Clinical trial NCT05160415
Conditions: Becker Muscular Dystrophy
Keywords: Becker Muscular Dystrophy
Sponsor: Edgewise Therapeutics, Inc.
Start date: 2021-12-28; Completion date: 2024-03-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The ARCH study was an open-label, single-center, Phase 1b study of sevasemtem (EDG-5506) to assess the safety and pharmacokinetics (PK) of sevasemten in adults with Becker muscular dystrophy (BMD).

Sevasemten is an investigational product intended to protect and improve function of dystrophic muscle fibers.

Detailed description:
This open-label study evaluated the safety, tolerability, and pharmacokinetics (PK) of sevasemten in participants with BMD who completed the first-in-human study, EDG-5506-001, as well as additional (treatment-naïve) participants from outside the EDG-5506-001 study to meet the target sample size.

All participants received sevasemten. This study had a 24 month treatment period, followed by an optional 4 week follow-up period. On-site visits occurred approximately monthly for the first 12 months, followed by every 3 months to assess safety and measures of function.

Arms: arm 1: Drug: Sevasemten
Interventions: intervention 1: Sevasemten
Intervention descriptions: intervention 1: Daily oral dose of 10 mg daily until Visit 8 (Day 57), followed by 15 mg daily until Visit 13 (Month 6), followed by 20 mg until Visit 21 (Month 15), followed by 10 mg daily to Visit 27 (Month 24).

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 1b, Open-label Study of the Safety and Pharmacokinetics of 
EDG-5506 in Adults with Becker Muscular Dystrophy 
Protocol Number: 
EDG-5506-002 
Version Number:  
Amendment 5 (Protocol Version 6) 
Compound: 
EDG-5506 
Brief Title:  
Phase 1b Study of EDG-5506 in Becker Muscular 
Dystrophy 
Study Phase:   
1b 
Sponsor Name:  
Edgewise Therapeutics 
Legal Registered Address: 
3415 Colorado Avenue 
Boulder, CO 80303 
Phone: 720-262-7002 
Regulatory Agency Identifier 
Number(s): 
 
IND 148144 
Approval Date: 
08-MAR-2023
Confidentiality Statement 
This document and accompanying materials contain confidential information belonging to Edgewise 
Therapeutics. Except as otherwise agreed to in writing, by accepting these documents, you agree to hold 
this information in confidence and not copy or disclose it to others (except where required by applicable 
law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, 
Edgewise Therapeutics must be promptly notified. 
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Sponsor Signature Page 
 
 
Study Title: 
A Phase 1b, Open-label Study of the Safety and Pharmacokinetics of EDG-5506 
in Adults with Becker Muscular Dystrophy 
Protocol No.: 
EDG-5506-002 
 
 
By signing below, I affirm that this protocol and the attachments are approved by the clinical 
trial Sponsor, Edgewise Therapeutics, Inc. 
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
Medical Monitor Name and Contact Information 
 
 
 
 
 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Amendment 5 (Version 6.0) 
08-MAR-2023
Amendment 4 (Version 5.0) 
11-OCT-2022
Amendment 3 (Version 4.0) 
02-JUN-2022
Amendment 2 (Version 3.0) 
03-FEB-2022
Amendment 1 (Version 2.0) 
20-DEC-2021
Original Protocol (Version 1.0) 
25-OCT-2021
Amendment 5 (Version 6.0) 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3: 
Schedule of Activities 
Addition of 3- and 6-month 
follow-up blood sample 
collection for those who 
withdraw prior to the Month 24 
visit. 
To follow the time course of 
biomarker response following 
treatment withdrawal 
Section 3: Objectives and 
Endpoints 
Inclusion of Efficacy and 
Clinical Outcomes as 
Tertiary/Exploratory 
Objectives  
To align with statistical analysis 
defined in Section 9 
Section 4.3: Justification for 
Dose 
Section 6.1: Study 
Intervention Administered 
Dose will be reduced from 
20 mg to 10 mg starting at 
Visit 21  
To determine biomarker and 
functional response at a lower dose 
based on emerging data.  
Section 7.2: Participant 
Discontinuation/Withdrawal 
from the Study 
Allow re-enrollment for 
participants who withdraw due 
to non-safety reasons 
Those who withdraw for a non-safety 
reason (e.g., for family planning due 
to contraceptive requirement within 
the study) may return at a later date 
(e.g., once able to comply with 
contraceptive requirements again) 
Global 
In addition, minor changes have been made to the text (addition of detail 
and for clarification), consistent with standard practices, which do not 
significantly change the intent of the document. 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ..............................................................................................................................8 
1.3. 
Schedule of Activities .......................................................................................................9 
2. 
Introduction ...................................................................................................................14 
2.1. 
Study Rationale ...............................................................................................................14 
2.2. 
Background .....................................................................................................................14 
2.2.1. 
Disease Background........................................................................................................14 
2.2.2. 
Overview of EDG-5506 ..................................................................................................14 
2.3. 
Benefit/Risk Assessment ................................................................................................15 
2.3.1. 
Risk Assessment .............................................................................................................15 
2.3.2. 
Benefit Assessment .........................................................................................................15 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................15 
3. 
Objectives and Endpoints ............................................................................................16 
4. 
Study Design ..................................................................................................................18 
4.1. 
Overall Design ................................................................................................................18 
4.2. 
Scientific Rationale for Study Design ............................................................................18 
4.3. 
Justification for Dose ......................................................................................................18 
4.4. 
End of Study Definition ..................................................................................................19 
5. 
Study Population ...........................................................................................................20 
5.1. 
Inclusion Criteria ............................................................................................................20 
5.2. 
Exclusion Criteria ...........................................................................................................20 
5.3. 
Lifestyle Considerations .................................................................................................21 
5.4. 
Screen Failures ................................................................................................................21 
6. 
Study Intervention(s) and Concomitant Therapy ......................................................22 
6.1. 
Study Intervention Administered ....................................................................................22 
6.1.1. 
Administration of EDG-5506 .........................................................................................22 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................22 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................23 
6.4. 
Study Intervention Compliance ......................................................................................23 
6.5. 
Dose Modification ..........................................................................................................23 
6.6. 
Continued Access to Study Intervention after the End of the Study ..............................23 
6.7. 
Treatment of Overdose ...................................................................................................23 
6.8. 
Concomitant Therapy .....................................................................................................24 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................25 
7.1. 
Discontinuation of Study Intervention ............................................................................25 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................25 
7.3. 
Lost to Follow-up............................................................................................................26 
8. 
Study Assessments and Procedures.............................................................................27 
8.1. 
Efficacy and Clinical Outcome Assessments .................................................................27 
8.1.1. 
Functional Assessments ..................................................................................................27 
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8.1.2. 
Clinical Outcome Assessments .......................................................................................28 
8.2. 
Safety Assessments .........................................................................................................29 
8.2.1. 
Physical and Neurological Examinations .......................................................................29 
8.2.2. 
Vital Signs .......................................................................................................................29 
8.2.3. 
Clinical Safety Laboratory Assessments ........................................................................29 
8.2.4. 
Electrocardiograms .........................................................................................................30 
8.2.5. 
Echocardiograms.............................................................................................................30 
8.2.6. 
DXA Assessment ............................................................................................................30 
8.2.7. 
Spirometry.......................................................................................................................30 
8.2.8. 
Oculofacial Assessments ................................................................................................30 
8.2.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................................30 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .........................31 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information ...........................31 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................31 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................31 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................31 
8.3.5. 
Pregnancy ........................................................................................................................32 
8.4. 
Pharmacokinetics ............................................................................................................32 
8.5. 
Genetics and/or Pharmacogenomics ...............................................................................33 
8.6. 
Biomarkers ......................................................................................................................33 
8.7. 
Immunogenicity Assessments.........................................................................................33 
8.8. 
Medical Resource Utilization and Health Economics ....................................................33 
9. 
Statistical Considerations .............................................................................................34 
9.1. 
Statistical Hypotheses .....................................................................................................34 
9.2. 
Sample Size Determination ............................................................................................34 
9.3. 
Analysis Sets ...................................................................................................................34 
9.4. 
Statistical Analyses .........................................................................................................34 
9.4.1. 
General Considerations ...................................................................................................34 
9.4.2. 
Safety Analyses ...............................................................................................................34 
9.4.3. 
Efficacy Endpoints ..........................................................................................................35 
9.4.4. 
Clinical Outcome Endpoints ...........................................................................................35 
9.4.5. 
Biomarkers ......................................................................................................................35 
9.4.6. 
Pharmacokinetics ............................................................................................................36 
9.5. 
Interim Analysis ..............................................................................................................36 
10. 
Supporting Documentation and Operational Considerations ..................................37 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .................................37 
A.1 
Regulatory and Ethical Considerations ...........................................................................37 
A.2 
Financial Disclosure ........................................................................................................37 
A.3 
Informed Consent Process ..............................................................................................37 
A.4 
Data Protection................................................................................................................38 
A.5 
Data Monitoring Committee ...........................................................................................38 
A.6 
Dissemination of Clinical Study Data .............................................................................39 
A.7 
Data Quality Assurance ..................................................................................................39 
A.8 
Source Documents ..........................................................................................................39 
A.9 
Study and Site Start and Closure ....................................................................................40 
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A.10 
Publication Policy ...........................................................................................................40 
Appendix B 
Clinical Laboratory Tests ...................................................................................42 
Appendix C 
AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...............................................................................................43 
C.1 
Definition of AE .............................................................................................................43 
C.2 
Definition of SAE ...........................................................................................................44 
C.3 
Recording and Follow-up of AE and/or SAE .................................................................45 
C.4 
Reporting of SAEs ..........................................................................................................47 
Appendix D 
Abbreviations .....................................................................................................48 
Appendix E 
Protocol Amendment History .............................................................................51 
11. 
References ......................................................................................................................54 
 
List of Figures 
Figure 1 
Study Schema ...................................................................................................... 9 
 
List of Tables 
Table 1 
Schedule of Activities ....................................................................................... 10 
Table 2 
Objectives and Endpoints .................................................................................. 16 
Table 3 
Examples of Prohibited Concomitant Medications ........................................... 24 
Table 4 
Analysis Sets ..................................................................................................... 34 
 
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Objectives 
Endpoints 
− 
Serum cardiac troponin T  
− 
Serum NT-proBNP  
− 
Plasma troponin I tissue-specific isoforms (fast 
skeletal, slow skeletal) 
− 
Plasma SomaScan® proteomics 
• 
To assess the effect of EDG-5506 on 
functional measures in adults with BMD 
• 
Change from baseline in: 
− 
NSAA 
− 
NSAD 
− 
4-stair climb 
− 
100-meter timed test 
• 
To assess the effect of EDG-5506 
treatment on self-reported outcomes in 
adults with BMD 
• 
Change from baseline in: 
− 
PROMIS-57 
− 
ACTIVLIM 
ACTIVLIM = activity limitations for participants with upper and/or lower limb impairments; BMD = Becker 
muscular dystrophy; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; FEV1 = forced 
expiratory volume in 1 second; FVC = forced vital capacity; NT-proBNP = N-terminal prohormone brain natriuretic 
peptide; NSAA = North Star Ambulatory Assessment; NSAD = North Star Assessment for Limb-Girdle Type 
Muscular Dystrophies; PROMIS-57 = Patient-Reported Outcomes Measurement Information System; 
PK = pharmacokinetics; SAE = serious adverse event; AE = adverse event 
Overall Design: 
This is an open-label, single-center, Phase 1b study to assess the safety and PK of EDG-5506 in 
adults with BMD. This study will enroll participants who completed (through Day 42) the first-
in-human study, EDG-5506-001. If necessary, additional (treatment-naïve) participants from 
outside the EDG-5506-001 study may be enrolled to meet the target sample size. 
Number of Participants: 
Enrollment target is based on approximately 8 evaluable participants.  
Intervention Groups and Duration: 
As this is an open-label study all participants will receive EDG-5506. EDG-5506 will be 
administered at a dose of 10 mg orally until Visit 8, a dose of 15 mg to Visit 13, a dose of 20 mg 
to Visit 21, followed by a dose of 10 mg to Visit 27.  
Data Monitoring Committee:  
An Independent Data Monitoring Committee (DMC) is being established to enhance the safety 
of trial participants by providing an independent review of the study data. 
1.2. 
Schema 
The study schema is shown in Figure 1. 
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Figure 1 
Study Schema 
 
1.3. 
Schedule of Activities 
The Schedule of Activities (SoA) is provided in Table 1.  
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Table 1 
Schedule of Activities 
 
Screen 
Open-label Treatment Period 
CSP Section | 
Appendix 
Visit Identifier 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
Days 
Months 
 
Study Day / Month 
-1 
1 
2 
8 
15 
29 
43 
57 
71 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12  
 
Visit Window (Days) 
-2 
0 
0 
±1 
±1 
±3 
±1 
±3 
±3 
±3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Site visit a 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
NA 
Telemedicine video call 
 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
NA 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A.3 
Demography and Medical Hx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NA 
Physical and neuro exam 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
8.2.1 
Weight 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
NA 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NA 
Vital signs c 
X 
X 
X  
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
8.2.2 
Hematology/Chemistry d 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
8.2.3 
Coagulation d 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
8.2.3 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
8.2.3 
Serology e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3 
PK sampling f 
 
X 
X 
 
 
X  
 
X  
 
X  
X 
 
X 
X 
X 
 
X 
 
X 
8.4 
Urine PK 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
8.4 
Biomarker collection 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
8.6 
SomaScan® collection 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
X 
NA 
Dispensing 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
NA 
Dose administration 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
6.1.1 
Accountability 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
6.2 
NSAA and NSAD 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
8.1.1.1 
4-stair climb, 100-m timed test 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
8.1.1.2, 8.1.1.3 
Muscle strength and Hand grip 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
8.1.1.4 
Pedometer 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.1.1.5 
DXA assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
8.2.6 
Cardiac assessment - Echo 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
8.2.5 
Spirometry 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
8.2.7 
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Screen 
Open-label Treatment Period 
CSP Section | 
Appendix 
Visit Identifier 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
Days 
Months 
 
Study Day / Month 
-1 
1 
2 
8 
15 
29 
43 
57 
71 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12  
 
Visit Window (Days) 
-2 
0 
0 
±1 
±1 
±3 
±1 
±3 
±3 
±3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
12-lead electrocardiogram 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
8.2.4 
C-SSRS 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
8.2.9  
ACTIVLIM, PROMIS-57 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
8.1.2.1, 8.1.2.2 
Contraception check 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
NA 
Concomitant medications 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
6.8 
SAE and AE monitoring  
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
8.3 
 
 
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Open-label Treatment Period 
CSP Section | 
Appendix 
Visit Identifier 
20 
21 
22 
23 
24 
25 
26 
27 
F/U g 
ET 3mi 
ET 6mi 
 
Study Monthh 
13.5 
15 
16.5 
 18 
19.5 
21 
22.5 
24/ET b 
25 
 
 
 
Visit Window (Days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±7 
 
Site visit  
 
X 
 
X 
 
X 
 
X 
 
X 
X 
NA 
Telemedicine video call 
X 
 
X 
 
X 
 
X 
 
X 
 
 
NA 
Physical and neuro exam 
 
X 
 
X 
 
X 
 
X 
 
 
 
8.2.1 
Weight 
 
 
 
 
 
 
 
X 
 
 
 
NA 
Height 
 
 
 
 
 
 
 
X 
 
 
 
NA 
Vital signs  
 
X  
 
X 
 
X 
 
X 
 
 
 
8.2.2 
Hematology/Chemistry d 
 
X 
 
X 
 
X 
 
X 
 
 
 
8.2.3 
Coagulation d 
 
 
 
 
 
 
 
X 
 
 
 
8.2.3 
PK sampling  
 
X 
 
X 
  
X 
 
X 
 
X 
 
8.4 
Biomarker collection 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
8.6 
SomaScan® collection 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
NA 
Dispensing 
 
X 
 
X 
 
X 
 
 
 
 
 
NA 
Dose administration 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
 
 
 
 
6.1.1 
Accountability 
 
X 
 
X 
 
X 
 
X 
 
 
 
6.2 
NSAA and NSAD 
 
X 
 
X 
 
X 
 
X 
 
 
 
8.1.1.1 
4-stair climb, 100-m timed test 
 
X 
 
X 
 
X 
 
X 
 
 
 
8.1.1.2, 8.1.1.3 
Muscle strength and Hand grip 
 
X 
 
X 
 
X 
 
X 
 
 
 
8.1.1.4 
DXA assessment 
 
 
 
 
 
 
 
X 
 
 
 
8.2.6 
Cardiac assessment - Echo 
 
 
 
 
 
 
 
X 
 
 
 
8.2.5 
Spirometry 
 
 
 
X 
 
 
 
X 
 
 
 
8.2.7 
12-lead electrocardiogram 
 
 
 
X 
 
 
 
X 
 
 
 
8.2.4 
C-SSRS 
 
 
 
X 
 
 
 
X 
 
 
 
8.2.9  
ACTIVLIM, PROMIS-57 
 
X 
 
X 
 
X 
 
X 
 
 
 
8.1.2.1, 8.1.2.2 
Contraception check 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
 
 
NA 
Concomitant medications 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
 
 
6.8 
SAE and AE monitoring  
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
 
 
8.3 
 
 
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AE = adverse event; ACTIVLIM = measure of activity limitations for patients with upper and/or lower limb impairments; CSP = clinical study protocol; C-SSRS = Columbia Suicide Severity Rating Scale; D = Day; 
DXA = dual-energy X-ray absorptiometry; ET = early termination; m = meter; NA = not applicable; NSAA = North Star Ambulatory Assessment; NSAD = North Star Assessment for Limb Girdle Type Muscular 
Dystrophies; PK = pharmacokinetics; PROMIS-57 = Patient-Reported Outcomes Measurement Information System – 57 items; SAE = serious adverse event; “X” = in-clinic; “→”=continuously 
Screening assessments may be performed over 2 days. 
 
a Day 2 Site visit for Treatment-naïve participants only 
b Early termination laboratory tests and assessments should mimic those of Month 24 however Medical Monitor discretion may be utilized especially if assessments were recently completed. 
Participants who withdraw prior to the Month 24 visit for non-safety reasons may re-enroll under the current protocol, or based on availability, the planned open-label extension study.  
c For treatment-naïve participants vital signs should be assessed 1, 2, 4, and 6 hours post-dose on Day 1 
d All laboratory tests must be performed before functional assessments 
e Serology only collected for participants enrolling from outside EDG-5506-001 
f  Single PK to be collected at each visit, except for Day 1. For treatment-naïve participants Day 1 is a serial collection at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 24 hours post-dose. The last 
timepoint is on Day 2. The dose on Day 2 should be administered only after the 24 hour timepoint. For treatment experienced, Day 1 is pre-dose only. 
g Based on availability, participants may roll over to the planned open-label extension prior to the Month 24 visit after completion of the ET visit. They are not required to perform the safety 
follow-up.  
h Starting at visit 10, study months are defined as 30 days. Monthly visits will be separated by 30 days +/- the visit window. 
i Laboratory collections for participants who withdraw prior to the Month 24 visit.  
 
 
 
 
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2. 
Introduction 
EDG-5506, a first-in-class orally bioavailable, small molecule that selectively inhibits type II fast 
skeletal muscle myosin is being developed for the treatment of Becker muscular dystrophy 
(BMD). 
2.1. 
Study Rationale 
EDG-5506 selectively modulates fast muscle myosin to reduce muscle stress caused by the 
absence of dystrophin. By protecting fast muscle fibers, EDG-5506 can potentially limit muscle 
breakdown and disease progression in muscular dystrophies such as Duchenne muscular 
dystrophy (DMD) and BMD. This open-label study will evaluate the safety, tolerability, and 
pharmacokinetics (PK) of EDG-5506 in participants with BMD who completed the first-in-
human study, EDG-5506-001 and if necessary, additional (treatment-naïve) participants from 
outside the EDG-5506-001 study to meet the target sample size. 
2.2. 
Background 
2.2.1. 
Disease Background 
BMD is an inherited condition that causes progressive weakness and wasting of the skeletal and 
cardiac muscles. Structural impairment of muscle from the genetic truncation of the dystrophin 
protein leads to myofiber membrane stress, hypercontraction, and subsequent degeneration with 
muscle use. Biomarkers of myofiber degeneration can be assessed in vivo with an elevation of 
creatine kinase (CK) and troponin in the blood. Human skeletal muscle consists of both fast (type 
IIa, IIx) and slow (type I) myofibers defined by myosin isoform, a protein integral for muscle 
contraction. In muscular dystrophy, fast (type II) myofibers appear to be particularly susceptible 
to early myofiber degeneration that ultimately proceeds to irreversible loss of muscle function 
with severe disability and early death (Webster 1988). Preventing hypercontraction of fast 
myofibers and therefore circumventing the loss of dystrophin’s structural function may prevent 
myofiber degeneration and preserve skeletal muscle function in BMD. 
2.2.2. 
Overview of EDG-5506 
EDG-5506, which is an allosteric, selective, fast myofiber (type IIa and IIx) myosin inhibitor 
(half-maximal inhibitory concentration [IC50] of 0.4 µM), has been designed to limit the number 
of fast skeletal myosin heads engaged in hypercontraction. EDG-5506 is inactive against slow 
myofiber (type I) myosin (IC50 >100µM), which is present in both skeletal muscle and the heart. 
It is also inactive against the more distantly-related myosin in smooth muscle.  
Nonclinical studies have shown acute prevention of ex vivo muscle injury upon treatment with 
EDG-5506. In dystrophic mouse muscle (mdx), modest force reduction secondary to fast 
myofiber inhibition is coupled to protect against hypercontraction induced force loss, membrane 
rupture, calcium entry, and myofiber degeneration. Single doses of EDG-5506 reduce circulating 
CK after strength or exercise tolerance tests in mdx mice without reducing performance. In 
chronic dosing studies using mdx mice, EDG-5506 reduces exercise-induced CK, decreases the 
appearance of fibrosis in the diaphragm and increases grip strength. In the more fibrotic DBA/2 
mdx mouse (Fukada 2010), chronic administration of EDG-5506 reduces fibrosis in multiple 
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muscle types including the heart. Finally, in dystrophinopathy dogs, a nonclinical model that 
more closely mimics human disease (Kornegay 2017), EDG-5506 reversibly decreases 
circulating CK and increases physical activity, as measured by a wearable device, in short term 
(2-week) dosing studies. 
Overall, results from the first-in-human Phase 1 study, EDG-5506-001, demonstrated that 
EDG-5506 was well tolerated at doses up to 40 mg once daily for 14 days in healthy volunteers 
(n=90) and 20 mg once daily for 14 days in adults with BMD (n=5). In participants treated with 
EDG-5506, reductions in CK and myoglobin were observed.   
A detailed description of the chemistry, pharmacology, efficacy, and safety of EDG-5506 is 
provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of EDG-5506 may be found in the IB.  
2.3.1. 
Risk Assessment 
As of May 8th, 2022, 90 healthy adult volunteers and 12 adults with BMD have received at least 
one dose of EDG-5506. EDG-5506 was well tolerated with no withdrawals due to treatment-
related AEs. The most common AEs were dizziness, drowsiness, and blurred vision.  These were 
self-limiting and generally occurred more frequently early in dosing despite continued increase 
in circulating levels of EDG-5506 later in dosing.  No AE in BMD patients resulted in 
withdrawal or dose-adjustment.  There were no SAEs or severe AEs. 
 
 
 
 
  
2.3.2. 
Benefit Assessment 
A substantial unmet need remains for people diagnosed with BMD. Nonclinical data with 
EDG-5506 have demonstrated improvements in biomarkers and function in mouse and dog 
models of muscular dystrophy, including reduced levels of CK and improved activity. In 
addition, treatment also demonstrated reduced fibrosis of the diaphragm and heart muscles. 
These results suggest that people diagnosed with BMD may benefit from treatment with 
EDG-5506, however, clinical benefit has not yet been investigated in humans. Refer to the IB for 
details. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified in association with EDG-5506 are justified by the anticipated benefits that may be 
afforded to participants with BMD. 
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ACTIVLIM = activity limitations for participants with upper and/or lower limb impairments; BMD = Becker 
muscular dystrophy; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; FEV1 = forced 
expiratory volume in 1 second; FVC = forced vital capacity; NT-proBNP = N-terminal prohormone brain natriuretic 
peptide; NSAA = North Star Ambulatory Assessment; NSAD = North Star Assessment for Limb-Girdle Type 
Muscular Dystrophies; PROMIS-57 = Patient-Reported Outcomes Measurement Information System; 
PK = pharmacokinetics; SAE = serious adverse event; AE = adverse event. 
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4. 
Study Design 
4.1. 
Overall Design 
This is an open-label, single-center, Phase 1b study to assess the safety and PK of EDG-5506 in 
adults with BMD. This study will enroll participants diagnosed with BMD who completed 
(through Day 42) the first-in-human study, EDG-5506-001. If necessary, additional participants 
(treatment naïve) from outside the EDG-5506-001 study may be enrolled to meet the target 
enrollment of 8 evaluable participants (see Section 9.2 for details). 
4.2. 
Scientific Rationale for Study Design 
Prior to the start of this study, EDG-5506 had been administered to a total of 90 healthy 
volunteers and 5 adults with BMD and demonstrated to be well tolerated at doses administered 
up to 40 mg once daily for 14 days in healthy volunteers and 20 mg once daily for 14 days in 
adults with BMD. The half-life of EDG-5506 is estimated to be approximately 18 days in healthy 
volunteers and approximately 7 days in adults with BMD. Pharmacokinetic modeling predicts 
that, in the healthy volunteer population, approximately one half of the steady state plasma 
concentrations are reached after approximately 2 weeks, which was the duration of the 
EDG-5506-001 multiple dose cohorts. In the Becker population approximately seventy five 
percent of steady state concentrations were reached on Day 14 in EDG-5506-001. This study 
aims to characterize the PK up to and including steady state, confirming the safety and 
tolerability observed at higher doses for 14 days, now in the setting of an extended dosing period. 
The study has an open-label design and will enroll participants who completed EDG-5506-001, 
which was randomized and placebo-controlled. In addition, to meet target enrollment, treatment-
naïve participants from outside EDG-5506-001 may be enrolled. Participants will be in clinic on 
Day 1 for initial dosing and assessments. Those participants who were randomized to placebo in 
EDG-5506-001 and treatment-naïve participants from outside the EDG-5506-001 study will 
undergo an additional day of on-site dosing to provide additional observation and PK 
assessments. All participants will continue dosing at home and will be instructed to take 
EDG-5506 at night prior to bedtime. 
4.3. 
Justification for Dose 
In EDG-5506-001, EDG-5506 was well tolerated in healthy volunteers at single doses of up to 
90 mg and once-daily doses of 40 mg for 14 days. All treatment emergent AEs were mild 
(Grade 1 based on DAIDS AE Grading) in multiple dose cohorts receiving up to 40 mg once-
daily for 14 days. In adults with BMD, 20 mg once-daily for 14 days was well-tolerated with the 
most common AEs being dizziness or somnolence.  
Adults with BMD enrolled in Study EDG-5506-001, had an apparent terminal half-life of 
approximately 7 days, suggesting approximately 75% of the steady state concentration was 
reached after 14 days of dosing.  Therefore, exposures at steady state with a daily dose of 15 mg 
in this study are anticipated to be similar to exposures observed in the Study EDG-5506-001 in 
participants with BMD or healthy adult volunteers, at which exposures EDG-5506 was 
well-tolerated with an acceptable safety profile. Participants will initially dose at 10 mg followed 
by 15 mg daily starting at Visit 8 and 20 mg starting at Visit 13. Dosing at 15 mg once-daily 
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continues to be well tolerated in all participants, including dosing of up to 3 months. Therefore, 
dose will be increased to 20 mg to further explore the safety, PK and effects on biomarkers at 
higher exposures. Data was also reviewed by the independent DMC who supported increase to 
20 mg at Visit 13.  
All doses were well tolerated. A near maximal reduction in biomarkers of muscle injury (creatine 
kinase, myoglobin and TNNI2) was seen after treatment with 10 mg, without further meaningful 
reductions observed on escalation to 15 mg or 20 mg. This is consistent with the 10 mg dose 
providing plasma exposures within or above the target therapeutic range observed in animal 
models of disease.  Therefore, at the 15-month visit, participants dose will be changed to 10 mg 
once-daily, and safety, biomarkers and functional measures will continue to be collected and 
analyzed to inform dosing in future trials.   
Since the most common AEs observed in the EDG-5506-001 were somnolence and dizziness, 
participants will be instructed to take EDG-5506 at night prior to bedtime. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in Table 1 Schedule of Activities (SoA) for the last participant in 
the study.  
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Type of Participant and Disease Characteristics 
Participants who have completed Study EDG-5506-001. 
Participants who were not from Study EDG-5506-001 must meet the following: 
a. Male sex at birth and aged 18 to 55 years inclusive at time of consent. 
b. Documented dystrophin mutation with phenotype consistent with BMD. 
c. Ambulatory at Screening (defined as ability to complete 100 meter [m] timed test, 
with or without assistance). 
d. Body weight ≥ 50 kg at the Screening visit. 
e. Body mass index (BMI) between 20 and 34 kg/m2 inclusive. 
2. Sex and Contraceptive/Barrier Requirements 
Female sexual partners of male participants must use highly effective contraception 
(<1% failure rate per year) through 6 months after last dose. 
f. Participants must agree to not donate sperm during the study and for at least 
6 months after last dose. 
3. Informed Consent 
Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any clinically significant changes during or following the completion of Study 
EDG-5506-001 that would affect the potential safety of the participant to receive 
EDG-5506. 
2. Cardiac echocardiogram ejection fraction <45% or New York Heart Association 
(NYHA) Class III or Class IV. 
3. Baseline 12-lead electrocardiogram (ECG) that demonstrates clinically relevant 
abnormalities that may affect participant safety or interpretation of study results. 
4. Forced vital capacity (FVC) predicted <65% or using daytime (mechanical or 
noninvasive) ventilatory support. 
5. Moderate or severe renal or hepatic impairment (eGFR <60 mL/min/1.73 m2).  
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6. Positive test for hepatitis C antibody (unless negative HCV PCR), hepatitis B surface 
antigen, or human immunodeficiency virus (HIV) antibody at screening. 
Prior/Concomitant Therapy 
7. History of substance abuse or dependency. 
8. Receipt of oral corticosteroids for >5 days in the previous 6 months at a dose of >5 mg 
equivalent per day. Lower oral doses or inhaled/intranasal steroids are permitted. 
9. Receiving moderate or strong cytochrome P450 CYP3A4 inhibitors or inducers. 
10. Participation in any other investigational drug study or use of use of an investigational 
drug within 30 days or 5 half-lives (whichever is longer) of dosing in the present study. 
Other Exclusions 
11. Participants who are unlikely to comply with the study protocol or, in the opinion of 
the Investigator, would not be a suitable candidate for participation in the study. 
12. Medical history or other medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation/behavior or laboratory result or abnormality that 
may increase the risk of study participation or, in the Investigator’s judgment, make the 
participant inappropriate for the study. Includes venous access that would be too 
difficult to facilitate repeated blood sampling.  
5.3. 
Lifestyle Considerations 
EDG-5506 may cause dizziness or drowsiness and so may impair the mental and/or physical 
ability required for the performance of potentially hazardous tasks. Participants should be 
cautioned about operating hazardous machinery, including automobiles, until they are reasonably 
certain that the drug treatment does not affect them adversely. Initial advice is to not drive a 
motor vehicle or undertake potentially dangerous work. This will be reassessed based on 
discretion of the Investigator at the Day 29 visit. However, participants should be reminded not 
to drive if, at any time, they feel impaired during the study. 
 
 
 
  
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study may be retested or 
rescreened.  
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as the investigational intervention, EDG-5506, intended to be 
administered to a study participant according to this study protocol. 
6.1. 
Study Intervention Administered 
Intervention name 
EDG-5506 
Type 
Drug 
Dose formulation 
Tablet  
Unit dose strengths 
2.5 mg or 10 mg 
Dosage level(s) 
10 mg daily until Visit 8 followed by 15 mg daily until Visit 13 
followed by 20 mg until Visit 21 followed by 10 mg daily 
Route of administration 
Oral 
Use 
Investigational 
Packaging and labeling 
Provided in HDPE containers with child-resistant screw caps  
Storage 
15ºC to 30ºC  
HDPE = high density polyethylene 
6.1.1. 
Administration of EDG-5506 
EDG-5506 will be provided as a 2.5 mg or 10 mg tablet. It should be taken at night prior to 
bedtime, with or without food. Time of dose will be recorded in the participant diary through the 
Month 12 visit, at that point only time of dose the night prior to PK collections are required.  
Refer to the Pharmacy Manual for information about missed doses. 
Treatment-experienced participants will take the first dose of EDG-5506 at the site, in the 
morning on Day 1 to support the PK collection. Participants will continue dosing at home, 
starting in the evening on Day 2.  
Treatment-naïve participants will take the first dose of EDG-5506 at the site in the morning on 
Day 1 and return to the site on Day 2 to complete the last PK timepoint before taking the second 
dose. Participants will remain at the site on Day 2 to be observed for a minimum of 2 hours post 
dose. Participants will continue dosing at home, starting in the evening on Day 3 after travel 
home from the site has been completed. 
6.2. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
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The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; hence, there will be no randomization or blinding. The participant 
will be assigned EDG-5506 using interactive response technology (IRT). The site will contact 
the IRT prior to the start of study intervention administration for each participant.  
6.4. 
Study Intervention Compliance 
When participants self-administer study intervention(s) at home, compliance will be assessed at 
each site visit. Compliance will be assessed by direct questioning and counting returned tablets 
and will be documented in the source documents and relevant forms. Deviation(s) from the 
prescribed dosage regimen will be recorded. In addition to each site visit, telehealth calls, which 
will occur throughout the study as noted in the SoA, will include a compliance check on 
EDG-5506 administration. 
A record of the quantity of EDG-5506 dispensed to and administered by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded. 
6.5. 
Dose Modification 
Dose modifications will be permitted following discussion with the Medical Monitor. This may 
include changes to dose or frequency of administration.  
6.6. 
Continued Access to Study Intervention after the End of the Study 
Following completion of the treatment period, an open-label extension study may be available 
for participants to continue receiving treatment with EDG-5506, pending approval by appropriate 
ethics committees and regulatory authorities. 
6.7. 
Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
• 
Contact the Medical Monitor immediately. 
• 
Evaluate the participant to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
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6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be reviewed by the Investigator and recorded in the 
source documents along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Use of strong or moderate CYP3A4 inhibitors or inducers, and examples, not intended to be 
exhaustive, are listed in Table 3. Potential interactions of EDG-5506 metabolites with 
transporters have not been studied, so narrow therapeutic index sensitive substrates of 
transporters are prohibited during the study. All medications will be recorded as concomitant 
medications. 
Table 3 
Examples of Prohibited Concomitant Medications 
Enzyme 
Strong 
Moderate 
CYP Inhibitors 
CYP3A4 
Echinacea, grapefruit juice, 
itraconazole, ketoconazole, 
voriconazole, clarithromycin, 
nefazodone, milk thistle 
Ciprofloxacin, diltiazem, 
dronedarone, erythromycin, 
fluconazole, fluvoxamine, 
verapamil, cimetidine 
CYP Inducers 
CYP3A4 
Carbamazepine, phenytoin, 
rifampin, St. John’s wort, 
barbiturates, modafinil 
Etravirine, phenobarbital, 
primidone 
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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
Individual dosing may be stopped until safety information can be reviewed in the event that: 
•
A subject experience an SAE that is considered related to EDG-5506
Because the transaminases ALT and AST that are typically followed to detect hepatotoxicity are 
elevated in BMD, the liver specific transaminase glutamate dehydrogenase will be followed 
(Schomaker 2020).  The following criteria will be used. 
Dosing will be paused for an individual until safety information is reviewed and drug induced 
liver injury is ruled out in the event that: 
•
Total bilirubin > 2.0 X ULN, or if baseline bilirubin is > ULN, an increase from baseline
value by an amount of at least 1 X ULN
AND either 
•
GLDH is > 2.5 X ULN (10 U/L)
OR 
•
ALT is increased by an absolute amount equal to 2.5 X the ULN with no corresponding
increase in CK to suggest muscle origin
The participant should be further evaluated as soon as possible, preferably within 48 hours from 
awareness of the abnormal results. This evaluation should include detailed history, physical 
assessment, and laboratory assessments, including at least AST, ALT, albumin, CK, direct and 
indirect bilirubin, GGT, PT/INR, and alkaline phosphatase. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. Discontinuation of study intervention does not imply withdrawal from the study. 
If study intervention is permanently discontinued, the participant may remain in the study to be 
evaluated. See the SoA (Table 1) for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
•
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon.
•
At the time of study discontinuation, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Table 1). See the SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to 
be completed.
•
The participant will be permanently discontinued both from the study intervention and 
from the study at that time. However, participants who withdraw for non-safety reasons 
may re-enroll (e.g., for family planning due to contraceptive requirement within the 
study)
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and may return at a later date (e.g., once able to comply with contraceptive requirements 
again). 
•
If the participant withdraws consent for disclosure of future information, the Sponsor
may retain and continue to use any data collected before such a withdrawal of consent.
•
If a participant withdraws from the study, he/she may request destruction of any samples
taken and not tested, and the Investigator must document this in the site study records.
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue in
the study.
•
Before a participant is deemed lost to follow-up, the Investigator or designee must make
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record.
Discontinuation of specific sites or of the study as a whole is described in Appendix A. 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers or 
exemptions are not permitted. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA. 
8.1. 
Efficacy and Clinical Outcome Assessments 
Planned time points for all efficacy and clinical outcome assessments are provided in the SoA 
(Table 1). 
8.1.1. 
Functional Assessments 
The functional assessments are briefly described below. Refer to the Clinical Evaluator Manual 
for details.  
8.1.1.1. 
NSAA and NSAD 
The North Star Ambulatory Assessment (NSAA) and North Star Assessment for Limb Girdle 
Type Muscular Dystrophies (NSAD) have substantial overlap, with almost all NSAA 
assessments being included in the NSAD. The NSAD includes assessments that are harder than 
the most difficult NSAA assessments and that are easier than the easiest NSAA assessments, and 
therefore decreases the likelihood of either a ceiling or a floor effect for the NSAA. To maintain 
the integrity of the NSAA, the assessments will be performed as a single sequence following the 
order of the NSAA so identical assessments will not be repeated. Assessments that are unique to 
the NSAD, starting with the easiest, will be performed after all NSAA assessments are complete.  
NSAA 
The NSAA is a 17-item test that grades performance of various functional skills from 0 (unable 
to perform), 1 (completes independently but with modifications), and 2 (complete without 
compensation) (Mazzone 2009). The NSAA also includes 2 timed functional tests: rise from 
floor and run 10 meters. The NSAA has been found to correlate with the 6-minute walk test and 
other functional outcomes in boys with DMD (Mazzone 2009). 
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NSAD 
The NSAD is a functional scale specifically designed to measure motor performance in 
individuals with limb-girdle muscular dystrophy and is being evaluated in BMD due to the 
similar limb-girdle pattern of weakness (Jacobs 2021). The NSAD consists of 29 items that are 
considered clinically relevant items from the adapted NSAA and the Motor Function Measure 
20 with a maximum score of 54 and higher scores indicating higher functional abilities.  
8.1.1.2. 
4-Stair Climb 
The 4-stair climb test (with or without the use of handrails) quantifies in seconds the time 
required for a participant to ascend 4 standard steps. The method the participant uses (e.g., using 
the handrails) to climb the stairs is recorded to understand any change in technique that occurs 
over time, however, at no time is the participant instructed on the preferred method (with or 
without the use of handrails) used to perform this test.  
8.1.1.3. 
100-Meter Timed Test 
The participant will be asked to complete 4 laps on a 25 meter track, for a total of 100 meters 
as quickly and safely as possible, running if able, and the time recorded in seconds.  
8.1.1.4. 
Muscle Strength Testing and Hand Grip Strength 
Muscle strength testing will include assessment of knee extension and flexion and elbow 
extension and flexion and hand grip strength. Muscle testing will be performed using a hand-held 
dynamometer. Knee myometry will be performed while the participant is in a sitting position 
with knee and hip flexed at 90 degrees. Elbow myometry will be performed while the participant 
is positioned supine with arm at the side and elbow flexed at 90 degrees.  
8.1.1.5. 
Pedometer 
To measure daily activity, participants will wear a pedometer daily during waking hours as listed 
the SoA. The pedometer will be returned to the site at each visit for data upload and returned to 
the participant for wear through the open-label treatment period to Visit 19. Data may also be 
collected during telemedicine video calls in between site visits. Participants will be instructed to 
document daily step count in the participant diary.   
8.1.2. 
Clinical Outcome Assessments 
8.1.2.1. 
ACTIVLIM 
This patient-reported measure of activity limitations is to assess individuals with upper and/or 
lower limb impairments (ACTIVLIM), which measures the ability to perform daily activities.  
8.1.2.2. 
PROMIS-57 
The Patient-Reported Outcomes Measurement Information System (PROMIS) is a set of 
57 patient-reported measures developed by a National Institute of Health and evaluates 
physical, mental, and social health.  
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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.2.1. 
Physical and Neurological Examinations 
A physical examination will include head, ears, eyes, nose, mouth, skin, heart and lung, lymph 
nodes, and gastrointestinal and musculoskeletal systems. A neurological examination will also be 
conducted to include upper and lower limb tone, power, reflexes and examination of cranial 
nerves II-XII (excluding ophthalmoscopy).  
Abnormal findings will be further characterized as clinically significant or not clinically 
significant for the purposes of reporting as AEs. 
8.2.2. 
Vital Signs 
Supine blood pressure (BP), pulse rate, respiratory rate, and temperature will be measured. 
Unscheduled collection times will be permitted, as necessary, to ensure appropriate collection of 
safety data. 
Supine blood pressure will be measured with the participant’s arm supported at the level of the 
heart and recorded to the nearest mmHg after at least 5 minutes of rest. Whenever possible, the 
same arm (preferably the dominant arm) should be used throughout the study. 
Wherever possible, the same size blood pressure cuff, which has been properly sized and 
calibrated, will be used to measure blood pressure each time. The use of automated devices for 
measuring blood pressure and pulse rate are acceptable, although, when done manually, pulse 
rate will be measured in the brachial/radial artery for at least 30 seconds. 
8.2.3. 
Clinical Safety Laboratory Assessments 
Refer to Appendix B for the list of clinical laboratory tests to be performed. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or Medical Monitor.  
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. 
All protocol-required laboratory tests, as defined in Appendix B, must be conducted in 
accordance with the laboratory manual and the SoA (Table 1). 
If laboratory values from non-protocol specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
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significant by the Investigator (e.g., SAE or AE or dose modification), then the results must be 
recorded. 
8.2.4. 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. All ECGs should be performed after 
the participant has rested quietly for at least 10 minutes in a supine position. 
At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. 
8.2.5. 
Echocardiograms 
Echocardiographic examinations will be performed by a qualified individual (sonographer) at the 
site to evaluate left-ventricular systolic and diastolic function, geometry, and mass, as well as 
left-atrial and right-ventricular function and geometry via two-dimensional, doppler, and/or 
speckle-tracking imaging techniques. Valvular competence, including presence or absence of 
regurgitation, will be evaluated and quantified, while overall cardiac health will be qualitatively 
evaluated (e.g., presence/absence of pericardiac effusion). Echocardiograms will be read locally 
at the site to satisfy inclusion requirements and ensure the safety of the participants; however, 
examinations may also be stored, reviewed, and/or analyzed centrally. 
8.2.6. 
DXA Assessment 
Dual-energy X-ray absorptiometry (DXA) will collect measures of total lean body mass, fat 
mass, and bone mineral density. The DXA assessment should be performed consistent with 
clinical practice. 
8.2.7. 
Spirometry 
Spirometry will be performed using a calibrated spirometer device to measure the forced vital 
capacity percentage (FVC%) predicted for the participant. 
The predicted FVC% and the largest FVC will be recorded at each time point. The predicted 
FVC% will be pulled against the third National Health and Nutrition Examination Survey 
(NHANES III) (Centers for Disease 1994). 
8.2.8. 
Oculofacial Assessments 
Examination of cranial nerves II-XII will be performed as part of the neurological examination at 
the time points specified in the SoA. 
8.2.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire used for suicide assessment developed by multiple institutions, 
including Columbia University, with National Institute of Mental Health support. The scale is 
evidence-supported and is part of a national and international public health initiative involving 
the assessment of suicidality. 
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8.3. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix C. 
Adverse events will be reported by the participant. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix C. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Table 1). 
All AEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Table 1). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix C. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor within 24 hours of awareness. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 
 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, the participant is lost to follow-up, or until the condition 
becomes chronic in nature (as defined in Section 7.3). Further information on follow-up 
procedures is provided in Appendix C. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
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• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review Investigator Site Files and notify the IRB/IEC, if appropriate, according to local 
requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. Expedited reporting within 7 days will be made for events 
deemed life threatening or death. For all other serious events, reporting shall occur within 
15 days. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected after 
the start of study intervention and until the time period for reporting pregnancies aligns 
with the time period for post-intervention contraception determined in Section 5.1. 
• 
If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy of the female partner of the participant (after obtaining the necessary signed 
informed consent from the female partner). 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• 
The pregnant female partner of the participant will be followed to determine the outcome 
of the pregnancy. The Investigator will collect follow-up information on the pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants’ pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting. 
8.4. 
Pharmacokinetics 
Samples will be collected for measurement of concentrations of EDG-5506 and metabolites of 
EDG-5506 as specified in the SoA (Table 1).  
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8.5. 
Genetics and/or Pharmacogenomics 
Genetics are not evaluated in this study. 
8.6. 
Biomarkers 
• 
Samples for biomarker research will be collected from all participants in this study as 
specified in the SoA. 
• 
Biomarker samples will be used for analysis of fast and slow skeletal troponin I, cardiac 
troponin I, cardiac troponin T, NT-proBNP, myoglobin, and creatine kinase. 
• 
In addition, these biomarker samples will be stored and used for biomarker research 
related to pathophysiology of muscular dystrophies.  
• 
No samples for genetic, genomic, or RNA analysis will be taken. 
• 
SomaScan® proteomics analysis will be performed to identify potential biomarkers and 
include evaluation of association under exploratory endpoints.  
8.7. 
Immunogenicity Assessments 
Not applicable. 
8.8. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
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overall, by maximum severity, and by relationship to EDG-5506. Serious adverse events will 
also be summarized. 
The change from baseline in the following safety endpoints will be summarized at each 
scheduled assessment time point using descriptive statistics: 
• Safety laboratory parameters 
• Vital signs 
• Physical and neurological examination 
• ECG parameters 
• LVEF as assessed by cardiac echogram 
• Pulmonary function as assessed by FEV1, FVC 
• C-SSRS 
9.4.3. 
Efficacy Endpoints 
The change from baseline in the following efficacy endpoints will be summarized at each 
scheduled assessment time point using descriptive statistics: 
• NSAA 
• NSAD 
• 4-stair climb 
• 100-meter timed test 
• Muscle strength testing 
9.4.4. 
Clinical Outcome Endpoints 
The change from baseline in the following efficacy endpoints will be summarized at each 
scheduled assessment time point using descriptive statistics: 
• ACTIVLIM 
• PROMIS-57 
9.4.5. 
Biomarkers 
The change from baseline in the following efficacy endpoints will be summarized at each 
scheduled assessment time point using descriptive statistics: 
• Serum CK 
• Serum cardiac troponin I 
• Serum myoglobin 
• Serum cardiac troponin T  
• Serum NT-proBNP  
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• Plasma troponin I tissue-specific isoforms (fast skeletal, slow skeletal) 
• Plasma SomaScan® proteomics  
9.4.6. 
Pharmacokinetics 
Treatment-experienced participants: Exposures will be summarized using descriptive 
statistics at each time point collected. Additional PK analysis may be done outside of the clinical 
study report (CSR). 
Treatment-naïve participants: For Day 1, standard PK parameters endpoints will be estimated 
and summarized using descriptive statistics based on the PK Evaluable Population.  
Exposures will be summarized using descriptive statistics at each time point collected. 
Additional PK analysis may be done outside of the CSR. 
9.5. 
Interim Analysis 
No formal interim analysis is planned. 
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10. 
Supporting Documentation and Operational Considerations 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations 
A.1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• 
Protocols and any substantial amendments to the protocol will require health authority 
approval (per local regulations) prior to initiation except for changes necessary to 
eliminate an immediate hazard to study participants. 
• 
The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
and all other applicable local regulations 
A.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study. 
A.3 
Informed Consent Process 
• 
The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
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21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
A.4 
Data Protection 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
A.5 
Data Monitoring Committee 
The Sponsor is establishing a DMC to enhance the safety of trial participants by providing an 
independent review of study data. 
The DMC shall be comprised of a minimum of 3 experts, including a neurologist, who are 
independent of the Sponsor study team. 
The DMC Charter for this study will define the exact membership, and who should be present 
for decisions to be made, how reviews will be performed, and how discussions will be 
documented. 
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A.6 
Dissemination of Clinical Study Data 
A description of this clinical study will be available on clinicaltrials.gov as will the summary of 
the study results when they are available. The clinical study and/or summary of study results may 
also be available on other websites according to the regulations of the countries in which the 
study is conducted. 
A.7 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic Case 
Report Forms (CRF/eCRF) unless transmitted to the Sponsor or designee electronically 
(e.g., laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
• 
Guidance on completion of CRFs will be provided in Case Report Completion 
Guidelines.  
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan  
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 2 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
A.8 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
A.9 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor 's procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the Investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up 
A.10 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
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The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
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Appendix B 
Clinical Laboratory Tests 
 
Chemistries 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine phosphokinase 
Creatinine 
Cystatin C 
Gamma-glutamyl transferase 
Glucose 
Glutamate dehydrogenase 
Lactate dehydrogenase 
Magnesium Phosphorus 
Potassium 
Sodium 
Total bilirubin 
(Reflex: Direct, indirect bilirubin) 
Total protein 
Triglycerides 
Uric acid 
 
Coagulation 
Prothrombin time/Partial 
thromboplastin time 
Hematology (CBC) 
Reticulocytes (%)  
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count  
White blood cell count 
White blood cell differential 
(Percentage and absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Urinalysis (UA) 
Bilirubin 
Color and appearance  
Glucose 
 Ketones 
Leukocytes 
Microscopica (includes RBC and 
WBC) 
Nitrite  
Occult blood 
pH 
Protein  
Specific 
gravity 
Urobilinogen 
Biomarkers 
Proteomics platform assessment 
(SomaScan® Assay) 
Troponin I (cardiac, slow skeletal, and 
fast skeletal) 
Myoglobin, and CK 
Cardiac Troponin 
T 
NT-proBNP 
 
Other Tests (Participants from 
outside EDG-5506-001 only):  
 HBsAg  
HCVAb (reflex if positive HCV RNA) 
HIVAb 
 
CBC = complete blood count; CK = creatine kinase; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; 
HCVAb = hepatitis C virus antibody; HIVAb = human immunodeficiency virus antibody; RBC = red blood cell; 
RNA = ribonucleic acid; WBC = white blood cell    
 
a Urine microscopy will be conducted only as a reflex test following abnormal urinalysis results. 
 
 
 
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Appendix D 
Abbreviations  
Abbreviation 
Definition/Explanation 
µM 
micromolar 
ACTIVLIM 
activity limitations for patients with upper and/or lower limb impairments 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-24 
Area under the plasma concentration-time curve from time zero to 24 hours 
BMD 
Becker muscular dystrophy 
BMI 
body mass index 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CRF 
case report form 
CSP 
clinical study protocol 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
D 
day 
DAIDS 
Division of Allergy and Infectious Diseases 
DMC 
Data Monitoring Committee 
DMD 
Duchenne muscular dystrophy 
DXA 
dual-energy X-ray absorptiometry 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ET 
end of treatment 
ECG 
electrocardiogram 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
FVC% 
forced vital capacity percentage 
GCP 
Good Clinical Practice 
GLDH 
glutamate dehydrogenase 
GGT 
gamma-glutamyl transferase 
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Abbreviation 
Definition/Explanation 
HBsAg 
hepatitis B surface antigen 
HDPE 
high density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
HIVAb 
human immunodeficiency virus antibody 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
kg 
kilogram 
LVEF 
left ventricular ejection fraction 
m 
meter 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
min 
minute 
mL 
milliliter 
ng 
nanogram 
NHANES III 
Third National Health and Nutrition Examination Survey 
NSAA 
North Star Ambulatory Assessment  
NSAD 
North Star Assessment for Limb Girdle Type Muscular Dystrophies 
NT-proBNP 
N-terminal prohormone brain natriuretic peptide 
NYHA 
New York Heart Association 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic(s) 
PR 
PR interval 
PROMIS-57 
Patient-Reported Outcomes Measurement Information System – 57 items  
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Abbreviation 
Definition/Explanation 
PT 
prothrombin time 
QRS 
QRS complex 
QT 
QT interval 
QTc 
QT interval corrected 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAD 
single ascending dose 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
TEAE 
treatment-emergent adverse event 
U/L 
units per liter 
ULN 
upper limit of normal 
WBC 
white blood cell 
 
 
 
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Appendix E 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
Amendment 4 (Version 5.0): 11 October 2022 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of Activities 
Treatment period has been 
extended from 12 months to 
24 months 
To support continued access with long-
term data collection of safety and 
biomarker data with EDG-5506 
Section 6.1 Study 
Intervention Administered 
Addition of 10 mg tablet 
strength 
To reduce tablet burden by minimizing 
the quantity to achieve the dose 
Global 
In addition, minor changes have been made to the text (addition of detail 
and for clarification), consistent with standard practices, which do not 
significantly change the intent of the document. 
Amendment 3 (Version 4.0): 02 June 2022 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1: Intervention 
Groups and Duration 
 
Section 4.3  
Justification for Dose 
 
Section 6.1  
Study Intervention 
Administered 
Dose will be escalated from 
15 mg to 20 mg starting at Visit 
13. 
To further explore the safety, PK and 
effects on biomarkers at higher 
exposures. 
Section 1.3 
Schedule of Activities 
Visit 14 telemedicine video call 
becomes a site visit.  
 
Functional measure and clinical 
outcome assessment collection 
added at Visit 13  
To collect 1 month safety, PK, and 
biomarker data after 20 mg dose 
escalation. 
To assess change from 20 mg dose 
escalation 
Global 
In addition, minor changes have been made to the text (addition of detail 
and for clarification), consistent with standard practices, which do not 
significantly change the intent of the document. 
 
 
 
 
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Amendment 2 (Version 3.0): 03 February 2022 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1: Intervention 
Groups and Duration 
 
Section 4.3  
Justification for Dose 
 
Section 6.1  
Study Intervention 
Administered 
Dose will be escalated from 
10 mg to 15 mg starting at 
Visit 8. 
Based on additional PK data from the 
Phase 1 Study EDG-5506-001, exposures 
at steady state with a daily dose of 15 mg 
in this study are anticipated to be similar to 
well-tolerated exposures observed in the 
Study EDG-5506-001 in participants with 
BMD or healthy adult volunteers, which 
supports an increase from 10 mg to 15 mg 
QD at Visit 8 (after 2 months at 10 mg).  
Section 6.8  
Concomitant 
Medications 
Removal of the requirement 
for concomitant medications 
to be approved by the 
Medical Monitor to allow 
review to be performed by the 
Investigator.   
Permit assessment to be completed by the 
Investigator.   
Section 1.3  
Schedule of Activities 
 
Section 8.1.1.5 
Pedometer 
 
Add pedometer data 
collection during 
telemedicine video calls 
starting at Visit 12. 
Permit pedometer data to be collected in-
between site visits during telemedicine 
video calls to account for larger visit 
windows. 
Global 
In addition, minor changes have been made to the text (addition of detail 
and for clarification), consistent with standard practices, which do not 
significantly change the intent of the document. 
 
 
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Amendment 1 (Version 2.0): 20 December 2021 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3: Schedule of 
Activities 
The PK collection and biomarker 
labs have been removed from 
visits: V5, V7, V9 
To align with site visits 
Height added at V1 
To allow BMI calculation and forced 
vital capacity percentage 
Spirometry moved from V2 to V1 
To use for eligibility 
Treatment period has been 
extended from 3 months to 12 
months  
To support long-term data collection of 
safety and biomarker data with EDG-
5506 
Section 4.2: Scientific 
Rationale for Study 
Design 
Section 4.3: Justification 
for Dose 
Section 6.1: Study 
Intervention 
Administered 
Dose has been updated from 
loading dose of 10 mg and 
maintenance dose of 7.5 mg to 
dose of 10 mg throughout open-
label treatment period  
Based on emerging data from the 
EDG-5506-001 study, the half-life of 
EDG-5506 is shorter in adults with 
BMD, approximately 7 days compared 
with 18 days in healthy volunteers. 
Steady-state concentrations at a dose 
of 10 mg are anticipated to be less than 
those previously evaluated at 20 mg 
once daily for 14 days in EDG-5506-
001 in participants with BMD.  
Section 5.1, 5.2: 
Inclusion/Exclusion 
Criteria 
Updated Sex and Contraceptive 
Requirements to include sperm 
donation restrictions 
To provide more robust guidance 
around contraceptive requirements  
Removed reference to Day 42 
labs for those previously enrolled 
in EDG-5506-001.  
Screening labs will be used to 
determine eligibility for all participants  
Global 
In addition, minor changes have been made to the text (addition of detail 
and for clarification), consistent with standard practices, which do not 
significantly change the intent of the document. 
 
 
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11. 
References 
Centers for Disease Control and Prevention. (1994). "National Health and Nutrition Examination 
Survey (NHANES III (1988-1994))." from 
https://wwwn.cdc.gov/nchs/nhanes/nhanes3/Default.aspx?CDC_AA_refVal=https%3A%2F%2F
www.cdc.gov%2Fnchs%2Fnhanes%2Fnh3data.htm. 
Fukada, S., D. Morikawa, Y. Yamamoto, T. Yoshida, N. Sumie, et al. (2010). Genetic 
background affects properties of satellite cells and mdx phenotypes. Am J Pathol, 176(5): 2414-
2424. 
Jacobs, M., M. K. James, L. P. Lowes, L. N. Alfano, M. Eagle, et al. (2021). Assessing 
Dysferlinopathy Patients Over Three Years With A New Motor Scale. Ann Neurol. 
Kornegay, J. N. (2017). The golden retriever model of Duchenne muscular dystrophy. Skelet 
Muscle, 7(1): 9. 
Mazzone, E. S., S. Messina, G. Vasco, M. Main, M. Eagle, et al. (2009). Reliability of the North 
Star Ambulatory Assessment in a multicentric setting. Neuromuscul Disord, 19(7): 458-461. 
Schomaker, S., D. Potter, R. Warner, J. Larkindale, N. King, et al. (2020). Serum glutamate 
dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle 
impairments. PLoS One, 15(5): e0229753. 
Webster, C., L. Silberstein, A. P. Hays and H. M. Blau (1988). Fast muscle fibers are 
preferentially affected in Duchenne muscular dystrophy. Cell, 52(4): 503-513. 
 
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SAP_001.pdf: 
Edgewise Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
EDG-5506-002 
 Version 1.0; 09Feb2024 
Page 1 of 20 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
A Phase 1b, Open-label Study of the Safety and 
Pharmacokinetics of EDG-5506 in Adults with Becker 
Muscular Dystrophy 
Protocol Number: 
EDG-5506-002 
Protocol Version/Date: 
V6, Amendment 5 / 08MAR2023 
Phase: 
Ib 
Investigational Product: EDG-5506 
Regulatory Agency 
Identifier: 
IND148144 
Sponsor: 
Edgewise Therapeutics 
1715 38th Street 
Boulder, CO 80301 
United States of America 
SAP Version/Date: 
1.0 / 09Feb2024 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of Edgewise Therapeutics except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical study for Edgewise Therapeutics. 
Disclosure of the contents of this document to the Institutional Review Board or Independent 
Ethics Committee and study personnel directly involved with conducting this protocol is allowed. 
Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Edgewise Therapeutics and that the information contained herein 
may not be further disclosed to third parties. 


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Statistical Analysis Plan 
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Version 1.0; 09Feb2024 
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SIGNATURE PAGE 
Protocol Title: 
A Phase 1b, Open-label Study of the Safety and 
Pharmacokinetics of EDG-5506 in Adults with Becker 
Muscular Dystrophy 
 
Protocol Number: 
EDG-5506-002 
SAP Version/Date: 
1.0 / 09Feb2024 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 Date 
 
  
 
 
 
 
 


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Statistical Analysis Plan 
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Version 1.0; 09Feb2024 
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VERSION HISTORY 
  
Version 
Version Date 
Description 
0.1 
07Mar2023 
First draft version. 
1.0 
09Feb2024 
Final version. 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 7 
2 
Study Overview ................................................................................................................... 7 
2.1 
Rationale and Design ................................................................................................... 7 
2.2 
Study Objectives and Endpoints .................................................................................. 7 
2.3 
Randomization and Blinding ........................................................................................ 8 
2.4 
Study Drug Administration ........................................................................................... 8 
2.5 
Sample Size Determination .......................................................................................... 9 
3 
Statistical Methodology ....................................................................................................... 9 
3.1 
General Considerations and Key Definitions ................................................................ 9 
3.1.1 
Study Enrollment .................................................................................................. 9 
3.1.2 
Analysis Day ......................................................................................................... 9 
3.1.3 
Definition of Baseline (BL)..................................................................................... 9 
3.1.4 
Change-from-Baseline (CFB) ...............................................................................10 
3.1.5 
Summary Statistics ..............................................................................................10 
3.1.6 
Hypothesis Testing ..............................................................................................10 
3.1.7 
Handling of Dropouts and Missing Data ...............................................................10 
3.1.8 
Treatment-Emergent Adverse Event (TEAE) .......................................................11 
3.2 
Analysis Populations ...................................................................................................11 
3.2.1 
Safety Population (SAF) ......................................................................................11 
3.2.2 
PK-Evaluable Population (PKP) ...........................................................................11 
3.3 
Subject Data and Study Conduct ................................................................................11 
3.3.1 
Patient Disposition and Withdrawals ....................................................................11 
3.3.2 
Demographic and Baseline (BL) Characteristics ..................................................12 
3.3.3 
Medical History ....................................................................................................12 
3.3.4 
Concomitant Medications .....................................................................................12 
3.3.5 
Protocol Deviations ..............................................................................................13 
3.3.6 
Study Drug Exposure and Compliance ................................................................13 
3.4 
Clinical and Functional Assessments ..........................................................................13 
3.4.1 
Functional Assessments ......................................................................................13 
3.4.2 
Clinical Outcomes ................................................................................................13 
3.4.3 
Subgroups ...........................................................................................................14 
3.5 
Safety Assessment .....................................................................................................14 
3.5.1 
Adverse Events (AEs) ..........................................................................................14 
3.5.2 
Physical and Neurological Examinations ..............................................................15 
3.5.3 
Clinical Laboratory Assessments .........................................................................15 
3.5.4 
Vital Signs ............................................................................................................15 
3.5.5 
Electrocardiograms (ECGs) .................................................................................16 
3.5.6 
Dual-energy X-ray Absorptiometry (DXA) Assessment ........................................16 


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3.5.7 
Spirometry ...........................................................................................................16 
3.5.8 
Other Safety Assessments ...................................................................................16 
3.6 
Pharmacokinetics (PK) ...............................................................................................16 
3.7 
Biomarkers .................................................................................................................16 
3.8 
Interim Analysis ..........................................................................................................17 
4 
Data Monitoring Committee (DMC) ....................................................................................17 
5 
Changes from Protocol-Specified Statistical Analyses .......................................................17 
6 
Programming Specifications ..............................................................................................17 
Appendix A:    Tables, Listings and Figures ..............................................................................18 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
BL 
Baseline 
BMD 
Becker Muscular Dystrophy 
CFB 
Change-from-baseline 
CK 
Creatine kinase 
CRF 
Case report form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NT-proBNP 
N-terminal prohormone brain natriuretic peptide 
PK 
Pharmacokinetics 
PKP 
Pharmacokinetics population 
PT 
Preferred Term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety population 
SAP 
Statistical Analysis Plan 
SI 
International System 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TFT 
Timed Function Test 
TLF 
Tables, Listings, Figures 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number EDG-
5506-002. This document is based on Protocol Amendment 4 (Protocol Version 5) dated 
11October2022. This SAP supersedes the statistical considerations identified in the study 
protocol; where considerations are substantially different, they will be so identified. The SAP will 
be finalized prior to database lock. Any deviations from or revisions to the SAP after database 
lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Rationale and Design 
EDG-5506 selectively modulates fast muscle myosin to reduce muscle stress caused by the 
absence of dystrophin. By protecting fast muscle fibers, EDG-5506 can potentially limit muscle 
breakdown and disease progression in Becker muscular dystrophy (BMD). This open-label 
study will evaluate the safety and pharmacokinetics (PK) of EDG-5506 in participants with BMD. 
This is an open-label, single-center, Phase 1b study to assess the safety and PK of EDG-5506 
in adults with BMD. This study will enroll participants who completed (through Day 42) the first-
in-human study, EDG-5506-001. If necessary, additional (treatment-naïve) participants from 
outside the EDG-5506-001 study may be enrolled to meet the target sample size. 
2.2 Study Objectives and Endpoints 
Primary Objective 
Primary Endpoints 
• 
To assess the safety and tolerability of 
EDG-5506 in adults with BMD 
• 
Incidence, frequency and severity of 
adverse events (AEs), and serious 
adverse events (SAEs) in participants 
treated with EDG-5506 
Secondary Objectives 
Secondary Endpoints 
• 
To assess the change in individual safety 
parameters 
• 
Incidence of treatment-emergent (TE) 
abnormal laboratory test results (clinical 
chemistry, hematology, coagulation and 
urinalysis) 
• 
Change from baseline (CFB) in: 
o Safety laboratory parameters 
o Vital signs 
o Physical and neurological 
examinations 
o Cardiac function, as assessed by 
electrocardiogram (ECG) 
parameters 
o Cardiac function, as assessed by 
an echocardiogram 
o Pulmonary function, as assessed 


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by forced expiratory volume in one 
second (FEV1) and forced vital 
capacity (FVC) 
o Columbia Suicide Severity Rating 
Scale (C-SSRS) 
• 
To assess the PK profile of EDG-5506 in 
adults with BMD 
• 
PK concentration levels of EDG-5506 
Tertiary/Exploratory Objectives 
Tertiary/Exploratory Endpoints 
• 
To investigate the effects of EDG-5506 on 
biomarkers of muscle fiber damage in 
adults with BMD 
• 
CFB in biomarker measures as assessed 
by: 
o Serum creatine kinase (CK)  
o Serum cardiac troponin I 
o Serum myoglobin 
o Serum cardiac troponin T 
o Serum N-terminal prohormone 
brain natriuretic peptide (NT-
proBNP) 
o Plasma troponin I tissue-
specific isoforms (fast-skeletal, 
slow-skeletal) 
o Plasma Somascan® 
proteomics 
• 
To assess the effects of EDG-5506 on 
functional measures in adults with BMD 
• 
CFB in functional assessments, as 
measured by: 
o NSAA 
o NSAD 
o 4-stair climb  
o 100-meter timed test 
o Muscle strength testing 
• 
To assess the effects of EDG-5506 on 
self-reported outcomes in adults with 
BMD 
• 
CFB in activity limitations and other self-
reported outcomes as assessed by: 
o PROMIS-57 
o ACTIVLIM 
 
2.3 Randomization and Blinding 
Not applicable. This is an open-label and non-randomized study. 
2.4 Study Drug Administration 
EDG-5506 Administration 
All participants will receive EDG-5506. EDG-5506 will be administered at a dose of 10 mg orally 
until Visit 8, followed by a dose of 15 mg until Visit 13, a dose of 20 mg until Visit 21, followed by 
a dose of 10 mg until Visit 27. 


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EDG-5506 will be provided as a 2.5-mg or 10-mg tablet and should be taken at night, prior to 
bedtime, with or without food. Time of dose will be recorded in the participant diary through the 
Month 12 visit.  Treatment-experienced participants will take the first dose of EDG-5506 at the 
study site in the morning of Day 1. Participants will continue dosing at home, starting in the 
evening on Day 2. 
Treatment-naïve participants will take the first dose of EDG-5506 at the study site in the 
morning of Day 1 and return to the site on Day 2 before taking the second dose. Participants will 
remain at the site on Day 2 to be observed for a minimum of two hours post dose.  Participants 
will continue dosing at home, starting in the evening on Day 3, after travel home from the site 
has been completed. 
2.5 Sample Size Determination 
Sample size has been set empirically based on the number of participants who completed 
(through Day 42) the first-in-human study, EDG-5506-001. If necessary, additional (treatment-
naïve) participants from outside the EDG-5506-001 study may be enrolled to meet the target 
sample size of approximately eight (8) evaluable participants. This will provide reasonable 
estimates of PK measures and important safety and tolerability measures for this early-stage 
clinical development. 
An evaluable participant is defined as a participant who completes the open-label treatment 
period without significant protocol deviations. 
No formal statistical hypothesis testing is planned. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations and Key Definitions 
3.1.1 Study Enrollment 
Study enrollment occurs when a patient is confirmed to be eligible for the study and commences 
EDG-5506 treatment. 
3.1.2 Analysis Day 
Analysis day will be calculated from the date of first dose of EDG-5506. The day of the first dose 
of study drug will be Day 1, and the day immediately before Day 1 will be Day -1. There will be 
no Day 0. 
3.1.3 Definition of Baseline (BL)  
For data collected pre-dose and post-dose, Baseline (BL) is defined as the last non-missing 
measurement prior to the date of first dose of EDG-5506. For data collected at other “off-
treatment” times (i.e., screening, admission [Day -1], and follow-up), BL is defined as the last 
non-missing measurement prior to dosing on Day 1.  For ACTIVLIM and PROMIS57 
assessments with no available measurement prior to first dose, if the first available 
measurement occurs on the date of first dose, then that measurement will be utilized as the BL 
value. 


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3.1.4 Change-from-Baseline (CFB) 
The CFB will be calculated by subtracting the BL values from the individual post-dose values. If 
the BL value is missing, the missed measurement will be replaced with the last previously-
populated value from the patient’s visits, including unscheduled visits, in a last-observation-
carried-forward (LOCF) approach.  Missing post-BL values will not be replaced.  That is, the 
LOCF approach will only be utilized in replacing BL values.  
3.1.5 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of patients. The 
denominator used for the percentage calculation will be clearly defined. Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, minimum, and maximum. 
3.1.6 Hypothesis Testing 
No formal hypothesis testing is planned.  
3.1.7 Handling of Dropouts and Missing Data 
Missing data will not be imputed unless otherwise specified. Only observed data will be used in 
the summaries and analyses. If a patient is lost to follow-up, then the last available 
measurement will be used. 
Missing/Partial Dates: 
• 
In cases of incomplete dates for AEs and concomitant medications, the missing 
component(s) will be assumed as the most conservative value possible. No imputation 
of start/end dates or times will be performed. 
o If a medication date is missing or partially missing and it cannot be determined 
whether it was taken prior or concomitantly, it will be considered a concomitant 
medication. 
o AEs with incomplete start date and times will be attributed to the treatment 
according to the following algorithm: 
1. Only the day is reported: The event will be considered treatment emergent 
unless the end date is present and indicates that the event ended prior to the 
first dose date. 
2. Only the start year or the day and start year is reported: If the year is after or 
the same as the year of the first dose date, then the event will be considered 
treatment emergent unless the end date is present and indicates that the 
event ended prior to the first dose date. 
3. Only the start month and year are reported: If the month/year is after or the 
same as the month/year of the first dose date, then the event will be 
considered treatment-emergent unless the end date is present and indicates 
that the event ended prior to the first dose date. 
4. Only the time is missing: If the time is missing, but the start date otherwise 
matches the date of first dose, then the event will be considered treatment-


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emergent unless the end date and time are present and indicate that the 
event ended prior to the first dose date and time. 
For treatment-emergent adverse events (TEAEs), time since first dose will be calculated as the 
difference between the event start date and the first date of dosing plus one and expressed in 
days. Time since first dose will not be calculated if the start date is partial. 
Duration will be calculated for AEs that resolve as the difference between the resolution date 
and onset date and will be expressed in days, hours and minutes. If either time is missing, 
duration will be calculated as the difference between the resolution date and onset date plus 
one and expressed in days. Time since dose and duration will only be calculated when both 
dates are complete. 
3.1.8 Treatment-Emergent Adverse Event (TEAE) 
A TEAE is defined as an AE that emerges after the first dose of EDG-5506, having been absent 
at pretreatment (BL) or:  
• 
Reemerges during treatment, having been present at pretreatment (BL) but stopped 
before treatment, or  
• 
Worsens in severity during treatment relative to the pretreatment state when the AE is 
continuous. 
Treatment-emergence will be determined by comparing the start date and time of the AE with 
the actual date and time of first dose of EDG-5506.  If the onset date of an AE is missing and 
the AE resolution date is either after the initial EDG-5506 dose date or is missing, then the AE 
will be considered treatment emergent. If the onset time of an AE is missing and the start date 
of the AE is on or before the EDG-5506 dose date, then the AE will be considered treatment 
emergent.  
3.2 Analysis Populations  
3.2.1 Safety Population (SAF) 
The safety population (SAF) includes all participants who received at least one dose of EDG-
5506. All safety analyses will be based on the SAF. The SAF will be used for all participant 
disposition, demographics, safety measures and functional/clinical assessments. 
3.2.2 PK-Evaluable Population (PKP) 
The PK-evaluable population (PKP) includes all participants who received at least one dose of 
EDG-5506 and have a sufficient PK profile to derive at least one PK parameter. The PKP will be 
used for all summaries of PK and biomarker data. 
3.3 Subject Data and Study Conduct 
3.3.1 Patient Disposition and Withdrawals 
The following patient disposition categories will be summarized via counts and percentages for 
all enrolled patients: 
• 
Patients who were enrolled 
• 
Patients who were treated with at least one dose of EDG-5506 


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• 
Patients who received all protocol-specified doses of EDG-5506 
• 
Patients who discontinued treatment of EDG-5506 
• 
Patients who completed the study  
• 
Patients who discontinued the study 
• 
Patients with interruption of study drug 
• 
Treatment status (experienced vs. naïve). 
Based on availability, patients may roll over to the open-label EDG-5506-203 protocol at a visit 
prior to Month 24. These patients will be considered as completing EDG-5506-002 and their last 
study visit in EDG-5506-002 will serve as the final data point. Patients in the SAF who 
discontinued study drug will be summarized by reason for discontinuation (all reasons) via count 
and percentage. Patients in the SAF who discontinued from the study will be summarized by 
reason for discontinuation (all reasons) as recorded on the Case Report Form (CRF) via count 
and percentage. 
3.3.2 Demographic and Baseline (BL) Characteristics 
The following demographic and BL characteristics will be summarized: 
• 
Age (years)  
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg). 
Demographic and BL disease characteristics will be summarized with descriptive statistics or 
counts and percentages, based on the number of participants in the SAF. 
3.3.3 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.1 or higher. Counts and percentages 
of patients with medical history by system organ class and preferred term will be summarized. 
The table and listing will be sorted alphabetically by System Organ Class (SOC) and Preferred 
Term (PT). Medical history will be listed by patient. The listing will also display the verbatim text 
from the study investigators. 
3.3.4 Concomitant Medications 
Prior and concomitant medications/therapies will be coded to anatomical therapeutic chemical 
(ATC) class and preferred term using the World Health Organization (WHO) Drug Dictionary 
version Sept 2021 B3. For summary purposes, medications will be considered prior medications 
if they stopped prior to the first dose of study drug and concomitant medications if they were 
taken at any time after the first dose of study drug (i.e., started prior to the first dose of study 
drug and were ongoing or started after the first dose of study drug). Counts and percentages of 
patients taking prior and concomitant medications will be summarized by ATC class and 
preferred term based on the SAF.   


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3.3.5 Protocol Deviations 
All protocol deviations will be presented in data listings.  
3.3.6 Study Drug Exposure and Compliance 
The extent of exposure to study drug EDG-5506 will be summarized by the following 
parameters: 
• 
Number of doses administered 
• 
Duration of exposure (in weeks) will be calculated as: [(last dose date of study treatment 
– first dose date of study treatment) + 1]/7 
• 
Total administered dose 
• 
Total administered dose as a percentage of total planned dose. 
The planned dose is defined as the dose that would be given if no doses were missed 
and/or no dose reductions were made. The total planned dose is the sum of all planned 
doses.  
• 
Dose discontinued, delayed or interrupted. 
Exposure measures will be summarized based on the SAF. 
3.4 Clinical and Functional Assessments 
Unless otherwise stated, clinical and functional analyses will be performed on the SAF. 
3.4.1 Functional Assessments 
The CFB for functional assessments will be summarized at each scheduled time point for the 
following measures:   
• 
NSAA  
• 
NSAD 
• 
Muscle strength test 
• 
Timed function tests (TFTs)  
o 4-stair climb test summarized as both time and velocity (unit=1/seconds)  
o 100-meter timed test summarized as both time and velocity (unit=meters/second)  
o 10-meter walk run test summarized as both time and velocity (unit=meters/second)  
o Rise from supine summarized as both time and velocity (unit=1/seconds). 
 
Note that the four TFT endpoints will be transformed from time to velocity (speed) as indicated 
by the endpoint’s units. If a participant is unable to complete the TFT a velocity of “0” will be 
imputed.   
 
3.4.2 Clinical Outcomes 
The CFB in the following clinical outcomes will be summarized at each scheduled time point: 
• 
Activity limitations (ACTIVLIM) 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS-57). 


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3.4.3 Subgroups 
No subgroup analyses or summaries will be performed. 
3.5 Safety Assessment 
All safety analyses will be performed using the SAF unless otherwise noted below. 
3.5.1 Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product. The AE does not necessarily have to have a causal relationship with the study drug. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
3.5.1.1 General Details  
Severity 
The severity of an AE will be graded, according to the study protocol definitions of AE 
severity/intensity, as “mild”, “moderate” or “severe”.  
Related 
Each AE relationship to the study drug will be classified as either “related” or “not related”. 
Each AE verbatim term will be coded in accordance with the MedDRA® dictionary to a SOC and 
PT within each SOC.  Analysis of AEs will then be performed using SOCs and PTs. 
3.5.1.2 AE Summaries 
A patient who reported multiple AEs that map to a common PT or SOC is counted only once for 
that PT or SOC at the highest severity reported and at the greatest relationship to study drug. 
The number and percentage of subjects who experienced at least one AE will be tabulated by 
SOC and PT with respect to dose level/treatment group for each study part. The same 
tabulation will also be applied to any SAE, any AE leading to premature discontinuation from the 
study, TEAEs and treatment-emergent SAEs. 
The number and percentage of patients who experienced at least one AE will also be tabulated 
by SOC and PT within each dose level/treatment group with respect to relationship to study 
drug (related, not related) and severity (mild, moderate, severe).   
Patient listings will also be provided for all AEs, all SAEs, all AEs leading to early 
discontinuation from the study and all AEs leading to study drug interruptions. Length of 
interruptions will also be provided. 
An overview of AEs will be provided including counts and percentages of patients with the 
following: 
• 
Any TEAEs (overall and by maximum severity) 
• 
Any study drug-related TEAEs 
• 
Any serious AEs (SAEs) 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any TEAEs leading to discontinuation of study 


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• 
Any AEs leading to death. 
Separate tables including counts and percentages of patients will also be presented by system 
organ class and preferred term for each of the categories in the overview.  
If an AE has incomplete start or stop dates, dates will be imputed to determine whether the AE 
was treatment-emergent. Details on the imputation for incomplete dates will be provided in the 
final SAP to correspond to CRF design and instructions. 
Patient listings of all AEs will be presented, as well as listings specifically for SAEs and TEAEs 
leading to discontinuation of study drug. 
3.5.2 Physical and Neurological Examinations 
All physical and neurological examination results will be presented in data listings.  
3.5.3 Clinical Laboratory Assessments 
Safety laboratory evaluations obtained from the following clinical laboratory tests will be 
collected:  
• 
Hematology – complete blood count, including: reticulocytes (%), hematocrit, 
hemoglobin, platelet count, red blood cell (RBC) count, white blood cell (WBC) count, 
WBC with differential, including percentage and absolute measures for neutrophils, 
lymphocytes, monocytes, eosinophils and basophils. 
• 
Chemistry – alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, blood urea nitrogen, calcium, chloride, cholesterol, 
creatine phosphokinase, creatinine, cystatin C, gamma-glutamyl transferase, glucose, 
glutamate dehydrogenase, lactate dehydrogenase, magnesium phosphorus, potassium, 
sodium, total bilirubin, direct bilirubin, indirect bilirubin, total protein, triglycerides and uric 
acid. 
• 
Coagulation – prothrombin time (partial) and thromboplastin time. 
• 
Urinalysis – bilirubin, color and appearance, glucose, ketones, leukocytes, RBC, WBC, 
nitrite, occult blood, pH, protein, specific gravity and urobilinogen. 
Results of all evaluations (normal, abnormal clinically significant, abnormal not clinically 
significant, not done) from each laboratory test will be tabulated by study visit. Descriptive 
statistics will be provided using the International System of Units (SI units), including absolute 
and percentage CFB. Both scheduled and unscheduled post-BL values will be included. 
Unscheduled visits will be summarized as one summary assessment at the end of all scheduled 
study visit summaries. 
A listing of all laboratory evaluations and abnormal clinically significant laboratory evaluations 
will also be provided. Laboratory values outside the normal ranges will be flagged in the data 
listings. 
3.5.4 Vital Signs 
Vital signs include systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), pulse 
rate (bpm), respiratory rate (bpm), temperature (°C), height (cm), weight (kg), arm span (cm) 
and ulna length (cm) (arm spans and ulna length only if subject is unable to stand for a standing 


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height measurement). .  Summary statistics for vital sign values and the CFB will be presented 
at each scheduled visit.  A listing of vital signs will also be provided. 
3.5.5 Electrocardiograms (ECGs) 
For standard supine resting 12-lead ECG parameters, descriptive statistics will be provided for 
the ECG measurements at BL (PR, QRS, QT, QTcB, QTcF, RR) and CFB for the minimum 
post-BL value, maximum post-BL value, and last post-BL value. Both scheduled and 
unscheduled post-BL values will be considered for the summaries. Outlying QTcF and QTcB 
intervals will be determined using the criteria outlined below. 
Absolute QTc interval prolongation categories include: 
• 
QTc interval >450 msec, 
• 
QTc interval >480 msec, or 
• 
Any QTc interval >500 msec. 
CFB measurement in QTc interval categories include: 
• 
QTc interval increase >30 msec, or 
• 
QTc interval increase >60 msec. 
Number and percentage of subjects for each category above will be provided.   
For 
interpretation 
of 
clinical 
significance 
(abnormal, 
indeterminate, 
normal, 
not 
evaluable/unknown), a frequency table will be presented at each post-dose assessment and for 
the worst value between post-dose assessments.   
Summary statistics for electrocardiogram values and the CFB will be presented by treatment 
group at each scheduled visit.  ECG results will be listed at each assessment. 
3.5.6 Dual-energy X-ray Absorptiometry (DXA) Assessment 
Summary statistics for DXA values and the CFB will be presented by treatment group at each 
scheduled visit.   
3.5.7 Spirometry 
All spirometry results will be presented in data listings.  
3.5.8 Other Safety Assessments 
All other safety assessments (echocardiograms, oculofacial assessments and C-SSRS will be 
presented in patient-level data listings. 
3.6 Pharmacokinetics (PK) 
Samples will be collected for measurement concentrations of EDG-5506 and its metabolites.  
Summary statistics of concentration values and associated listings will be provided. 
3.7 Biomarkers 
Biomarker samples will be used for analysis of fast and slow skeletal troponin I, cardiac troponin 
I, cardiac troponin T, NT-proBNP, myoglobin and CK. Summary statistics of these values and 
associated listings will be provided. 


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3.8 Interim Analysis  
No formal interim analysis is planned. 
4 DATA MONITORING COMMITTEE (DMC) 
An independent Data Monitoring Committee (DMC) will be established to enhance the safety of 
trial participants by providing an independent review of the study data. Details related to the 
DMC responsibilities, authorities and procedures will be documented in the DMC Charter. 
5 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
This SAP does not deviate from the statistical analysis described in Amendment 4, Version 5 of 
the study protocol. Any deviations from the protocol or SAP will be described in the CSR.  
6 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher. All available data will be 
presented in patient-level data listings which will be sorted by patient identification number and 
visit date as applicable. Detailed programming specifications will be provided in a separate 
document. TLF shells and specifications will be provided separately as stand-alone documents.