, if 
needed.  Blood draws for laboratory testing at the screening visit will be collected in a 
fasted state (after an 8-hour fast).  No other blood draw will require fasting. 
4. Medical history should include detailed FOP history, and prior medication and surgery for 
treatment of FOP. 
5. Documentation of ACVR1 genotype, including classic [R206H] or different ACVR1 
mutations should be obtained for study file.  If at the time of screening, the patient doesn’t 
have documentation of what ACVR1 mutation he/she carries or it cannot be retrieved, then 
the study site staff should collect a blood sample for the testing by the investigator to 
determine the ACVR1 mutation prior to randomization.  This testing, which will be 
performed on an as needed basis, is separate from the mandatory whole blood collection 
described in footnote #21.   
6. All patients who receive study drug will be closely monitored after each study drug 
administration for at least 2 hours. 
7. Study procedures within each visit may be conducted on different days, within the stated 
visit window.  If conducted on the same day, vital signs and ECG will be conducted before 
blood sampling, and blood samples (except 18F-NaF tracer concentrations) will be collected 
before imaging procedures. Study drug administration will be performed last at that study 
visit.   
8. On study day 1 (Period 1) and on study day 197 (Period 2), vital signs will be collected 
pre-dose and post-dose at 1 hour and 4 hours after the end of infusion.  On subsequent 
visits, vital signs will be collected prior to dosing. 
9. On study day 1 (Period 1) and on study day 197 (Period 2), ECG will be conducted pre-
dose and post-dose 1 hour and 4 hours after the end of infusion.  On subsequent visits, ECG 
will be conducted prior to dosing.  ECG and symptom-directed physical examination may 
be performed during Period 3 at the investigator’s discretion. 
10. Menstrual history and pregnancy status of WoCBP will be determined at the screening 
visit.  Menstrual events and pregnancy status of WoCBP will be monitored at each visit, 
except visit 3 and visit 4.  For all patients, contraception use will be confirmed.  A negative 
result for the pregnancy test must be obtained prior to each study drug administration. After 
week 56, urine pregnancy testing will be performed prior to each REGN2477 dose 
administration.  A serum pregnancy test will be performed at the patient’s end of study 
visit. 
11. In some patients, it may not be possible to obtain venous blood samples for all tests. Serum 
pregnancy tests and other blood tests for determining eligibility must be obtained.  Blood 
samples for safety labs will be prioritized. 
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12. The baseline imaging assessments by 18F-NaF PET and low dose CT must be conducted 
between day-7 to day -1. 
13. The 18F-NaF PET may be performed at a separate location than the study clinic, within the 
visit window, before study drug administration.  Blood samples for the determination of 
the tracer concentration in plasma will be collected for baseline and week 56 imaging 
sessions from a subset of patients who will undergo an optional dynamic PET scan.  Any 
incidental findings identified through PET/CT scans will be reported to the investigator 
and medical monitor.  The investigator will communicate any findings to the patient. 
14. Daily pain NRS score and FOP disease activity will be collected as entries in a diary 
completed by.  If the patient is physically unable to or requires assistance to complete the 
e-diary on their own caregivers can complete or provide assistance in completion of the e-
diary.  Caregivers can only physically assist with completion of the e-diary and there is to 
be no interpretation of patient disease activity on their part. 
15. Separate consent is required for participation in the optional genomic DNA sub-study and 
collection of blood sample (DNA).  The blood sample for genomic DNA should be 
collected on day 1 or may be collected at any visit. 
16. Patients will undergo end of double-blind treatment (Period 1) assessments at the week 28 
visit (Period 1), which is the first visit in the open-label treatment (Period 2) with 
administration of open-label REGN2477. 
17. The week 80 column illustrates additional visits and procedures to be performed Q4W 
(study drug administration, concomitant medications, and safety assessments) and every 
24 weeks (laboratory testing, clinical endpoint measures, PK/drug concentration and ADA 
samples).  The first collection of the assessments conducted every 24 weeks would be at 
week 100 (visit 29).  The serum pregnancy test should only be required when the patient is 
performing the last visit in the study and thereafter will not receive additional infusions of 
REGN2477.  The criteria for continued administration of REGN2477 after week 76 is 
described in Section 5.1.4. 
18. The baseline entry for both the daily pain NRS and the daily FOP disease activity diary 
will be on day -1. 
19. Patients will undergo end of open-label treatment (Period 2) assessments at the week 56 
visit, which is the first visit of the follow-up treatment period (Period 3). 
20. Patients can be rescreened for study participation. 
21. All patients will have a whole blood sample collected, preferably at the screening/baseline 
visit, for future ACVR1 gene sequencing.  However, the sample can be collected at any 
time during the study period, as the result of this test is not to be used for assessment of 
study eligibility. 
22. Depending upon the level of musculoskeletal compromise for a patient, the measurement 
of the patient’s height may not be precise or sometimes not possible to be assessed. 
23. A urinalysis and culture will be collected/performed if there is an AESI (only applicable to 
male patients). 
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24. With the exception of the Daily Pain NRS and FOP disease activity e-diary, if a study 
questionnaire is not available in a patient’s native language at the time of enrollment that 
questionnaire will not be part of the required study procedures for that patient.  
25. For patients already enrolled in the study, the blood sample for these assessments will be 
collected at their next visit, unless these assessments have been performed in the past year.  
These assessments will be conducted locally.   
26. Study drug to be administered IV by trained nursing staff either at study site or in local 
community healthcare setting close to patient or at a home visit.  
27. A low-dose CT only scan may be performed if 18F-NaF tracer or PET/CT scanner is 
unavailable during a scheduled visit (Section 5.1.3, Section 5.1.4).  This low-dose CT scan 
may be performed by trained staff either at study site, at other clinical sites with access to 
a CT scanner, or using a mobile qualified CT scanner at a local community healthcare 
setting close to patient or at a home visit.  
28. After the week 56 visit, samples for hematology, blood chemistry and urinalysis will be 
collected every 24 weeks. After the week 80 visit (visit 24) samples will continue to be 
collected as outlined in footnote 17 with the next sample collection at week 100 (visit 29). 
Although blood for safety will be collected approximately every 6 months, at the discretion 
of the study physician, additional blood and urine samples may be collected if a safety 
concern arises. 
8.1.2. 
Early Termination Visit 
Patients who are permanently withdrawn from the study drug will be asked to return to the clinic 
for an early termination visit consisting of week 56 study assessments.  Patients who permanently 
discontinue from study drug and who do not withdraw from the study will be asked to return to 
the clinic for all remaining study visits per the visit schedule and for blood sample collection for 
measurement of serum drug and target, and ADA: at 4 weeks, 8 weeks, 16 weeks, and 28 weeks 
after the last dose of study drug.  Safety lab exams (ie, hematology, blood chemistry and urinalysis) 
may also be collected during these visits at the investigator's discretion (Section 7.2.2).  A blood 
sample collection for assessment of ADA will occur at the patient’s last visit. 
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  medical, prior medication, and surgical history, 
urogenital exam and scrotum ultrasound with Doppler (for male patients only), confirmation of 
FOP diagnosis including documentation of ACVR1 mutation, blood collection for ACVR1 gene 
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sequencing, height measurement, HbA1c measurement, and assessment of a patient’s ability to 
undergo imaging and other procedures described in the study protocol. 
8.2.2. 
Imaging Procedures 
8.2.2.1. 
Positron Emission Tomography/Computed Tomography Procedures 
Positron emission tomography with 18F-NaF and volumetric CT will be used to measure the change 
in heterotopic bone formation.  The PET/CT scans will be performed at the time points specified 
in Section 8.1.  PET/CT scans will be used to assess changes to the uptake of 18F-NaF in suspected 
active HO lesions as well as uptake into new lesions over time.  A PET/CT scanner will be used 
to acquire dynamic and/or static emission and CT images from patients with FOP.  All patients 
will undergo whole body static emission 18F-NaF PET scan.  An optional dynamic emission 18F-
NaF PET scans may be performed in a subset of patients, based on sites’ capabilities and patients’ 
consent, over a predefined region of the body using a single-bed position.  Static emission PET 
scans will be performed in the same session after the dynamic scan is completed.  Static emission 
PET scans axial field of view will be specified in the imaging manual.  Low-dose CT acquisitions 
will be performed contemporaneously and will cover similar regions as those of the static emission 
PET scan.  Blood samples will be collected for assessment of 18F-NaF concentration in plasma 
from the subset of patients who will consent and undergo dynamic emission 18F-NaF PET scans.  
Patients will not need to fast, and may take all their usual medications as permitted by the study 
(see Section 7.6).  Patients should be well hydrated to promote rapid excretion of the tracer to 
decrease radiation dose and to improve image quality.  Patients should be positioned comfortably 
on the bed of the scanner with supportive aids (eg, pillows and blankets) as necessary to minimize 
involuntary movement during the scan. 
Detailed descriptions of the PET/CT procedures and the criteria for identifying active HO lesions 
will be provided in the study imaging manual.  Personnel at all sites will undergo training for 
PET/CT acquisition procedures as described in the study imaging manual.  The sponsor or its 
representative(s) will conduct site visits to monitor and ensure that the study is executed according 
to the study protocol.  The PET/CT scans will be read and analyzed using a blinded central reading 
center.  The investigator will be allowed to independently read and analyze baseline PET/CT 
images while blinded to subsequent study treatment.  In order to avoid potential unblinding, the 
investigator will not be allowed to read or analyze PET/CT images acquired from a patient 
randomized into the study after study drug dosing has been initiated. 
In the event that a pathological finding that potentially requires medical attention (eg, suspected 
malignancy) is identified, the sponsor and the investigator will be informed of the finding. The 
imaging data may be provided to the investigator upon discussion with the sponsor.  The 
investigator will communicate any findings to the patient. 
In light of the public health emergency related to the COVID-19 pandemic, Investigators may 
perform study visit 18 (week 56) and/or visit 23 (week 76) imaging exams employing only 
whole-body low-dose CT scans.  Assessment of imaging endpoints without the PET scan may be 
implemented to mitigate the delay to acquire images due to the inaccessibility to PET/CT imaging 
centers and/or unavailability of the 18F-NaF tracer.  In addition, the window for the week 56 
imaging assessments can be flexible (eg, as soon as feasible or later when possible) to respond to 
COVID-19 related travel restrictions.  This low-dose CT scan may be performed by trained staff 
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either at study site, at other clinical sites with access to a qualified CT scanner, or using a mobile 
qualified CT scanner at a local community healthcare setting close to patient or at a home visit, 
contingent upon prior concurrence and approval from the Investigator and Regeneron medical 
director. 
8.2.3. 
Clinical Endpoint Measures 
With the exception of the Daily Pain NRS and FOP disease activity e-diary, if a study questionnaire 
is not available in a patient’s native language at the time of enrollment that questionnaire will not 
be part of the required study procedures for that patient. 
8.2.3.1. 
Numeric Rating Scale Pain Evaluation 
The NRS is a categorical rating scale used by patients to rate their pain associated with FOP.  
Patients will be asked to rate their pain on a scale that ranges from “0” (no pain) to “10” (worst 
possible pain).  The NRS measurements will be performed at the screening and baseline visits, and 
daily throughout the study and the results recorded in the e-diary device.  Patients and their 
caregiver (if applicable) will be trained on its use at the screening/baseline visit (Section 8.1) and 
are instructed to record their current, least, and worst pain scores in the e-diary each day throughout 
the study.  The average of the 3 ratings will be used to represent the patient’s level of pain over 
the previous 24 hours (McCaffery 1989).  Completion of the Daily Pain NRS will be reviewed at 
the visits listed in Section 8.1.  The baseline entry for the daily pain NRS diary is day-1. 
8.2.3.2. 
FOP Disease Activity Assessment  
Assessment of FOP disease activity, including flare-up location, frequency, and duration, as well 
as the severity of selected FOP disease signs and symptoms, including pain, swelling, joint 
stiffness, and decrease in movement which will be rated by patients using a 4-point scale for each 
(0: no symptom; 1: mild; 2: moderate; 3: severe). 
Patients and their caregiver (if applicable) will be trained on its use at the screening/baseline visit 
(Section 8.1) and are instructed to record their scores in the e-diary each day throughout the study.  
The FOP disease activity diary will be reviewed at the visits listed in Section 8.1.  The baseline 
entry for the daily FOP disease activity diary is day -1. 
8.2.3.3. 
FOP Independent Activities of Daily Living 
Patient reported ability to independently perform activities of daily living (I-ADL) will be assessed 
via a questionnaire, FOP I-ADL.  Questions in the FOP I-ADL are selected from the PROMIS 
bank of questions.  For questions 1 to 24, each activity is rated from (1) “unable to do” to (5) 
“without any difficulty”, and for questions 25 to 28, each activity is rated from (1) “cannot do” to 
(5) “not at all”.  The FOP I-ADL will be reviewed at baseline and at the visits listed in Section 8.1.  
For languages where the FOP I-ADL questionnaire is not currently available in a validated form, 
patients will not complete this assessment during the course of the study. 
8.2.3.4. 
EQ-5D-3L Questionnaire 
The EQ-5D-3L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.  The EQ-
5D-3L as a measure of health related quality of life, defines health in terms of 5 dimensions:  
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mobility, self-care, usual activities, pain/discomfort, anxiety/depression.  Each dimension has 
3 ordinal levels of severity: absence of problems or issues with the specific dimension, eg, “no 
problems” (1), “some problems” (2), “severe problems” (3). Overall health state is defined as a 5-
digit number.  Health states defined by the 5-dimensional classification can be converted into 
corresponding index scores that quantify health status, where 0 represents “death” and 1 represents 
“perfect health”.  In the final part of the EQ-5D-3L, participants are asked to rate “your own health 
state today” from 100 (best imaginable health state) to 0 (worst imaginable health state).  Patients 
will complete the questionnaire at time points according to Section 8.1.  For languages where the 
EQ-5D-3L questionnaire is not currently available in a validated form, patients will not complete 
this assessment during the course of the study.  
8.2.3.5. 
Cumulative Analog Joint Involvement Scale 
Physician assessment of joint involvement will be conducted using the CAJIS at the visits listed 
in Section 8.1.  The CAJIS is an assessment of 15 major joints; each major joint rated normal 
unaffected (0), affected (1), or completely functionally ankylosed (2) (Kaplan 2017).  The total 
score ranges from 0 to 30.  Physicians at all sites will undergo training for CAJIS assessment. 
8.2.3.6. 
Pulmonary Function by Spirometry 
Forced vital capacity [FVC] and FEV1 [forced expiratory volume in 1 second] and the ratio of 
FEV1/FVC will be determined by spirometry in patients who are able to undergo this procedure 
at baseline, week 28, week 56, and week 76. 
8.2.4. 
Safety Procedures 
8.2.4.1. 
Vital Signs 
Vital signs, including body temperature, blood pressure, heart rate, pulse, and respiration, will be 
collected at the visits specified in Section 8.1, and at the early termination visit, if applicable.  
Blood pressure will be measured from a consistent resting position. 
8.2.4.2. 
Physical Examination 
A thorough and complete physical examination will be performed at the visits specified in 
Section 8.1, and at the early termination visit, if applicable.  Care should be taken to examine and 
assess any abnormalities that may be present, as indicated by the patient’s medical history.  
Targeted physical examinations may be performed, if appropriate, depending upon AEs and/or 
laboratory or ECG abnormalities. 
Physical exams for the screening visit may be conducted on a different day from the initial 
screening visit, as long as they are conducted within the screening window. 
8.2.4.3. 
Menstrual History 
Assessment of menstrual cycle history for WoCBP will be conducted at baseline and at the visits 
specified in Section 8.1 to identify any changes in occurrence, frequency, duration following study 
drug treatment. 
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8.2.4.4. 
Electrocardiogram 
Electrocardiograms should be performed before blood is drawn during visits requiring blood 
draws.  A standard 12-lead ECG will be performed at the visits specified in Section 8.1 and at the 
early termination visit, if applicable.  The ECG should be performed prior to administration of 
study drug, if these were to occur on the same day. 
Each ECG consists of a 10-second recording of the 12 leads simultaneously, leading to a single 
12-lead ECG (25 mm/s, 10 mm/mV) printout with evaluation (HR, PR, QRS, RR, QT intervals, 
and QTc) including date, time, number of the patient, signature of the research physician, and at 
least 3 complexes for each lead.  The automatic reading will be used for immediate safety 
assessment.  The investigator’s medical opinion and automatic values will be recorded in the 
electronic case report form (CRF). 
8.2.4.5. 
Laboratory Testing 
Blood draws for laboratory testing at the screening visit will be collected in a fasted state (after an 
8-hour fast).  No other blood draw will require fasting.  Hematology, chemistry, and urinalysis 
testing samples will be analyzed by a central laboratory.  Detailed instructions for blood sample 
collection are located in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected at visits according to Section 8.1.  Tests will 
include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Bicarbonate 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
Magnesium 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
Hematology and Coagulation 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
 
Activated partial thromboplastin time 
Prothrombin time 
Thrombin Time 
 
International Normalized Ratio (INR) 
Platelet effector function 
Fibrinogen 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
 
 
 
Other Laboratory Tests 
Blood samples will be collected during screening to measure HbA1c and for DNA isolation for 
ACVR1 gene sequencing (the DNA samples will be stored until sequencing is performed). 
Blood samples will be collected at the visits specified in Section 8.1 to measure 
adrenocorticotropic hormone (ACTH), growth hormone (GH), testosterone (total and free; male 
patients only), LH, FSH, estradiol, thyroid stimulating hormone (TSH) and free thyroxine (T4), 
amylase, and lipase. 
Blood or urine samples will be collected from female patients at the visits specified in Table 1 for 
a pregnancy test before study drug administration. 
A urinalysis and culture will be collected/performed if there is an AESI (only applicable to male 
patients). 
Blood samples will be collected at baseline and various timepoints (Table 1 and Table 2) for 
measurement of coagulation parameters (including, but not limited to activated partial 
thromboplastin time, prothrombin time, INR, thrombin time), fibrinogen, and platelet effector 
function.  For all patients who are currently enrolled in the study, blood samples will be collected 
prior to next administration of study drug for measurement of coagulation parameters (activated 
partial thromboplastin time, prothrombin time, INR, thrombin time), fibrinogen, and platelet 
effector function, unless these tests have been performed in the past year.  These assessments will 
be conducted locally.  If possible, for patients with a moderate or severe AESI of epistaxis or other 
non-traumatic bleeding, the investigator should attempt to obtain an unscheduled assessment of 
coagulation parameters and platelet effector function as close as possible to the time of this AESI.  
Abnormal Laboratory Values and Laboratory Adverse Events 
• All laboratory values must be reviewed by the investigator or authorized designee. 
• Significantly abnormal test results that occur after start of treatment must be repeated 
to confirm the nature and degree of the abnormality.  When necessary, appropriate 
ancillary investigations should be initiated.  If the abnormality fails to resolve or cannot 
be explained by events or conditions unrelated to the study medication or its 
administration, the medical monitor must be consulted. 
• The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
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8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.5.1. 
Drug Concentration and Total Activin A Concentration Measurements and 
Samples 
Serum samples for measurement of drug concentration and total activin A concentration will be 
collected at visits listed in Section 8.1.  Samples will be collected before dosing on days when 
study drug is administered.  
Any unused serum samples collected for drug concentration measurements may be used for 
exploratory biomarker research (Section 8.2.6) or future biomedical research (see Section 8.2.7). 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples 
Serum samples for ADA assessment will be collected at visits listed in Section 8.1.  Samples will 
be collected before dosing on days when study drug is administered.  Any unused serum samples 
collected for ADA assessments may be used for exploratory biomarker research (Section 8.2.6) or 
future biomedical research (see Section 8.2.7). 
8.2.6. 
Biomarker Procedures 
Blood samples for analysis of biomarkers and whole blood for RNA analysis will be collected at 
visits according to Section 8.1.  The biomarkers studied will be ones considered to be relevant to 
the pathophysiology of FOP, target engagement, safety and the mechanism of action of anti-activin 
A treatment. 
Biomarker measurements, including those of the biochemical bone formation markers and 
inflammation markers, will be performed in serum or plasma samples to discover and determine 
effects on biomarkers of FOP or on relevant physiological and pathogenic processes.  Biomarkers 
studied may include but need not be limited to biochemical bone and cartilage formation markers 
(BSAP, osteocalcin, P1NP), Total Procollagen Type 1 C-Terminal Propeptide, matrix 
metalloproteinase 13, and type IIA procollagen amino terminal propeptide or inflammation 
markers (hs-CRP).  The list may change, as it is recognized that more relevant or novel biomarkers 
may be discovered during the process of this study.  Investigators will be blinded to the bone 
biomarker data. 
Markers related to the Activin A and the Activin receptor pathway including but not limited to 
Activin and BMP ligands may be explored to understand the impact to other ligands that signal 
through mutant ACVR1 and that may be impacted by REGN2477. 
RNA may be isolated from whole blood to evaluate the gene expression relating to the activin A 
pathway, FOP disease, other bone diseased related to HO, and anti-activin A treatment using 
methods that may include transcriptome sequencing. 
The RNA samples will be double-coded as defined by the International Council for Harmonisation 
(ICH) guideline E15. 
Samples (biomarker or RNA) may be stored for up to 15 years after the final date of the database 
lock and may be used for research purposes.  Any residual samples will be destroyed. 
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8.2.7. 
Future Biomedical Research 
Additional serum and plasma will be banked for future biomedical research to further explore 
hormonal levels, biomarkers associated with FOP, bone and cartilage formation, and inflammation 
as specified in Section 8.2.6, and with anti-activin A inhibition by REGN2477 (Section 8.1), and 
in the event that additional biomarkers are discovered in the field of FOP research.  These 
biomarkers may be evaluated following completion of the study and will not be reported in the 
clinical study report. 
The biomarker samples for study-related research, as well as unused PK and ADA samples, will 
be stored for up to 15 years after the final date of the database lock.  The samples may be utilized 
for future biomedical research of FOP, and bone diseases related to HO.  No additional samples 
will be collected for future biomedical research.  After 15 years, any residual samples will be 
destroyed. 
8.2.7.1. 
Optional Genomic Study: DNA Analysis 
Patients who agree to participate in the optional genomics sub-study will be required to sign a 
separate informed consent form (ICF) before collection of the sample.  Patients are not required to 
participate in the genomics sub-study in order to enroll in the primary study.  Blood samples for 
DNA extraction should be collected on day 1/baseline (pre-dose), but may be collected at any 
study visit after screening. 
The DNA sample for the sub-study will be double-coded as defined by the ICH guideline E15.  
Sub-study samples will be stored for up to 15 years after the final date of the database lock and 
may be used for research purposes.  The purpose of the genomic analyses is to identify genomic 
associations with clinical or biomarker responses, other clinical outcome measures and possible 
AEs.  In addition, associations between genomic variants and prognosis or progression of FOP as 
well as other HO and bone diseases may also be studied.  These data may be used or combined 
with data collected from other studies to identify and validate genomic markers related to the 
REGN2477 or FOP, and other HO and bone diseases.  Analyses may include sequence 
determination or single nucleotide polymorphism studies of candidate genes and surrounding 
genomic regions. Other methods, including whole-exome sequencing, whole-genome sequencing, 
DNA copy number variation may also be performed.  The list of methods may be expanded to 
include novel methodology that may be developed during the course of this study or sample storage 
period.  The results of these analyses will be reported separately from the clinical study results.  
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients.  This includes death from any cause 
and all SAEs related to the use of the study drug.  It is recommended that all SAEs be reported to 
the IRB/EC, regardless of assessed causality. 
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9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IRBs/EC as appropriate, and to the 
investigators. 
Any AE not listed as an expected event in the IB or in this protocol will be considered unexpected.  
Any worsening of or new onset of symptoms related to FOP that occur during the 
screening/washout period prior to study drug administration will be considered expected. 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the study drug to the health authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IRB/EC as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  In-
patient hospitalization is defined as admission to a hospital or an emergency room for 
longer than 24 hours.  Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than originally anticipated for the event, or is prolonged due to the 
development of a new AE, as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
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• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Note:  In addition to the criteria above, a new diagnosis or progression of a malignancy in patients 
enrolled in the study will also be considered a SAE.  
Criteria for reporting SAEs must be followed for these events.  See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.  Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (eg, regulators) might also be warranted (Section 9.4.3) 
9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 2 hours after the 
infusion is completed.  All infusion reactions must be reported as AEs (defined in Section 9.3) and 
graded using the grading scales as instructed in Section 9.5.1. 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study.  Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study reference manual for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
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In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study or within 113 days of last study 
drug administration if the patient was terminated early from the study:  the SAE will 
be reported to the sponsor.  The investigator should make every effort to obtain follow-
up information on the outcome until the event is considered chronic and/or stable. 
• SAE with an onset day greater than 30 days from the end of study/early termination 
visit:  only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female or female partner of a male, during the study 
or within 30 weeks of the last dose of study drug.  Any complication of pregnancy 
affecting a female study patient or female partner of a male study patient, and/or 
fetus and/or newborn that meets the SAE criteria must be reported as an SAE.  
Outcome for all pregnancies should be reported to the sponsor.  The investigator 
will be provided a pregnancy tracking form and follow the pregnancy until delivery.  
If the pregnancy continues to term (delivery), the health of the infant will be 
followed-up for a period of 3-months postnatally. 
Adverse Events of Special Interest: 
All AESI, serious and non-serious, must be reported 
within 24 hours of identification using the same reporting process as for SAE 
reporting, per Section 9.4.2. 
AESI for this program at current time are: 
• Epididymitis 
• Orchitis (inflammation of the testicles) 
• Hydrocele (fluid buildup around 1 or both testicles) 
• Scrotum pain  
• Scrotum swelling 
• Moderate to severe episodes of non-traumatic bleeding 
• Moderate epistaxis (defined as any episode lasting longer than 30 minutes or 
requiring professional medical intervention)  
• Severe epistaxis (based on definition of a severe AE as described in Section 9.5.1) 
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Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• the test result is associated with accompanying symptoms, and/or 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
• Mild:  Does not interfere in a significant manner with the patient’s normal functioning 
level.  It may be an annoyance.  Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
• Moderate:  Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
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• Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health.  Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
• Mild:  Mild transient reaction; infusion interruption not indicated; intervention not 
indicated. 
• Moderate:  Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hours. 
• Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae; life-threatening consequences; urgent 
intervention indicated; death. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the blinded investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
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Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the blinded investigator, and will be 
a clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Injection Procedure: 
The relationship of AEs to injection procedure will be assessed by the blinded investigator, and 
will be a clinical decision based on all available information.  The following question will be 
addressed: 
Is there a reasonable possibility that the AE may have been caused by the injection procedure? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
injection procedure 
Related: 
There is a reasonable possibility that the event may have been caused by the 
injection procedure 
A list of factors to consider in assessing the relationship of AEs to injection procedure is provided 
in Appendix 1. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments (eg, 
Global Patient Safety; Biostatistics and Data Management).  Safety monitoring will be performed 
on an ongoing basis (eg, individual review of SAEs) and on a periodic cumulative aggregate basis. 
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9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the IB or this 
protocol, and has a reasonable suspected causal relationship to the medicinal/study drug). 
10. 
STATISTICAL PLAN 
This Section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP for Period 1 (double-blind treatment period; week 28) was issued before 
the database was locked (19 Nov 2019 for clinical results and 13 Dec 2019 for imaging results).  
No changes have been made to the SAP with regard to the specified Period 1 analyses as those 
analyses have already been conducted. 
Prior to the DBL for Period 2 (open-label treatment period; week 56), an SAP amendment will be 
issued to present the definition of the separate study hypothesis for the open-label treatment period 
(week 28 to week 56; Period 2) and the new analyses to test efficacy of REGN2477 in preventing 
the formation of new HO lesions.  
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypotheses 
10.1.1. 
Statistical Hypothesis (Period 1 [Week 28]) 
The primary efficacy endpoints of the study are   
• Time-weighted average (standardized area under the curve [AUC]) of the percent 
change from baseline in total lesion activity by 18F-NaF PET over 28 weeks in AHO 
• Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 in AHO 
• Time-weighted average (standardized area under the curve [AUC]) of the percent 
change from baseline in total lesion activity by 18F-NaF PET over 28 weeks in AHOC 
• Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 in AHOC 
The key secondary efficacy endpoints are  
• Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks in AHO 
• Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks in AHOC  
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The following null and alternative hypotheses will be tested for efficacy endpoints respectively: 
H0: No treatment difference between REGN 2477 and placebo 
H1: There is a treatment difference between REGN 2477 and placebo 
Testing of the primary and key secondary efficacy endpoints will follow a hierarchical testing 
procedure to address multiplicity at an overall 2-sided alpha=0.05 significance level.  Testing of 
the key secondary efficacy endpoints will follow a hierarchical testing sequence only if statistical 
significance is established for all primary endpoints.  The order of testing sequence for primary 
and key secondary efficacy endpoints is detailed in Section 10.4.3.1.4.  No further adjustments 
will be made for other secondary and exploratory endpoints, for which nominal p-values will be 
provided for descriptive purpose only. 
10.1.2. 
Statistical Hypothesis (Period 2 [Week 56]) 
For the efficacy analyses in Period 2 (week 56), the key statistical comparisons will be based on 
within group (placebo/REGN2477) comparisons for the patients who were randomized to placebo 
in the double-blind period and switch to REGN 2477 in the open-label period (Period 2). 
For the Period 2 (week 56) analyses, the following primary and key secondary null hypotheses 
will be tested:  
• H1,1: There is no difference in number of new (relative to week 28 scan) HO lesions as 
assessed by CT per patient at week 56 compared to the number of new (relative to 
baseline scan) HO lesions as assessed by CT per patient at week 28 in 
placebo/REGN2477 group in AHO (primary) 
• H2,1: There is no difference in total volume of new (relative to week 28 scan) HO lesions 
per patient as assessed by CT at week 56 compared to the total volume of new (relative 
to baseline scan) HO lesions per patient as assessed by CT at week 28 in 
placebo/REGN2477 group in AHO (key secondary) 
• H2,2: There is no difference in number of new (relative to week 28 scan) HO lesions 
per patient as assessed by 18F-NaF PET at week 56 compared to the number of new 
(relative to baseline scan) HO lesions per patient by 18F-NaF PET at week 28 in 
placebo/REGN2477 group in AHO (key secondary) 
• H2,3: There is no difference in total lesion activity per patient by 18F-NaF PET in new 
(relative to week 28 scan) lesions at week 56 compared to the total lesion activity per 
patient by 18F-NaF PET in new (relative to baseline scan) lesions at week 28 in 
placebo/REGN2477 group in AHO (key secondary) 
• H2,4: There is no difference in percent of patients with new HO lesions as assessed by 
CT at week 56 relative to week 28 scan in placebo/REGN2477 group in AHO (key 
secondary) 
• H2,5: There is no difference in percent of patients with new HO lesions as assessed by 
18F-NaF PET at week 56 relative to week 28 scan in placebo/REGN2477 group in AHO 
(key secondary) 
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To control the type-I error rate at 0.10 for the primary and key secondary null hypotheses in 
Period 2, a hierarchical testing procedure will be applied at a 2-sided 10% significant level as 
detailed in Section 10.4.3.2.4.  No further adjustments will be made for other secondary and 
exploratory endpoints in Period 2, for which estimates, 95% CI, and/or nominal p-values will be 
provided for descriptive purpose. 
10.2. 
Justification of Sample Size 
Randomization will be stratified by the presence/absence of active HO lesions at baseline, to allow 
analyses of efficacy endpoint measures defined solely for patients with active HO at baseline 
(Section 10.3.1).  Patients without active HO lesions at baseline will contribute to the assessment 
of safety and other endpoint measures (Section 10.3.4, Section 10.3.3).  Randomization will also 
be stratified by gender and classic ACVR1[R206H] mutation/different ACVR1 mutations. 
The sample size estimation for at least 24 patients (12 patients per treatment group) with active 
HO at baseline and classic ACVR1[R206H] mutation is based on statistical considerations for the 
following efficacy endpoints: percent change from baseline in (1) total lesion activity by 18F-NaF 
PET over 28 weeks, (2) total volume of HO lesion by CT at week 28, and (3) 18F-NaF SUVmax at 
week 8.  Accounting for a 20% dropout rate at week 28, the sample size would yield approximately 
10 patients per treatment group for week-28 analyses.  This sample size will provide 80% power 
at a 2-sided 0.05 significance level in allowing the detection of an observed treatment difference 
in the order of 57%, 65%, and 40% reduction in the total lesion activity by 18F-NaF PET, the total 
volume of HO lesion by CT, and the 18F-NaF SUVmax, respectively, if the measure variability in 
FOP patients is similar to that observed in other bone diseases and the FOP mouse model (Table 4).  
Recent in vitro studies demonstrated that different mutations in the ACVR1 receptor transduced 
BMP signaling when stimulated with activin A (Hino 2015).  These results suggest that 
REGN2477 may provide beneficial clinical impact on HO in patients with FOP, irrespective of 
the underlying ACVR1 mutation. 
No prior published data on treatment effects in patients with FOP using these endpoints are 
available; however, numerous case reports show positive 99mTc methylene diphosphonate (MDP) 
bone scan, as well as an abnormally high 18F-NaF PET signal in a small cohort of patients with 
FOP at the site of flare-up and "asymptomatic" locations. 
There is no precedent in patients with FOP to allow estimation of variance or clinically meaningful 
effect sizes for these endpoints. Based on studies in other bone diseases in human and in the FOP 
mice, changes are estimated at a magnitude of 73% for the total lesion activity by 18F-NaF PET, 
65% for the total volume of HO lesion by CT, and 50% for 18F-NaF SUVmax PET. 
There are 18F-NaF PET (SUVmax) data available from a bisphosphonate treatment study of 
14 patients with Paget's disease (Installe 2005). In this study, 18F-NaF PET/CT was used to monitor 
treatment effects on bone. The SUVmax and bone influx constants (Ki) were found to be 
significantly higher in Pagetic bone than normal bone (mean±SD are 35.07±23.86 vs. 7.15±4.76 
and 0.114±0.115 vs. 0.014±0.008 mL/min/mL, respectively, where p<0.05 for both measures). 
Following treatment with bisphosphonates, a significant reduction of PET signal in Pagetic bone 
was observed compared to baseline (-27.84±24.59% at 1 month and -44.64±23.61% at 6 months, 
P<0.05 at both time points (Installe 2005). These data yielded a log-scale SD~0.36 for 1-month 
change. Assuming a 50% reduction by REGN2477 versus placebo in total lesion activity by 
18F-NaF SUVmax PET and a log-scale SD~0.36, the sample size required for week-28 analysis 
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assuming the effect size of 1.9 is 6 patients with active lesion per arm for 80% power at a 2-sided 
0.05 significance level. 
Prior data for total lesion activity by 18F-NaF PET and total volume of HO lesion by CT in FOP 
are available only in mice. 
REGN2477 treatment yielded an effect size of 2.2 and a log-scale SD of approximately 0.60 in 
reducing induced HO total lesion activity in mice as measured by 18F-NaF PET AUC. Assuming 
an effect size of 2.2, the sample size required for week-28 analysis is 5 patients with active lesion 
per arm for 80% power at a 2-sided 0.05 significance level. 
Effect sizes for total volume of HO by CT ranged 0.9 to 1.4 with a log-scale SD of 0.75 to 1.0. 
Assuming larger effect size of 1.4 and smaller log-scale SD of 0.75, the required sample size for 
week-28 analysis is 10 patients with active lesion per arm for 80% power at a 2-sided 0.05 
significance level. 
Considering that FOP is a rare disease and the robust preclinical efficacy of REGN2477, in the 
interest of maintaining smallest reasonable sample size, larger target effect sizes are used to 
compute power for potential sample size for this study.  The calculations, which were carried out 
on log-scale (ie, ln[post/pre]) and back-transformed to express differences in percent change scale, 
are summarized in Table 4. 
Table 4: 
Sample Size (Total Lesion Activity by 18F-NaF PET, Total Volume of HO 
Lesions by CT, and SUVmax) at Week 28 for Comparisons between REGN2477 
and Placebo Treatment Groups 
Endpoint 
Sample Sizea 
TRUE  
Underlying 
Difference 
Log-Scale SD 
TRUE  
Effect Size 
Time-weighted average (standardized 
AUC) percent change in total lesion 
activity 
by 
18F-NaF 
PET 
over 
28 weeks 
5 
73% reduction 
0.60 
2.2 
10 
57% reduction 
0.60 
1.4 
Percent change in total volume of HO 
lesions by CT at week 28 
10 
65% reduction 
0.75 
1.4 
12 
60% reduction 
0.75 
1.2 
Percent change in 18F-NaF SUVmax at 
week 8 
6 
50% reduction 
0.36 
1.9 
10 
40% reduction 
0.36 
1.4 
a N / treatment group for 80% power to yield statistically significant difference (alpha=0.05, 2-sided) 
10.3. 
Analysis Sets 
10.3.1. 
Baseline-Active HO Analysis Set 
The baseline active HO analysis set (AHO) includes all randomized patients who had active HO 
lesion at baseline; it is based on the treatment allocated (as randomized).  For analyses of change 
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from week 28, baseline will be defined as week 28.  The endpoints that will be analyzed using the 
AHO set are listed in Section 4.2. 
10.3.2. 
Baseline-Active HO Classic ACVR1[R206H] Mutation Analysis Set 
The baseline active HO classic ACVR1[R206H] mutation analysis set (AHOC) includes all 
randomized patients with the classic ACVR1[R206H] mutation and who had active HO lesion at 
baseline; it is based on the treatment allocated (as randomized).  For analyses of change from week 
28, baseline will be defined as week 28.  The endpoints that will be analyzed using the AHOC set 
are listed in Section 4.2.   
10.3.3. 
Full Analysis Set 
The full analysis set (FAS) includes all randomized patients; it is based on the treatment allocated 
(as randomized).  The endpoints that will be analyzed using the FAS set are listed in Section 4.2. 
10.3.4. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
10.3.5. 
Other Analysis Sets 
The pharmacokinetic analysis set included all treated patients who received any REGN2477 or 
placebo and who had at least 1 non-missing analyte measurement following the first dose of 
REGN2477 or placebo. 
The ADA analysis set included all treated patients who had received any amount of REGN2477 
or placebo and had at least 1 non-missing post-dose anti-drug antibody result following the first 
dose of REGN2477 or placebo. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics by treatment group will include the following 
information: the number of patients reflected in the calculation (n), mean or geometric mean, 
median, SD or log-scale SD, Q1, Q3, minimum, and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category 
by treatment group. 
10.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients:  met the inclusion criteria and exclusion 
regarding the target indication and signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients in each analysis set 
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• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined. 
10.4.3. 
Efficacy Analyses 
10.4.3.1. Analysis of Efficacy Endpoints in Period 1 (Week 28)  
This section was updated (amendment 6) to match the final SAP for Period 1 (double-blind 
treatment period; week 28) issued before the DBL.  In the final SAP, the planned statistical method 
for the primary endpoint was changed from mixed model repeated measures (MMRM) to analysis 
of covariance (ANCOVA) to address feedback from a health authority. 
The analysis strategy used for the primary and key secondary efficacy endpoints is presented in 
Table 5.  
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Table 5: 
Analysis Strategy for Primary and Key Secondary Efficacy Endpoints 
Endpoint 
(Description, Time Point) 
Primary versus 
Supportive 
Approach 
Statistical 
Method 
Analysis Set 
Primary Efficacy Endpoints 
TWA of PCFB in total lesion activity by 
18F-NaF PET over 28 weeks 
P 
ANCOVA 
AHO 
PCFB in the total volume of HO lesions 
as measured by CT at week 28 
P 
MMRM 
AHO 
TWA of PCFB in total lesion activity by 
18F-NaF PET over 28 weeks 
P 
ANCOVA 
AHOC 
PCFB in the total volume of HO lesions 
as measured by CT at week 28 
P 
MMRM 
AHOC 
Key Secondary Efficacy Endpoints 
TWA of CFB in daily pain due to FOP, 
as measured using the daily NRS over 28 
weeks 
P 
ANCOVA 
AHO 
TWA of CFB in daily pain due to FOP, 
as measured using the daily NRS over 28 
weeks 
P 
ANCOVA 
AHOC 
AHOC=active HO with classic ACVR1 mutation; AHO=active HO; ANCOVA=analysis of covariance; CFB=change 
from baseline; MMRM=mixed model with repeated measures; PCFB=percentage change from baseline; TWA=Time-
weighted average (standardized area under the curve [AUC]). 
The MMRM model will include treatment, gender, ACVR1 mutation type (AHO analysis set only) as fixed effects, 
time point, and treatment-by-time point interaction, as well as, the continuous fixed covariates of baseline value.  In 
case of substantial imbalance at baseline in the number of patients in the randomization strata: gender, ACVR1 
mutation type, strata factor(s)may be excluded from the model. An unstructured covariance matrix can be used in this 
model to account for within-patient correlation.  Different parameterization of MMRM model will be utilized if at 
least 1 patient is missing all post-baseline values. 
The ANCOVA model contains treatment, gender, ACVR1 mutation type (AHO analysis set only) as factor, and the 
baseline value as continuous covariate. 
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10.4.3.1.1. Primary Endpoints: Total Lesion Activity by 18F-NaF PET  
For 18F-NaF uptake at HO site, measured by SUV, the following analysis is planned: 
• All active HO lesions per patient will be identified and indexed at baseline. Up to 
7 lesions will be identified as target lesions, and their associated 18F-NaF SUVmean, 
SUVmax by PET, and their volume by CT will be derived.  These index lesions will be 
assessed again on the post-dose treatment period visit scans.  New lesions that arise 
during the post-dose treatment period will be assessed similarly. 
• Total lesion activity by PET per patient will be derived for each time point as the sum 
of individual target HO lesion SUVmean x metabolic volume.  Percent time weighted 
average (standardized AUC, ie, AUC divided by 28) of percent change from baseline 
will be calculated for each patient as the AUC of percent change from baseline in total 
lesion activity by 18F-NaF PET over 28 weeks divided by 28. The ANCOVA model 
will be used to analyze time weighted average of percent change over 28 weeks.  The 
model will include treatment, gender, ACVR1 mutation type (classic, nonclassic) and 
baseline total lesion activity as a covariate.  In case of substantial imbalance at baseline 
in the number of patients in the randomization strata: gender, ACVR1 mutation type, 
strata factor(s) may be excluded from the model.  If both imaging scans at week 8 and 
28 are missing, then mean of percent changes of placebo group at week 8 and 28 will 
be used for imputation.  If imaging scan for only week 8 is missing, linear interpolation 
of percent change between the baseline and week 28 will be used to calculate AUC.  If 
imaging scan for week 28 is missing, percent change at week 8 will be carried forward 
to week 28 for calculating AUC.  
10.4.3.1.2. Primary Endpoints: Total HO Volume by CT 
• Total HO volume by CT in each patient will be derived for each time point as the Sum 
of all individual HO lesion volume  
• Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 will be analyzed in AHO or AHOC using MMRM model.  The model will 
include treatment, gender, ACVR1 mutation type as fixed effects, time point, and 
treatment-by-time point interaction, as well as, the continuous fixed covariates of 
baseline value.  In case of substantial imbalance at baseline in the number of patients 
in the randomization strata: gender, ACVR1 mutation type, strata factor(s) may be 
excluded from the model.  An unstructured covariance matrix can be used in this model 
to account for within-patient correlation.  Different parameterization of MMRM model 
will be utilized if at least 1 patient is missing all post-baseline values. 
10.4.3.1.3. Key Secondary Endpoints: Pain NRS-AUC  
Analysis of Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP by the daily NRS over 28 weeks will be performed in AHO or AHOC using the 
ANCOVA with treatment, gender, ACVR1 mutation type (analysis set only) as fixed factors, and 
the baseline value as continuous covariate.  
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10.4.3.1.4. Multiplicity Considerations for Efficacy Analyses for Period 1 (Week 28) 
In order to handle multiple testing of the 4 primary and 2 key secondary efficacy endpoints, a 
hierarchical testing procedure will be applied at a 2-sided 5% significance level.  Key secondary 
efficacy endpoints will be tested in a (hierarchical order after all primary efficacy endpoints 
achieve statistical significance at an overall 2-sided alpha=0.05 significance level. The testing 
sequence is as follows: 
Time-weighted average (standardized AUC) of the percent change from baseline in 
total lesion activity by18F-NaF PET over 28 weeks in AHO 
 
Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 in AHO 
 
Time-weighted average (standardized AUC) of the percent change from baseline in 
total lesion activity 18F-NaF PET over 28 weeks in AHOC 
 
Percent change from baseline in the total volume of HO lesions as assessed by CT at 
week 28 in AHOC 
 
Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks in AHO 
 
Time-weighted average (standardized AUC) of the change from baseline in daily pain 
due to FOP, as measured using the daily NRS over 28 weeks in AHOC 
No further multiplicity adjustments will be made for testing other secondary efficacy and 
exploratory week-28 endpoints where nominal p-values will be provided for descriptive purpose.   
Sensitivity analyses will be performed for the primary and key secondary efficacy endpoints when 
misclassification of ACVR1 mutation type occurs. 
10.4.3.2. Analysis of Efficacy Endpoints in Period 2 (Week 56) 
In the placebo/REGN2477 group (placebo patients who switch to REGN2477 after the 
double-blind period), efficacy analyses will focus on the within group statistical comparisons of 
Period 1 versus Period 2. 
The COVID-19 pandemic has affected the conduct of the study mainly by causing delay in dose 
administration, delay in the collection of the PET/CT scans due to site closure, and unavailability 
of 18F-NaF due to interruption of tracer production. Some patients may not be able to complete 
their week 56 scans within the protocol-specified visit window and may only be able complete 
their scans using CT-only modality.  
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The week 56 efficacy analyses of imaging endpoints will be conducted using COVID-19 modified 
Intent-To-Treat (COVID-19 mITT) principle which will analyze only those patients for whom:  
• at least 1 post-week 28 scan is collected and, 
• the time period between any 2 consecutive doses is less than 9 weeks (63 days) in 
Period 2 and, 
• no more than 1 dose was missed in Period 2 
This will ensure that primary analyses for imaging endpoints will include patients with continuous 
saturating levels of REGN2477. For patients whose week 56 scans are delayed, the first delayed 
scan available after the week 28 scan will be used to impute the week 56 data in the primary 
analyses. In the absence of a PET/CT scan, data from available CT-only scans will be used to 
analyze the primary endpoint and other secondary imaging endpoints, if applicable. This 
imputation ensures that the estimation of the treatment effect will not be biased by the COVID-19 
pandemic. 
In the REGN2477/REGN2477 group (patients who continue receiving REGN2477 beyond 
week 28), the estimates of treatment effects at week 56 will be provided with 95% confidence 
interval on the endpoints related to new HO lesions (new relative to baseline scan).  
Estimates of the treatment effects with 95% confidence interval on the endpoints related to new 
HO lesions from Period 1 (new relative to baseline scan) in the REGN2477/REGN2477 group 
patients will be descriptively compared with the estimates from Period 2 (new relative to week 28) 
in the placebo/REGN2477 group.  
The missing data handling rules used for the Period 2 (open-label treatment period) analyses will 
be specified in the final SAP (week 56).   
10.4.3.2.1. Primary Efficacy Endpoints in Period 2 (Week 56) 
Number of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in 
patients switching from placebo to REGN2477 after the double-blind period) in AHO 
The number of new HO lesions as assessed by CT at week 56 relative to week 28 scan will be 
summarized for the placebo/REGN2477 group.  Wilcoxon signed rank test will be used for the 
within group comparison in the placebo/REGN2477 group to compare the number of new HO 
lesions by CT at week 56 relative to week 28 scan with the number of new HO lesions by CT at 
week 28 relative to baseline scan. 
The number of new HO lesions as assessed by CT at week 56 relative to week 28 scan in the 
placebo/REGN2477 group will also be descriptively compared with the number of new HO lesions 
as assessed by CT at week 28 relative to baseline scan in the REGN2477/REGN2477 group.  
10.4.3.2.2. Key Secondary Efficacy Endpoints in Period 2 (Week 56) 
Total volume of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in 
patients switching from placebo to REGN2477 after the double-blind period) in AHO 
The total volume associated with new HO lesions as assessed by CT at week 56 relative to week 28 
scan will be summarized for the placebo/REGN2477 group. Wilcoxon signed rank test will be 
used for the within group comparison in the placebo/REGN2477 group to compare the total 
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volume at week 56 associated with new HO lesions relative to week 28 scan with the total volume 
associated with new CT lesions at week 28 relative to baseline scan.  
The total volume associated with new HO lesions by CT at week 56 relative to week 28 scan in 
the placebo/REGN2477 group will be descriptively compared with the total volume associated 
with new HO lesions by CT at week 28 relative to baseline scan in the REGN2477/REGN2477 
group.  
Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 scan 
(in patients switching from placebo to REGN2477 after the double-blind period) in AHO 
The number of new HO lesions at week 56 relative to week 28 scan will be summarized for the 
placebo/REGN2477 group. Wilcoxon signed rank test will be used for the within group 
comparison in the placebo/REGN2477 group to compare the number of new HO lesions as 
assessed by PET at week 56 relative to week 28 scan with the number of new HO lesions at 
week 28 relative to baseline scan. 
The number of new HO lesions by PET at week 56 relative to week 28 scan in placebo/REGN2477 
group will also be descriptively compared with the number of new HO lesions by PET at week 28 
relative to baseline scan in the REGN2477/REGN2477 group  
Total lesion activity by 18F-NaF PET in new HO lesions at week 56 relative to week 28 scan 
(in patients switching from placebo to REGN2477 after the double-blind period) in AHO 
The total lesion activity associated with new HO lesions by PET at week 56 relative to week 28 
scan will be summarized for the placebo/REGN2477 group.  Wilcoxon signed rank test will be 
used for the within group comparison in the placebo/REGN2477 group to compare the total lesion 
activity associated with new HO lesions by PET at week 56 relative to week 28 scan with the total 
lesion activity associated with new HO lesions by PET at week 28 relative to baseline scan.  
The total lesion activity associated with new HO lesions by PET at week 56 relative to week 28 
scan in the placebo/REGN2477 group will be descriptively compared with the total lesion activity 
associated with new HO lesions by PET at week 28 relative to baseline scan in the 
REGN2477/REGN2477 group.  
Percent of patients with new HO lesions as assessed by CT at week 56 relative to week 28 
scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO) 
Number and percent of patients with new HO lesions by CT at week 56 relative to week 28 will 
be provided for the placebo/REGN2477 group.  The within group comparison to compare the 
percent of patients with new HO lesions by CT at week 56 relative to week 28 scan with the percent 
of patients with new HO lesions by CT at week 28 relative to baseline scan will be performed 
using McNemar’s test in placebo/REGN2477 group. 
The percent of patients with new HO lesions by CT at week 56 relative to week 28 scan in the 
placebo/REGN2477 group will be descriptively compared with the percent of patients with new 
HO lesions by CT at week 28 relative to baseline scan in the REGN2477/REGN2477 group. 
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Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 relative to 
week 28 scan (in patients switching from placebo to REGN2477 after the double-blind 
period) (AHO) 
Number and percent of patients with new HO lesions by PET at week 56 relative to week 28 scan 
will be provided for the placebo/REGN2477 group.  The within group comparison to compare the 
percent of patients with new HO lesions by PET at week 56 relative to week 28 scan with the 
percent of patients with new HO lesions by PET at week 28 relative to baseline scan will be 
performed using McNemar’s test in placebo/REGN2477 group. 
The percent of patients with new HO lesions by PET at week 56 relative to week 28 scan in the 
placebo/REGN2477 group will be descriptively compared with the percent of patients with new 
HO lesions by PET at week 28 relative to baseline scan in the REGN2477/REGN2477 group. 
10.4.3.2.3. Other Secondary Efficacy Endpoints in Period 2 (Week 56) 
Percent of patients with new investigator-assessed flare-ups in Period 2 (in patients switching 
from placebo to REGN2477 after the double-blind period) 
Number and percent of patients with new investigator-assessed flare-ups in the open-label period 
(Period 2; week 56) will be provided for the placebo/REGN2477 group. The within group 
comparison to compare the percent of patients with investigator-assessed flare-ups during the 
double-blind period (Period 1) with the percent of patients with new investigator-assessed 
flare-ups in the open-label period (Period 2; week 56) will be performed using McNemar’s test in 
placebo/REGN2477 group.  
The percent of patients with new investigator-assessed flare-ups in Period 2 (week 56) of the 
placebo/REGN2477 group will be descriptively compared with the percent of patients with new 
investigator-assessed flare-ups in Period 1 of the REGN2477/REGN2477 group.  
Percent of patients with new flare-ups (using patient diary) in Period 2 (in patients switching 
from placebo to REGN2477 after the double-blind period) 
Number and percent of patients with new flare-ups (using patient e-diary) in the open-label period 
(period 2; week 56) will be provided for the placebo/REGN2477 group. The within group 
comparison to compare the percent of patients with flare-ups (using patient e-diary) during the 
double-blind period with the percent of patients with new flare-ups (using patient e-diary) in the 
open-label period (period 2; week 56) will be performed using McNemar’s test in 
placebo/REGN2477 group. 
The percent of patients with new flare-ups (by patient e-diary) in Period 2 (week 56) of the 
placebo/REGN2477 group will be descriptively compared with the percent of patients with new 
flare-ups (by patient e-diary) in Period 1 of the REGN2477/REGN2477 group.  
10.4.3.2.4. Multiplicity Considerations for Period 2 (Week 56) 
The type-I error rate will be controlled at 0.10 for the primary and key secondary null hypotheses 
in Period 2 (week 56) (described in Section 3.3.4). 
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To control the type-I error rate for the primary and key secondary endpoints in Period 2 (week 56), 
a hierarchical testing procedure will be applied at a 2-sided 10% significant level to test the above 
hypotheses in the specified order.  The key secondary efficacy endpoints will be tested only if 
statistical significance is established for the primary endpoint. 
No further adjustments will be made for other secondary and exploratory endpoints in Period 2 
(week 56), for which estimates, 95% CI, and/or nominal p-values will be provided for descriptive 
purpose. 
10.4.4. 
Safety Analysis 
10.4.4.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to the time before 
the first dose of study drug. 
• Double blind period is defined as day 1 from start of administration of the first dose of 
study drug through week 28 of the double-blind period  
• Open label and follow-up period is defined as from date of first dose of open label to 
date of last visit of the follow-up period. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
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10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value at any 
post-randomization time point will be summarized for each clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
10.4.4.3. Treatment Exposure 
The treatment duration during the study will be presented by treatment and calculated as: (date of 
last study drug administration – date of first study drug administration) + 28.  The observation 
period will be presented by treatment group and calculated as: (date of the last study visit – date 
of first study drug administration) +1.  The number (%) of patients randomized and exposed to 
double-blind study drug will be presented by specific time periods for each treatment group.  The 
time periods of interest will be specified in the SAP.  In addition, duration of exposure during the 
study will be summarized for each treatment group using number of patients, means, SD, 
minimums, medians, and maximums.  A summary of the number of doses by treatment group will 
be provided. 
10.4.4.4. Treatment Compliance 
Compliance with protocol-defined investigational product will be calculated as follows:  
Treatment compliance = (Number of injections of study drug during exposure period)/(Number of 
planned injections of study drug during exposure period on or before the time that the patient 
discontinues from the study) x 100%. 
Treatment compliance will be presented by specific ranges for each treatment group.  The ranges 
of interest will be specified in the SAP. 
10.4.5. 
Analysis of Drug Concentration and Total Activin A Concentration Data 
Drug and total target concentrations at each sampling time will be summarized using descriptive 
statistics.  Summary of drug and total target concentrations will be presented by nominal time point 
(ie, the time points specified in the protocol).  Individual data will be presented by actual time.  
Plots of the concentrations of functional REGN2477 and total activin A will be presented over 
time (linear and log scales).  When the scale is linear, concentrations below the lower limit of 
quantification (LLOQ) will be set to zero.  In the log-scaled figures, concentrations below the 
LLOQ will be imputed as LLOQ/2. 
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10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and treatment group will be 
provided.  Prevalence of treatment-emergent and treatment-boosted ADA will be assessed as 
absolute occurrence (N) and percent of patients (%), grouped by treatment group. 
The impact of treatment-emergent and treatment-boosted ADAs on drug and total activin A 
concentration-time profiles will be evaluated. The impact of treatment-emergent and 
treatment-boosted ADA on efficacy and safety will also be evaluated. 
10.4.7. 
Analysis of Quality of Life Data 
Quality of life data will be summarized descriptively by study visit and treatment group.  Change 
from baseline in quality of life data through the end of the study will be similarly summarized. 
10.4.8. 
Analysis of Biomarker Data 
Descriptive statistics on levels of biomarkers by study visit and by treatment group will be 
generated.  Levels of biomarkers including mean and medians will be evaluated for change from 
baseline through the end of the study. 
Biomarker endpoints may be further assessed using an MMRM based on log-transformed data.  
Results will be back-transformed and expressed as percent change from baseline for each 
treatment. Time weighted average (standardized AUC) may be compared between treatments if 
appropriate. 
10.5. 
Primary and Additional Analysis 
Primary analysis of safety and efficacy data of the randomized double-blind placebo-controlled 
period (Period 1) of the study will be performed once all data have been collected and validated 
through the end of this period (Period 1, week 28; DBL 1).  Additional analyses of safety and 
efficacy data will be performed following the open-label REGN2477 treatment (Period 2, week 56; 
DBL 2), and at the end of the follow-up treatment period at week 76 (Period 3, week 76; DBL 3).  
Since the key efficacy measure data collection for Period 1 will have been concluded at the time 
of the first analysis (Period 1, week 28; DBL 1) and the radiographic data for subsequent periods 
had not been read nor entered into the database, the final analysis for Period 1 for subsequent 
periods is not considered an interim analysis and no multiplicity adjustments are needed.   
10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
• Unless otherwise specified, the baseline assessment for all measurements will be the 
latest available valid measurement taken prior to the administration of investigational 
product. 
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General rules for handling missing safety data: 
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed. 
• No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
10.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an EDC tool, Medidata RAVE. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IRT system – randomization, study drug supply,  
• Medidata RAVE- EDC system, data capture 
• Statistical Analysis System – statistical review and analysis 
• ARGUS – a pharmacovigilance and clinical safety software system for collection and 
reporting of safety data Study Monitoring 
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12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel.  All required CRFs must be completed for each patient 
enrolled in the study.  After review of the clinical data for each patient, the investigator must 
provide an electronic signature.  A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
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pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient. 
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
14.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by their patient identification number, 
only, on CRFs or other documents submitted to the sponsor.  Documents that will not be submitted 
to the sponsor (eg, signed ICF) must be kept in strict confidence. 
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The patient's and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a significant change in the design of the protocol or ICF without 
an IRB/EC-approved amendment.  Depending on local legislation, regulatory authority approval 
may also be required. 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT 
OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy or 
safety, among others.  Should the sponsor decide to terminate the study, the investigator(s) will be 
notified in writing. 
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16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRFs that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
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18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A Randomized, Placebo-Controlled Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Effects on Heterotopic Bone Formation of REGN2477 in 
Patients with Fibrodysplasia Ossificans Progressiva”, and agree to abide by all provisions set forth 
therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
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APPENDIX 1. 
FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG AND STUDY CONDUCT  
Is there a reasonable possibility that the event may have been caused by the study drug or study 
conduct? 
No: 
• due to external causes such as environmental factors or other treatment(s) being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug  
• do not reappear or worsen when dosing with study drug is resumed 
• are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• could not be explained by the patient’s disease state or clinical condition 
• follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
• resolve or improve after discontinuation of study drug  
• reappear or worsen when dosing with study drug is resumed 
• are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
NOTE:  This list is not exhaustive. 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
 
Study Title: 
“A Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Effects on Heterotopic Bone Formation of REGN2477 in Patients with 
Fibrodysplasia Ossificans Progressiva” 
 
Protocol Number: 
R2477-FOP-1623 
 
Protocol Version: 
R2477-FOP-1623 Protocol Amendment 6 Global Admin 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00123469-1.0 Approved - 28 Aug 2020 GMT-5:00

Signature Page for VV-RIM-00123469 v1.0
Signature Page for VV-RIM-00123469 v1.0 Approved
ESig Approval
000
ESig Approval
-2020 20:41:00 GMT+0000
ESig Approval
20 09:28:09 GMT+0000
ESig Approval
-2020 13:31:12 GMT+0000
                                        VV-RIM-00123469-1.0 Approved - 28 Aug 2020 GMT-5:00