Conditions: Centronuclear Myopathy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 14
Healthy volunteers: no

Brief summary:
There are no available treatments aside from supportive care for patients with Centronuclear myopathy (CNM). This trial will assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)/preliminary efficacy of a new medicine called DYN101 in patients ≥ 16 years of age with CNM caused by mutations in Dynamin2 (DNM2) or Myotubularin1 (MTM1).

The trial will consist of a consent, a screening period, a run-in period (if applicable), a Single dose treatment part (SAD) with 4 weeks of follow-up after the drug administration and a washout period of at least 12 weeks (followed by follow-up phone calls), a Multiple dose treatment part (MAD) of 12 weeks of weekly dosing, and a Multiple dose extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD extension parts, unless they withdraw. During this time, multiple test will be performed in order to better understand how the drug is distributed and then later removed from the body and whether there any signs of an effect.

As this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their disease.

Detailed description:
There are currently no available treatments aside from supportive care for patients with Centronuclear myopathy (CNM). This trial will assess the safety, tolerability, PK and PD/preliminary efficacy of DYN101 in patients ≥ 16 years of age with CNM caused by mutations in DNM2 or MTM1.

DYN101 is a synthetically manufactured constrained ethyl gapmer antisense oligonucleotide (ASO) directed against DNM2 pre-messenger ribonucleic acid (mRNA). DYN101 will be provided as a sterile concentrated solution for reconstitution into an infusion solution for intravenous (IV) administration, and will be diluted into a 0.9% sodium chloride solution before administration.

The trial will consist of a pre-screening consent, a screening period, a run-in period (if applicable), a SAD part with 4 weeks of follow-up after investigational medicinal product (IMP) administration and a washout period of at least 12 weeks (followed by follow-up phone calls until the MAD part starts), a MAD part of 12 weeks, and a MAD extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD extension parts, unless they withdraw. End-of-treatment assessments will be performed after 24 weeks of MAD treatment have been completed, i.e. at the Week 25 visit. Subjects will be followed up on adverse events (AEs) and concomitant medications 3 months after the last IMP administration.

An interim analysis will be performed when all subjects in cohort 1 and 2 have completed 12 weeks of MAD treatment. The primary analysis will be performed when all subjects in all cohorts have completed 12 weeks of MAD treatment or discontinued earlier. The final analysis will be performed when all subjects have completed 24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD extension part; Week 25 visit) or discontinued earlier.

As this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their pathology, and the knowledge that they contribute to RNA-targeted therapy for CNM patients carrying MTM1 and DNM2 mutations.

Arms:
arm 1: DYN101 in a low dose (1.5 mg/kg), (unless the independent data monitoring committee \[IDMC\] advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b). arm 2: DYN101 in a middle dose (4.5 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b). arm 3: DYN101 in a high dose (9 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).

Interventions: intervention 1: DYN101
Intervention descriptions: intervention 1: DYN101, is a constrained ethyl gapmer ASO directed against human DNM2 RNA

Protocol document:
Prot_000.pdf: 
DYN101-C101 Protocol (Non-substantial administrative correction) 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
Page 1 of 100 
CLINICAL TRIAL PROTOCOL 
Trial Title: 
A Phase 1/2 trial on the safety, tolerability, pharmacokinetics, 
pharmacodynamics and exploratory efficacy of DYN101 in 
patients ≥ 16 years of age with centronuclear myopathies 
caused by mutations in DNM2 or MTM1. 
Trial Design: 
This is a first-in-human, Phase 1/2, open-label, multi-center 
trial, to evaluate single ascending doses (SAD) and multiple 
ascending doses (MAD) of DYN101. 
Short Title: 
Research Using an Investigational Treatment for CNM 
(Unite-CNM) 
Protocol Identification: 
DYN101-C101 
EudraCT No.: 
2018-004089-33 
Name of Investigational Medicinal 
Product: 
DYN101 
Sterile concentrated solution for reconstitution into an infusion 
solution for intravenous administration. 
IND No.: 
Not applicable 
Indication Studied: 
Centronuclear myopathies (CNMs) in subjects > 16 years of 
age with mutations in dynamin 2 (DNM2) or myotubularin 1 
(MTM1). 
Developmental Phase of Trial: 
Phase 1/2 
Name of the Sponsor/Company: 
Dynacure  
Bioparc 3 
850 Boulevard Sébastien Brant   
67400 Illkirch-Graffenstaden 
France 
Coordinating Investigator: 
 
Protocol Version and Date: 
Version 8.1 (non-substantial administrative correction), EU 
version 
01 December 2021, Final 
This trial, including the archiving, will be conducted in compliance with Good Clinical Practice (GCP) 
according to the International Council for Harmonisation (ICH) Harmonized Tripartite Guideline 
(CPMP/ICH/135/95). 
Confidentiality Statement 
This Dynacure document is confidential. The information within this document may not be reproduced 
or otherwise disseminated without approval of Dynacure.  


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Clinical Trial Protocol Signature Page 
Sponsor’s Approval 
Signature: 
Date: 
 
 
 
 
 
Version History 
Version Final Version Date 
Countries 
Concerned 
Comment 
1.0 
06 Dec 2018 
All 
Not submitted outside of company 
2.0 
01 Feb 2019 
All 
Not submitted outside of company 
3.0 
25 Feb 2019 
All 
Submitted to MHRA (rejected)  
4.0 
11 Apr 2019 
All 
Substantial Amendment 01 
5.0 
09 Aug 2019 
All 
Substantial Amendment 02 
6.0 
26 May 2020 
All 
Amendment 03 
6.1 
24 Aug 2020 
US only 
US version Amendment 03 
6.2 
17 May 2021 
US only 
FDA feedback 
7.0 
31 Mar 2021 
All 
Amendment 04 
7.1 
12 Aug 2021 
US only 
US version Amendment 04 
8.0 
15 Sep 2021 
All 
Substantial Amendment 05 
8.1 
01 December 2021 
All 
Non-substantial administrative correction 
 
 
 
 
 
 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
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Page 3 of 100 
Investigator’s Acknowledgement 
I have read this protocol. 
Protocol ID: DYN101-C101 
Title: A Phase 1/2 trial on the safety, tolerability, pharmacokinetics, pharmacodynamics and 
exploratory efficacy of DYN101 in patients ≥ 16 years of age with centronuclear myopathies 
caused by mutations in DNM2 or MTM1. 
I have fully discussed the objectives of this trial and the contents of this protocol with the sponsor’s 
representative. 
I understand that the information in this protocol is confidential and should not be disclosed, other 
than to those directly involved in the execution or the scientific/ethical review of the trial, without 
written authorization from the sponsor. It is, however, permissible to provide the information 
contained herein to a subject in order to obtain his/her consent to participate. 
I agree to conduct this trial according to this protocol and any trial specific manuals, to comply 
with its requirements, ethical and safety considerations and guidelines, and to conduct the trial in 
accordance with the International Council for Harmonisation guidelines on Good Clinical Practice 
and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to my 
participation as an investigator for this trial to be terminated. 
I understand that the sponsor may decide to suspend or prematurely terminate the trial at any time 
for whatever reason; such a decision will be communicated to me in writing. Conversely, should I 
decide to withdraw from execution of the trial, I will communicate my intention immediately in 
writing to the sponsor. 
Investigator Name: 
 
Site Number: 
(please handwrite, print or type) 
 
 
 
 
 
Institution and Address: 
 
 
 
 
 
 
 
Phone: 
 
Signature: 
 
Date: 
 
 
 
 
 
If the address or telephone number of the investigator changes during the course of the trial, written notification will 
be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 


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Emergency Contact Information 
In the event of a serious adverse event (SAE), the investigator must complete the electronic case 
report form (eCRF) and submit within 1 business day to the contract research organization (CRO) 
responsible for Pharmacovigilance: 
 
Worldwide Clinical Trials 
Email: drugsafety@worldwide.com  
Fax: +44 (0)115 922 096 
 
In case of medical questions during the trial, the investigator must contact the medical monitor: 
Worldwide Clinical Trials Medical Monitor 
Email: UniteCNM_MM @worldwide.com 
Phone: the number is on contact list in the Site File 
If after working hours: dyn101@promedim.com or +44 203 356 9696 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................ 9 
CLINICAL TRIAL PROTOCOL SYNOPSIS ......................................................................... 11 
TRIAL SCHEDULES ................................................................................................................. 18 
1) PRE-SCREENING, SCREENING, AND RUN-IN PERIOD ............................................. 18 
2) BASELINE AND SAD ........................................................................................................... 21 
3) SAD FOLLOW-UP AND WASHOUT ................................................................................. 25 
4) MAD PART ............................................................................................................................. 28 
5) MAD EXTENSION PART .................................................................................................... 31 
6) FOLLOW-UP POST MAD WEEK 25 ................................................................................. 34 
1. 
INTRODUCTION................................................................................................................ 36 
1.1 
Condition Background and Current Treatment .......................................................... 36 
1.1.1 
X-linked CNM ........................................................................................................... 36 
1.1.2 
Autosomal Dominant CNM ...................................................................................... 37 
1.2 
RNA-targeted Therapeutic Concept ............................................................................. 37 
1.3 
Investigational Medicinal Product Background .......................................................... 38 
1.3.1 
Nonclinical Information ........................................................................................... 39 
1.3.2 
Clinical Information ................................................................................................. 39 
1.4 
Rationale for the Trial .................................................................................................... 39 
1.5 
Risk/Benefit Considerations ........................................................................................... 40 
2. 
TRIAL OBJECTIVES AND HYPOTHESIS .................................................................... 42 
2.1 
Primary Objective ........................................................................................................... 42 
2.2 
Secondary Objectives ...................................................................................................... 42 
2.3 
Exploratory Objectives ................................................................................................... 42 
2.4 
Hypothesis ........................................................................................................................ 42 
3. 
TRIAL DESIGN................................................................................................................... 42 
3.1 
Overall Trial Design ........................................................................................................ 42 
3.1.1 
Overview of Trial Periods ........................................................................................ 42 
3.1.2 
Replacement of Subjects ........................................................................................... 46 
3.2 
Trial Design Rationale .................................................................................................... 47 
3.2.1 
Rationale for Choice of Design ................................................................................ 47 
3.2.2 
Rationale for Choice of Eligibility Criteria ............................................................ 47 
3.2.3 
Rationale for Choice of Safety Assessments ........................................................... 48 
3.2.4 
Rationale for Choice of PD/Exploratory Efficacy Assessments ............................ 49 
3.2.5 
Rationale for Choice of Doses, Route of Administration and Dosing 
Regimen ...................................................................................................................... 50 
3.3 
Trial Endpoints ............................................................................................................... 51 
3.3.1 
Primary Endpoint ..................................................................................................... 51 
3.3.2 
Secondary Endpoints ................................................................................................ 51 
3.3.3 
Exploratory Endpoints ............................................................................................. 52 
3.4 
Sample Size ...................................................................................................................... 53 
3.5 
Sites and Regions ............................................................................................................. 53 
4. 
TRIAL POPULATION ....................................................................................................... 53 
4.1 
Inclusion Criteria ............................................................................................................ 53 
4.2 
Exclusion Criteria ........................................................................................................... 54 


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4.3 
Reproductive Potential ................................................................................................... 54 
4.4 
Prohibitions and Restrictions ......................................................................................... 55 
4.5 
Subject Withdrawal and Trial Termination ................................................................ 56 
5. 
TRIAL TREATMENT ........................................................................................................ 57 
5.1 
Investigational Medicinal Product................................................................................. 57 
5.2 
Dosage and Administration ............................................................................................ 57 
5.3 
Treatment Allocation ...................................................................................................... 58 
5.4 
Labeling, Packaging, Storage, and Handling ............................................................... 59 
5.4.1 
Labeling and Packaging ........................................................................................... 59 
5.4.2 
Storage ........................................................................................................................ 59 
5.4.3 
Handling ..................................................................................................................... 59 
5.5 
Prior and Concomitant Medication/Therapy ............................................................... 59 
5.5.1 
Prior Medication/Therapy ....................................................................................... 59 
5.5.2 
Concomitant Medication/Therapy .......................................................................... 60 
5.6 
Treatment Compliance and Drug Accountability ........................................................ 60 
6. 
TRIAL SCHEDULE AND ASSESSMENTS..................................................................... 61 
6.1 
Trial Schedule .................................................................................................................. 61 
6.1.1 
Pre-screening and Screening Period ....................................................................... 61 
6.1.2 
Run-in Period (if Applicable) ................................................................................... 62 
6.1.3 
Treatment Periods ..................................................................................................... 62 
6.1.4 
End of Treatment Follow-up Visit ........................................................................... 64 
6.1.5 
Early Discontinuation ............................................................................................... 64 
6.1.6 
Additional Care of Subjects After the Trial ........................................................... 64 
6.2 
Trial Evaluations ............................................................................................................. 64 
6.2.1 
Demographic and Other Baseline Characteristics ................................................. 64 
6.2.2 
Safety Evaluations ..................................................................................................... 64 
6.2.3 
Pharmacokinetic Evaluations .................................................................................. 68 
6.2.4 
Pharmacodynamic/Exploratory Efficacy Evaluations .......................................... 70 
6.2.5 
Collection of Optional Samples for Exploratory Research (Blood 
Biomarkers) ............................................................................................................... 73 
6.2.6 
Muscle Biopsy ............................................................................................................ 73 
6.2.7 
Volume of Blood to be Drawn from Each Subject ................................................. 74 
6.2.8 
Sample Management ................................................................................................. 75 
7. 
SAFETY DEFINITIONS, REPORTING AND FOLLOW-UP ....................................... 75 
7.1 
Adverse Event Definitions .............................................................................................. 75 
7.2 
Adverse Events of Special Interest ................................................................................ 76 
7.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .................................................................. 77 
7.4 
Overdose .......................................................................................................................... 78 
7.5 
Adverse Event Assessment Definitions ......................................................................... 78 
7.5.1 
Severity ....................................................................................................................... 78 
7.5.2 
Relationship to Investigational Medicinal Product ................................................ 79 
7.6 
Reporting of Adverse Events.......................................................................................... 79 
7.7 
Prompt Reporting of Serious Adverse Events .............................................................. 80 
7.8 
Regulatory Reporting Requirements for Serious Adverse Events and Other 
Events ............................................................................................................................... 80 
7.9 
Reporting of Pregnancies ............................................................................................... 81 


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7.10 
Follow-up on Adverse Events ......................................................................................... 81 
7.11 
Pausing/Stopping Rules .................................................................................................. 82 
7.11.1 
Pausing/Stopping Rules for the Trial ...................................................................... 82 
7.11.2 
Individual Treatment Interruptions and Dose Adjustments ................................ 83 
8. 
DATA MANAGEMENT ..................................................................................................... 84 
8.1 
Data Collection ................................................................................................................ 84 
8.2 
Clinical Data Management ............................................................................................. 84 
9. 
STATISTICAL METHODS ............................................................................................... 84 
9.1 
Statistical Analysis .......................................................................................................... 84 
9.2 
Planned Interim Analysis and Adaptive Design ........................................................... 85 
9.3 
Selection of Subjects to be Included in the Analyses ................................................... 85 
9.4 
Subject Disposition .......................................................................................................... 85 
9.5 
Demographic and Baseline Characteristics .................................................................. 85 
9.6 
Investigational Medicinal Product Exposure ............................................................... 86 
9.7 
Prior and Concomitant Medication ............................................................................... 86 
9.8 
Safety Analyses ................................................................................................................ 86 
9.9 
Pharmacokinetics Analyses ............................................................................................ 87 
9.10 
Pharmacodynamics/Exploratory Efficacy Analyses .................................................... 87 
9.11 
Sample Size Justification ................................................................................................ 88 
9.12 
Independent Data Monitoring Committee.................................................................... 88 
9.13 
Missing Data .................................................................................................................... 89 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ..................................... 89 
10.1 
Sponsor’s Responsibilities .............................................................................................. 89 
10.1.1 
Good Clinical Practice Compliance ......................................................................... 89 
10.1.2 
Indemnity/Liability and Insurance .......................................................................... 90 
10.1.3 
Public Posting of Trial Information ........................................................................ 90 
10.1.4 
Submission of Summary of Clinical Trial Report to Competent 
Authorities of Member States Concerned and Independent Ethics 
Committees/Independent Review Boards ............................................................... 90 
10.1.5 
Trial Suspension, Termination, and Completion ................................................... 91 
10.2 
Investigator’s Responsibilities........................................................................................ 91 
10.2.1 
Good Clinical Practice Compliance ......................................................................... 91 
10.2.2 
Protocol Adherence and Investigator Agreement .................................................. 91 
10.2.3 
Documentation and Retention of Records .............................................................. 92 
10.3 
Trial Documentation ....................................................................................................... 93 
10.4 
Ethical Considerations .................................................................................................... 93 
10.4.1 
Informed Consent ..................................................................................................... 93 
10.4.2 
Independent Ethics Committee/Independent Review Board ................................ 94 
10.4.3 
Protocol Amendments ............................................................................................... 95 
10.4.4 
Long-term Retention of Samples for Additional Research (Optional) ................ 95 
10.5 
Privacy and Confidentiality ........................................................................................... 96 
10.6 
Publication Policy ............................................................................................................ 96 
11. ADMINISTRATIVE ASPECTS......................................................................................... 97 
12. REFERENCE LIST ............................................................................................................. 98 
 


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List of In-text Tables 
Table 1: 
Calculated Weekly Human Dose* ..................................................................... 51 
Table 2: 
Prohibited Medication and Washout Period .................................................... 60 
Table 3: 
Pharmacokinetic Sampling Schedule ................................................................ 68 
Table 4: 
Volume of Blood to be Drawn from Each Subject ........................................... 74 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Trial Design: Trial Periods ................................................................................. 43 
Figure 2: 
Trial Cohorts and IDMC Reviews ..................................................................... 45 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ADA 
anti-drug antibodies 
ADCNM 
autosomal dominant centronuclear myopathy 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ARCNM 
autosomal recessive centronuclear myopathy 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
BIN1 
amphiphysin II 
BUN 
blood urea nitrogen 
C3 
complement component 3 
C5a 
complement component 5a 
CBb 
complement factor B 
CGI-I 
Clinical Global Impression of Improvement 
CI 
confidence interval 
CNM 
centronuclear myopathy 
CRO 
contract research organization 
CRP 
c-reactive protein 
DNM2  
dynamin 2 
EAT-10 
Eating Assessment Tool 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EoT 
End of Treatment 
ESR 
erythrocyte sedimentation rate 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV 
forced expiratory volume 
FU 
follow-up 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyltransferase 
GLP 
Good Laboratory Practice 
hCG 
human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  


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IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IMP 
investigational medicinal product 
INR 
International normalized ratio 
IPF 
immature platelet fraction 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous(ly) 
LLN 
lower limit of normal 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP 
maximum expiratory pressure 
MFM 
Motor Function Measure 
MHRA 
Medicines and Healthcare products Regulatory Agency (UK) 
MIP 
maximum inspiratory pressure 
MRSD 
minimal recommended starting dose 
MTM1 
myotubularin 1 
NHP 
non-human primate(s) 
NHS 
Natural History Study 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PGI-C 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
QoL 
quality-of-life 
RBC 
red blood cell 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
XLCNM 
X-linked centronuclear myopathy 
 
 
Definition of Terms 
For the definitions of the pharmacokinetic parameters, refer to Section 6.2.3.4. 


DYN101-C101 Protocol (Non-substantial administrative correction) 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Protocol Number: DYN101-C101 
Investigational 
Medicinal 
Product: 
DYN101 
Title of the Trial: A Phase 1/2 trial on the safety, tolerability, pharmacokinetics, 
pharmacodynamics and exploratory efficacy of DYN101 in patients ≥ 16 years of age with 
centronuclear myopathies caused by mutations in DNM2 or MTM1. 
Planned Number of Subjects: 
The target is to enroll 18 subjects, with approximately 6 subjects per dose level. In each cohort, 
the target will be up to 6 subjects with a mutation in dynamin 2 (DNM2) (sub-cohort a) and up to 
3 subjects with a mutation in myotubularin 1 (MTM1) (sub-cohort b). 
Planned Number of Sites:  
This trial is planned to be conducted at 5 to 10 sites in Europe and the United States of America, 
with an estimation of 1 to 5 subjects per site. 
Coordinating Investigator: Dr. N. Voermans 
Trial Period (Planned): 
First Subject Screening: September 2019  
Last Subject Last Visit: April 2023 
Clinical Phase: 
1/2 
Indication/Trial Population: 
Centronuclear myopathies (CNMs) in subjects ≥ 16 years of age* with mutations in DNM2 or 
MTM1. 
*for Germany, the subject must be ≥ 18 years of age in accordance with local and national 
regulations. 
Objectives: 
Primary: 
• 
To assess the safety and tolerability of 3 single ascending dose (SAD) levels and 
3 multiple ascending dose (MAD) levels of DYN101. 
Secondary: 
• 
To assess the pharmacokinetics (PK) of SAD and MAD of DYN101. 
• 
To explore target engagement in muscle of DYN101. 
Exploratory:  
• 
To investigate the effect of DYN101 treatment on the clinical assessments in various 
affected domains (respiratory function, muscle strength and function, dysphagia). 
• 
To explore the impact of CNM and its treatment on symptoms, functioning, and 
health-related quality-of-life (QoL). 
• 
To assess the presence of anti-drug antibodies (ADA) against DYN101 by collecting 
blood samples. 
• 
To assess the metabolic profile of DYN101 by collecting blood and urine samples. 
• 
To contribute to the global understanding of CNM and its treatment by collecting 
blood and muscle samples for further exploratory biomarker/genetic research. 
Rationale: 
There are currently no available treatments aside from supportive care for subjects with CNM. 
This trial will assess the safety, tolerability, PK and PD/preliminary efficacy of DYN101 in 
subjects ≥ 16 years of age* with CNM caused by mutations in DNM2 or MTM1 (*for Germany, 


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the subject must be ≥ 18 years of age in accordance with local and national regulations). DNM2 
protein is ubiquitously present and a complete knock-out of DNM2 mRNA is lethal in mice. 
Elevations in DNM2 protein levels or DNM2 function have been demonstrated in preclinical 
models and human tissues of X-linked CNM (XLCNM) and autosomal dominant CNM 
(ADCNM), respectively. Preclinical models of these mutations have shown the potential of 
reducing DNM2 mRNA to prevent and reverse the clinical status. 
 
 
 
 Moreover, an increased uptake of ASO was seen in muscle 
of diseased mice over their wild-type counterparts. This first-in-human trial for DYN101 will 
therefore be conducted in patients and not in healthy volunteers to assess safety, PK and dose 
selection based on PD/preliminary efficacy. 
Investigational Medicinal Product, Dose and Mode of Administration: 
 
 
 
Low (1.5 mg/kg), middle (4.5 mg/kg) and high (up to 9 mg/kg) dose levels of DYN101 were 
selected based on preclinical and toxicology data from ongoing studies. These may be adjusted 
based on recommendations of the Independent Data Monitoring Committee (IDMC) (see 
further). 
The investigational medicinal product (IMP) will be administered IV as single and multiple 
(weekly) doses.  
Trial Design/Methodology: 
This is a first-in-human, Phase 1/2, open-label, multi-center trial to evaluate the safety, 
tolerability, PK, PD and preliminary efficacy of DYN101 after SAD and MAD in subjects 
≥ 16 years of age with CNMs caused by mutations in DNM2 or MTM1. 
Sufficient subjects will be screened in order to ascertain that approximately 18 subjects will be 
dosed and finish the trial. Additionally, there will be stand-by subjects for replacement of subjects 
who discontinue the trial early, if needed. Stand-by subjects will perform run-in visits until the 
last MAD subject has completed Week 13, unless needed for replacement. 
The trial will consist of a pre-screening consent, a screening period, a run-in period (if applicable), 
a SAD part with 4 weeks of follow-up after IMP administration and a washout period of at least 
12 weeks (followed by follow-up phone calls until the MAD part starts), a MAD part of 12 weeks, 
and a MAD extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD 
extension parts, unless they withdraw. End of Treatment (EoT) assessments will be performed 
after 24 weeks of MAD treatment have been completed, i.e. at the Week 25 visit. Subjects will 
return to the clinic 3 months after the last IMP administration to follow-up on the subject’s status 
including abnormal laboratory results, adverse events (AEs), and concomitant medications. 
Subjects will give a ‘pre-screening’ consent to be entered as ‘pre-screened’ in the Interactive 
Response Technology (IRT) system. The pre-screening consent process can be managed 
remotely. Subsequently, subjects will sign the main informed consent form (ICF) and screening 
will be performed to assess eligibility.  
Subjects who are participating in the Natural History Study (NHS) and have at least 2 data time 
points available from the NHS to assess their pre-trial condition do not require a mandatory run-in 
visit. For these subjects, screening should be performed within 6 weeks before the baseline visit. 
There should be a minimum of 3 data time points to assess their pre-trial condition. The screening 
visit can be the third data time point. 


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Subjects who have not participated in the NHS or who do not have at least 2 data time points 
from the NHS will have a mandatory run-in period before continuing to the baseline visit. At 
least 1 run-in visit needs to be performed in order to obtain 3 data time points to assess their 
pre-trial condition; screening can be the first data time point, baseline can be the third data time 
point. There should be a minimum of 28 days between screening and the first run-in visit. 
At baseline, subjects will be enrolled into the trial (if all in- and exclusion criteria are still met), 
until recruitment in the last cohort is reached, including replacement subject(s) who were amongst 
the stand-by subjects. 
In the SAD part, subjects will receive a single dose of DYN101 at Day 1. In the MAD part, 
subjects may receive the same or a different dose as in the SAD part, with weekly administrations 
of DYN101 for a period of 12 weeks, followed by a MAD extension part with an additional 12 
weeks of treatment (weekly administrations). After Week 24, all subjects will remain on 
treatment with weekly IMP administrations and assessments every 2 weeks until the last MAD3 
subject has completed the MAD Week 25 visit. 
Subjects will receive DYN101 in a low (1.5 mg/kg), middle (4.5 mg/kg), or high (up to 9 mg/kg) 
dose level in Cohorts 1, 2, and 3, respectively. In the MAD part, subjects may receive a different 
dose than what they received in the SAD part. In each cohort, the target will be up to 6 subjects 
with a mutation in DNM2 (sub-cohort a) and up to 3 subjects with a mutation in MTM1 (sub-
cohort b).  
Cohorts will be enrolled in a sequential, staggered approach, with an interval of at least 7 days 
between dose administration of the first and the next subject in a cohort, irrespective of their sub-
cohort. The first subject (i.e. the sentinel subject) in each cohort will be ≥ 18 years of age. The 
48-hour safety data from the first subject in a cohort will be reviewed by the medical monitor 
before the next subject can be dosed. In addition, any serious adverse event (SAE) data from the 
first subject received up until the moment of treatment of the second subject will be taken into 
account.  
Pausing/stopping rules will be applied in this trial. 
An IDMC will be established to monitor the safety data on a regular basis to ensure the continuing 
safety of the enrolled subjects. The IDMC may meet at any time based on emerging safety and 
tolerability data. At a minimum, the IDMC must meet after all subjects of a cohort have been 
dosed, to advise to continue each MTM1 and/or DNM2 sub-cohort to the next dose level or 
discontinue the MTM1 and/or DNM2 sub-cohort of the trial. Escalation of each MTM1 and/or 
DNM2 sub-cohort to the next increased dose level will not take place until the IDMC has 
reviewed the data of the previous (sub-)cohort (including subjects who have discontinued the 
trial). The data reviewed by the IDMC for dose escalation decisions will be as clean as possible 
prior to their review. The IDMC can recommend adjusting dose levels or stopping the dose 
escalation scheme for each MTM1 and/or DNM2 sub-cohort and/or individual subjects based on 
the totality of available data (safety and tolerability data and/or level of target engagement). At 
each IDMC review, different decisions for the sub-cohorts (DNM2 vs MTM1) can be made based 
on the emerging data. If needed, the IDMC review can be split over separate meetings for the 
sub-cohorts, although the available data from the other sub-cohort will also be taken into account 
at each meeting.  
 
The IDMC will convene at least 4 times: 
• 
The trial will start with the enrollment of approximately 6 subjects in Cohort SAD1.  
• 
Cohort SAD2 can start after a favorable IDMC review of the 2-week safety and PK 
data of SAD1 (IDMC1). 


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• 
Cohorts SAD3 and MAD1 can start after a favorable IDMC review of the 2-week 
safety and PK data of SAD2 (IDMC2). 
• 
Cohort MAD2 can start after a favorable IDMC review of the 2-week safety and PK 
data of SAD3, if available, as well as the 6-week safety and PK data of MAD1 
(IDMC3). 
• 
Cohort MAD3 can start after a favorable review of the 12-week safety and PK data 
of MAD1 and MAD2 as well as the MAD1 and MAD2 12-week PK muscle biopsy 
data (IDMC4). In this meeting the IDMC will also recommend a starting dose for 
the pediatric DYN101-C102 study.  
Assessments: 
Safety and tolerability will be evaluated throughout the trial from signing of the main ICF 
onwards until the last trial visit (i.e. EoT follow-up visit 3 months after the last IMP 
administration). Safety evaluations will include monitoring of SAEs/AEs, clinical laboratory 
evaluations, electrocardiograms (ECGs), vital signs, and physical examinations at specified time 
points. 
All enrolled subjects will undergo blood sampling for PK evaluations at specified time points. In 
addition, blood and/or urine samples will be collected for analysis of ADA and metabolic 
profiling. 
PD/exploratory efficacy parameters including respiratory function, muscle strength and function, 
and dysphagia will be assessed, and a muscle biopsy will be taken at specified time points. 
For subjects who provided a separate informed consent, blood samples will be collected for 
further exploratory research on blood biomarkers (including DNA). Participation in this part of 
the trial is optional and does not impact the subject’s eligibility for participation in the trial. 
Subjects may continue to participate in the trial if they refuse to provide a sample or if they 
withdraw their samples. 
The impact of CNM and its treatment (safety and efficacy) on QoL and health outcomes will be 
evaluated at specified time points, using questionnaires. 
Inclusion and Exclusion Criteria: 
Inclusion criteria: 
1. Male or female aged ≥16 years of age* on the date of signing the main ICF. The first subject 
(i.e. the sentinel subject) in each cohort must be ≥ 18 years of age.  
*for Germany, the subject must be ≥ 18 years of age in accordance with local and national 
regulations. 
2. Have a documented mutation in DNM2 or MTM1. 
3. Platelet count >150,000/µL. 
4. Have a symptomatic CNM in the opinion of the investigator, at least mild to moderately 
affected, i.e. showing clinical symptoms in at least 2 of the 4 relevant domains that will be 
investigated in this trial (respiratory function, muscle strength, muscle function, and 
dysphagia), and be ambulatory, i.e. being able to walk 10 steps, if needed with 
support/assisted. If a subject is non-ambulatory but highly functioning in the view of the 
investigator, he/she may be included following discussion with the sponsor. 
5. Have an understanding, ability and willingness to fully comply with visit frequency, trial 
procedures and restrictions, including contraceptive requirements. 
6. Able to provide written, signed and dated informed consent/assent to participate in the trial. 
Parental consent (one or both parents) and an assent for subjects < 18 years may be required 
per local legislation. 


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Exclusion criteria: 
1. Clinically significant liver disease. 
2. Clinically significant renal disease. 
3. Presence of significant co-morbidities or conditions other than CNM or clinically significant 
findings during screening of medical history, physical examination, laboratory testing, vital 
signs or ECG recording for which, in the opinion of the investigator and the medical monitor, 
participation would not be in the best interest of the subject (e.g. compromise the safety or 
well-being) or that could prevent, limit, or confound the protocol-specified assessments (e.g. 
taking a muscle biopsy). 
4. For female subjects of child-bearing potential: pregnant or breastfeeding or planning to 
become pregnant during the trial. 
5. Current or past abuse of alcohol or recreational/narcotic drugs (with the exception of caffeine 
and nicotine), which in the investigator’s opinion would compromise the subject’s safety 
and/or compliance with the trial procedures. 
6. Currently enrolled in any interventional trial or scheduled to participate in such a trial whilst 
participating in this trial. Subjects are allowed to participate in registry studies. 
7. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to fully complete the trial, or any condition 
that presents undue risk from the IMP or procedures. 
8. Intake of any disallowed therapies as noted in the protocol within 12 weeks before the 
planned first IMP administration. 
9. Known or suspected intolerance or hypersensitivity to IMP ingredients or closely-related 
compounds, or history of a significant allergic reaction to IMP ingredients as determined by 
the investigator, such as anaphylaxis requiring hospitalization.  
10. Legally incapacitated or have limited legal capacity. Lack of mental capacity to fully 
understand the protocol requirements and complete all trial required procedures.  
Note: Retesting of subjects should always be discussed with the sponsor and/or medical 
monitor. Retesting of laboratory values that lead to exclusion will be allowed once using an 
unscheduled visit during the screening period to assess eligibility. This visit should be at 
least 2 weeks later than the original screening visit.  
Duration of Subject Involvement in the Trial: 
The duration of participation in the trial for an individual subject in any cohort, from screening 
(excluding the run-in period) to the last trial visit (i.e. EoT follow-up visit), will be at least 60 
weeks. 
The end of the trial is defined as the last visit of the last subject. 
Endpoints and Statistical Analysis: 
Trial Endpoints: 
• 
Primary Endpoint: 
• 
Comparison of adverse event (AE, SAE, AESI) frequency and severity by dose 
(cohort), for single or multiple administration, and by mutated gene (sub-cohort) and 
overall using the Safety Analysis Set following 12 weeks of MAD treatment and 
after 24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the 
MAD extension part; Week 25 visit) or discontinued earlier.    
• 
Secondary Endpoints 


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• 
Comparison of means for PK parameters of DYN101 in plasma (AUCτ, AUClast, 
AUC∞, Rac(AUC), Rac(Cmax), Cmax, Cav SS, CL, λz, t1/2, tmax, Vz) by dose (cohort), for 
single or multiple administration, and by mutated gene (sub-cohort) and overall using 
the Pharmacokinetic Set. 
• 
Comparison of geometric means for PK parameters of DYN101 in plasma (Cmax and 
AUCs) by dose (cohort), for single or multiple administration, and by mutated gene 
(sub-cohort) and overall using the Pharmacokinetic Set. 
• 
Comparison of means on DNM2 mRNA levels and DYN101 concentrations using 
muscle biopsy data by dose (cohort), for single or multiple administration, and by 
mutated gene (sub-cohort) and overall using the Pharmacokinetic Set.  
• 
Comparison of means change from baseline in vital signs, laboratory data, and ECG 
by dose (cohort), for single or multiple administration, and by mutated gene (sub-
cohort) and overall. 
• 
Exploratory Endpoints 
• 
Difference in mean change from baseline for clinical assessments in various affected 
clinical domains (respiratory, muscle strength and function, dysphagia) using the 
Pharmacokinetic Set by dose (cohort), for single or multiple administration, and by 
mutated gene (sub-cohort) at each post-baseline visit. The parameters to be analyzed 
for respiratory function are FVC (L), %FVC Predicted, FEV1 (L), %FEV1 
Predicted, FEV1/FVC, MEP (cm H2O), %MEP Predicted, MIP (cm H2O), %MIP 
Predicted, Oxygen Saturation (%). The MyoGrip Test score will be used for 
analyzing muscle strength. The following parameters will be analyzed for muscle 
function: D1 Standing and transfers (%), D2 Axial and proximal motor function (%), 
D3 Distal motor function (%), Total MFM32 Score (%). Dysphagia will be assessed 
using the EAT-10 total score.  
• 
Difference in mean change from baseline for PROMIS Questionnaire T-scores for 
the following domains (Anxiety, Depression, Fatigue, Pain Interference, Ability to 
Participate, and Physical Function) using the Pharmacokinetic Set by dose (cohort), 
for single or multiple administration, and by mutated gene (sub-cohort) at each post-
baseline visit. 
• 
Comparison of proportion of CGI-I responders (responders defined as responding 1 
or 2) using the Pharmacokinetic Set by dose (cohort), for single or multiple 
administration, and by mutated gene (sub-cohort) at each post-baseline visit. 
• 
Comparison of proportion of PGI-C responders (responders defined as responding 1 
or 2) using the Pharmacokinetic Set by dose (cohort), for single or multiple 
administration, and by mutated gene (sub-cohort) at each post-baseline visit. 
• 
Comparison of proportion of Goal Attainment Scaling (GAS) Questionnaire 
responders (responders defined as responding ‘YES - MUCH BETTER’, ‘YES - A 
LITTLE BETTER’) using the Pharmacokinetic Set by dose (cohort), for single or 
multiple administration, and by mutated gene (sub-cohort) at each post-baseline visit. 
• 
Comparison of means of ADA against DYN101 using the Pharmacokinetic Set by 
dose (cohort), for single or multiple administration, and by mutated gene (sub-
cohort) at each post-baseline visit. 
• 
Comparisons of the metabolic profile of DYN101 in blood and urine using the 
Pharmacokinetic Set by dose (cohort), for single or multiple administration, and by 
mutated gene (sub-cohort) at each post-baseline visit. 


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Hypothesis: 
As this trial is designed to provide descriptive information regarding safety and tolerability, no 
formal statistical hypothesis testing is planned. 
Statistical Analysis: 
An interim analysis will be performed when all subjects in Cohorts 1 and 2 have completed 12 
weeks of MAD treatment or discontinued earlier, or if the sponsor deems a risk/benefit analysis 
necessary at any time point. 
The primary analysis will be performed when all subjects in all cohorts have completed 12 weeks 
of MAD treatment or discontinued earlier. The final analysis will be performed when all subjects 
have completed 24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD 
extension part; Week 25 visit) or discontinued earlier.  
In general, descriptive statistics and/or frequency tabulations will be presented overall and by 
dose (cohort), for single or multiple administration, and by mutated gene (sub-cohort). Listings 
and figures presenting individual data will be generated as appropriate. Advanced analyses and 
models for the respiratory function and the muscle strength and function tests data will be used 
to summarize in a more effective way the potential effect of the treatment and are not aimed for 
inferential purposes since the trial is not powered for that purpose. 
 


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Page 18 of 100 
TRIAL SCHEDULES 
Subjects will be confined to the clinic for at least 7 hours after SAD dosing, , the first dosing during MAD or a change in dosing during MAD, 
for at least 4 hours during all other clinic visits during MAD, and may be confined to the clinic for any 24-hour urine collection. Additionally, the 
subject may be confined to the clinic for their convenience if assessments will be performed on consecutive days. 
1) PRE-SCREENING, SCREENING, AND RUN-IN PERIOD 
 
PRE-SCREENING, SCREENING, and RUN-IN PERIOD 
Trial Period 
Pre-screening a) 
Screening Period b),c) 
[Run-in Period] c),d) 
Time Point 
Any time before 
screening 
Maximum 6 weeks  
[minimum 28 days in case of run-in period] 
[Minimum 28 days; can be 1 or more visits]  
Screening/Administrative 
 
Pre-screening consent (confirmation of 
NHS, age and mutation) 
 
 
 
Informed consent/(assent) e) 
 
 
 
Inclusion/exclusion criteria  
 
 
 
Demographics and medical history 
 
 
 
Concomitant medications 
 
 
 
Safety Assessments 
 
Physical examination f) 
 
 
 
Triplicate 12-lead ECG  
 
 
 
Vital signs (pulse rate, BP, RR, 
temperature, pulse oximetry) 
 
 
 
Liver ultrasound including hepatic 
elastography  
 
 
 
Platelet count g) 
 
 
() h) 
Clinical laboratory assessments i) 
 
  
() h) 


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PRE-SCREENING, SCREENING, and RUN-IN PERIOD 
Trial Period 
Pre-screening a) 
Screening Period b),c) 
[Run-in Period] c),d) 
Time Point 
Any time before 
screening 
Maximum 6 weeks  
[minimum 28 days in case of run-in period] 
[Minimum 28 days; can be 1 or more visits]  
Complement assessments 
 
  
() h) 
Coagulation assessments j) 
 
 
() h) 
Urinalysis (dipstick) 
 
 
 
Urine pregnancy test k) 
 
 
 
Collect AEs/SAEs 
 
 
 
PD/Exploratory Efficacy Assessments  
 
 
 
PROMIS questionnaires 
 
 
 
GAS questionnaire 
 
 
 
EAT-10 Dysphagia questionnaire 
 
  
 
Respiratory function l) 
 
 
 
MyoGrip l) 
 
 
 
MFM32 l) 
 
 
 
Muscle ultrasound imaging l) m) 
 
 
 
AE: adverse event; BP: blood pressure; EAT-10: Eating Assessment Tool; ECG: electrocardiogram; GAS: Goal Attainment Scaling; MFM: Motor Function Measure; 
NHS: Natural History Study; PD: pharmacodynamics; PROMIS: Patient Reported Outcomes Measurement Information System; RR: respiratory rate; SAE: serious adverse 
event. 
a) Before entering a potentially eligible subject in the Interactive Response Technology (IRT) system, at least a pre-screening consent needs to be fully signed by the 
subject (and his/her parent(s), as locally required for subjects < 18 years of age). The pre-screening consent process can be managed remotely (please refer to the Site 
Operations Manual for more details). 
b) Subjects who are participating in the NHS and have at least 2 data time points available from NHS to assess their pre-trial condition do not require a mandatory run-
in visit. There should be a minimum of 3 data time points to assess their pre-trial condition. The screening visit can be the third data time point. For subjects who are 
participating in the NHS, the screening visit should be performed within 6 weeks before the baseline visit. Subjects who have not participated in the NHS or who do 
not have at least 2 data time points from the NHS will have a mandatory run-in period before continuing to the baseline visit. 
c) Assessments of a single visit can be split over 2 consecutive days, if required.  
d) Subjects who previously participated in the NHS and have at least 2 data time points available from NHS to assess their pre-trial condition do not require a 
mandatory run-in visit; screening should be performed within 6 weeks before the baseline visit. There should be a minimum of 3 data time points to assess their pre-
trial condition. The screening visit can be the third data time point. The run-in period is mandatory for subjects who did not participate in the NHS or who do not 


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Page 20 of 100 
have at least 2 data time points from the NHS.  At least 1 run-in visit needs to be performed in order to obtain 3 data time points to assess their pre-trial condition; 
screening can be the first data time point, baseline can be the third data time point. The run-in period is optional for stand-by subjects who participated in the NHS 
and have at least 3 data time points. Run-in visits should be repeated until the sponsor deems there are sufficient data time points for an individual subject, or until a 
cohort is declared open. During the run-in period, if there was an unscheduled visit for additional laboratory assessments, the initial visit date is taken for the 
calculation to schedule the next visit. There should be a minimum of 28 days between screening and the first run-in visit. Thereafter, run-in visits may be performed 
every 12 weeks (±14 days), until the cohort is declared open. If there is only 1 run-in visit, there should be a minimum of 28 days between the run-in visit and the 
baseline visit. If there is more than 1 run-in visit, there should be 12 weeks (±14 days) in between the run-in visits unless it is known that the baseline visit can be 
scheduled within 14 days following a run-in visit; in that case, the last run-in visit should be dropped. Stand-by subjects will perform run-in visits until the last 
MAD subject has completed Week 13, unless needed for replacement. 
e) Informed consent (and assent, if applicable) must be obtained before any trial procedures are performed. This applies to the main informed consent form (ICF) and 
optional ICFs as applicable. 
f) 
A complete physical examination (including height, body weight and body systems) will be performed at screening. At all other time points, a symptom-directed 
physical examination will be performed.  
g) Platelet counts will be assessed by the local as well as the central laboratory. If platelet clumping is observed in a local sample, the test should be repeated locally 
before IMP administration. In addition, a smear may be performed locally at the investigator’s discretion. 
h) Only to be performed during the run-in period in case the screening laboratory results became available more than 12 weeks before the baseline visit. 
i) 
All parameters that are not described in a separate assessment in this Trial Schedule are to be performed by the central laboratory, as specified in Section 6.2.2.2. 
j) 
Coagulation parameters will be assessed by the local laboratory only. 
k) Only applicable for female subjects of child-bearing potential. 
l) 
Assessments should be performed in the order they are listed after all the questionnaires. 
m) To determine which muscle should be taken for muscle biopsies in this trial. 
 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 
 
 


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2) BASELINE AND SAD 
 
BASELINE and SAD 
Trial Period 
Single Dose Treatment  
Time Point: Day (D) 
Day 0 or 1 a) 
Day 1 
Time Point  
Pre-dose/ 
Baseline 
Pre-dose 
0.5h 
after 
start of 
infusion 
Immediately 
after end of 
infusion 
1h after 
end of 
infusion 
3h after 
end of 
infusion 
7h after 
end of 
infusion 
Time Window 
 
 
±10 
min 
±10 min 
±10 
min 
±10 
min 
±1h 
Administrative 
 
Enrollment  
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical examination b) 
 
 
 
 
 
 
 
Vital signs (pulse rate, BP, RR, temperature, pulse oximetry) 
 c) 
 d) 
 d) e) f) 
 d) e) f) 
 d) 
 d) 
 d) 
Liver ultrasound including hepatic elastography 
() g) 
 
 
 
 
 
 
Platelet count h) 
  
 
 
 
 
 
 
Clinical laboratory tests i) u) 
  
 
 
 
 
 
 
Cardiac troponin j) 
 
 
 
 
 
 
 
Complement assessments i) j)  
 
 
 
 
 
 
 
Coagulation assessments k) 
 
 
 
 
 
 
 
Erythrocyte sedimentation rate k) 
 
 
 
 
 
 
 
Urinalysis (dipstick) 
 
 
 
 
 
 
 
Urine pregnancy test l) 
  
 
 
 
 
 
 
Collect AEs/SAEs 
 
 
 
 
 
 
 


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BASELINE and SAD 
Trial Period 
Single Dose Treatment  
Time Point: Day (D) 
Day 0 or 1 a) 
Day 1 
Time Point  
Pre-dose/ 
Baseline 
Pre-dose 
0.5h 
after 
start of 
infusion 
Immediately 
after end of 
infusion 
1h after 
end of 
infusion 
3h after 
end of 
infusion 
7h after 
end of 
infusion 
Time Window 
 
 
±10 
min 
±10 min 
±10 
min 
±10 
min 
±1h 
PD/Exploratory Efficacy Assessments  
 
Blood sample for biomarkers (optional)  
  
 
 
 
 
 
 
DNA sample (optional)  
  
 
 
 
 
 
 
PROMIS and GAS questionnaires  
  
 
 
 
 
 
 
EAT-10 Dysphagia questionnaire 
 
 
 
 
 
 
 
Respiratory function m) 
  
 
 
 
 
 
 
MyoGrip m) 
  
 
 
 
 
 
 
MFM32 m) 
  
 
 
 
 
 
 
Muscle ultrasound imaging m) 
() n) 
 
 
 
 
 
 
Muscle biopsy m) 
o)  
 
 
 
 
 
 
Single Dose Treatment 
 
Triplicate 12-lead ECG and ECG monitoring p) 
 
 
 
 
Until end of 
infusion 
 
 
 
Start of IMP administration (IV) q) r) 
 
 
 
 
 
 
 
PK Assessments 
 
Blood sample for PK s) 
() t) 
 
 
 
 
 
 


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AE: adverse event; BP: blood pressure; EAT-10: Eating Assessment Tool; ECG: electrocardiogram; EoT: End of Treatment; FU: follow-up; GAS: Goal Attainment Scaling; 
IMP: investigational medicinal product; IPF: immature platelet fraction; IV: intravenous; MFM: Motor Function Measure; PD: pharmacodynamics; PK: pharmacokinetics; 
PROMIS: Patient Reported Outcomes Measurement Information System; RR: respiratory rate; SAD: single ascending dose; SAE: serious adverse event. 
a) If needed, all assessments that need to be performed pre-dose can be done over 2 consecutive days (i.e. Day 0 or Day 1); any exceptions to doing over 2 consecutive 
days due to an open biopsy with general anesthetic must be discussed with the medical monitor in advance for approval. There must be at least 24 hours between an 
open biopsy with general anesthesia and IMP administration. The investigator is to get approval from the medical monitor if additional time is required to perform all 
needed Pre-dose/Baseline assessments. 
b) A symptom-directed physical examination (including a neurologic assessment) and measurement of body weight will be performed. A neurologic assessment is also 
to be performed. 
c) If baseline and IMP administration occur on the same day, vital signs should only be performed once, i.e. immediately before dosing. 
d) Vital signs are to be obtained prior to any PK samples. 
e) Vital signs are to be monitored continuously during infusion such that vital signs will be taken every 5 minutes for the first 15 minutes of the infusion and every 
15 minutes until the infusion is completed. If the infusion is stopped for any reason and restarted, vital signs are to be taken according to this schedule until the 
infusion is completed. All vital signs will be noted as normal, abnormal not clinically significant, or abnormal clinically significant. Any abnormal clinically significant 
vital signs results are to be recorded as an AE.  
f) 
Pulse oximetry device should remain in place throughout the IMP administration; any clinical findings during the continuous monitoring are to be reported.  
g) Only applicable if the screening liver ultrasound and/or hepatic elastography is older than 12 months. 
h) Platelet counts will be assessed by the local as well as the central laboratory. Local results should be available and within acceptable ranges to allow the IMP infusion. 
If platelet clumping is observed in a local sample, the test should be repeated locally before IMP administration. In addition, a smear may be performed locally at the 
investigator’s discretion. If thrombocytopenia is reported after the first IMP administration, and if an IPF test is available at the local laboratory, an IPF should be 
obtained in addition to the platelet count. The IPF is the ratio of immature platelets to the total number of platelets, indicating the percentage of young, so-called 
‘reticulated’ platelets. 
i) 
All parameters that are not described in a separate assessment in this Trial Schedule are to be performed by the central laboratory, as specified in Section 6.2.2.2. 
j) 
Will be assessed by the central laboratory.  
k) Will be assessed by the local laboratory only. 
l) 
Only applicable for female subjects of child-bearing potential. 
m) Assessments should be performed in the order they are listed after all the questionnaires. 
n) Only applicable if the screening muscle ultrasound imaging is older than 6 months. 
o) The muscle biopsy should be obtained after all muscle assessments have been performed. Platelet counts as determined by the local laboratory need to be within 
normal ranges before performing the muscle biopsy. In case general anesthesia is used for an open biopsy (see Section 6.2.6), there should be at least 24 hours between 
the muscle biopsy and the IMP administration. Consequently, platelet counts will need to be verified again before IMP administration (local assessment) only if 
previous platelet count is more than 3 days old. 
p) A triplicate 12-lead ECG will be performed on Day 1, within 30 minutes before the start of IMP administration and within 15 minutes after the end of infusion, and 
ECG monitoring will be performed during the infusion (accompanied by oximetry and vital signs monitoring).   
q) Platelet counts as determined by the local laboratory need to be within normal ranges before IMP administration. If a decreased platelet count is detected 
(value < LLN), a retest should be performed immediately in the local laboratory. If this retest confirms that the platelet count value is below LLN, the subject may 
NOT be dosed. For details see Section 7.11.2. 
r) 
Slow infusion over 1 hour; subjects will be monitored on site by qualified site personnel for a minimum of 1 hour after the infusion for safety. 
s) 
Blood samples for PK will be taken pre-dose (i.e. before the start of infusion), at 30 minutes after start (during infusion), immediately after the end of infusion, and 
at 1, 3, and 7 hours after the end of infusion (on Day 1). See also Section 6.2.3.1. 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 24 of 100 
t) 
The pre-dose PK sample should be taken on Day 1 immediately before the start of IMP infusion. 
u) At timepoints when platelets will be counted, a blood sample will be analyzed centrally for biochemistry and hematology. At timepoints without platelet count, only 
biochemistry samples will be analyzed centrally.  
 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 
Note: In case of early discontinuation, the subject should be encouraged to perform end-of-treatment assessments as detailed for the MAD Week 25 visit (excluding IMP 
administration). SAD subject who discontinued prior to MAD part do not need to have a second muscle biopsy. If subjects agree, they will also have an EoT FU visit 3 months 
after their last IMP administration. 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 25 of 100 
3) SAD FOLLOW-UP AND WASHOUT 
 
SAD FOLLOW-UP and WASHOUT 
Trial Period 
Single Dose Follow-up and Washout Periods a),b) 
Time Point: Week (W) 
SAD 
W1 
SAD 
W2 
SAD 
W3 
SAD 
W5 
SAD 
W7 
SAD 
W9 
SAD 
W11 
SAD 
W13 
SAD 
W15 
SAD 
W17 
Phone 
call c) 
Time Point: Day (D) 
D2 
D3 
D8 
D11 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
Every 
2 weeks 
after 
W17 
Time Window 
 
 
±1d 
±1d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Timing Relative to Baseline 
+24h 
+48h 
+7d 
+10d 
+2w 
+4w 
+6w 
+8w 
+10w 
+12w 
+14w 
+16w 
 
Administrative 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical examination d)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (pulse rate, BP, RR, temperature, pulse oximetry)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet count e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests f) k) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac troponin g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complement assessments g) 
 
 
 
 
 
  
 
  
 
  
 
 
 
Coagulation assessments h)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte sedimentation rate h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (dipstick)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test i) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect AEs/SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 26 of 100 
 
SAD FOLLOW-UP and WASHOUT 
Trial Period 
Single Dose Follow-up and Washout Periods a),b) 
Time Point: Week (W) 
SAD 
W1 
SAD 
W2 
SAD 
W3 
SAD 
W5 
SAD 
W7 
SAD 
W9 
SAD 
W11 
SAD 
W13 
SAD 
W15 
SAD 
W17 
Phone 
call c) 
Time Point: Day (D) 
D2 
D3 
D8 
D11 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
Every 
2 weeks 
after 
W17 
Time Window 
 
 
±1d 
±1d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Timing Relative to Baseline 
+24h 
+48h 
+7d 
+10d 
+2w 
+4w 
+6w 
+8w 
+10w 
+12w 
+14w 
+16w 
 
PK Assessments 
 
Blood sample for PK j) 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD/Exploratory Efficacy Assessments 
 
CGI-I and PGI-C questionnaires  
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory function   
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; BP: blood pressure; CGI-I: Clinical Global Impression of Improvement; EoT: End of Treatment; FU: follow-up; IPF: immature platelet fraction; IV: 
intravenous; MFM: Motor Function Measure; PD: pharmacodynamics; PGI-C: Patient Global Impression of Change; PK: pharmacokinetics; RR: respiratory rate; SAD: single 
ascending dose; SAE: serious adverse event. 
Due to restrictions imposed in response to a pandemic that restrict subject visits, please contact the medical monitor to determine strategy for continuing the subject in the trial. 
All efforts must be employed to maintain subject safety. Assessments, if feasible, must be collected during a phone call with the subject. The site should arrange the collection 
of the blood and urine samples, if at all possible. 
a) Assessments of a single visit can be split over 2 consecutive days, if required.  
b) Where possible, the visits as of Day 8 will take place on the same day of the week as the baseline visit (Day 1). 
c) Subjects will be contacted by phone by qualified site personnel every 2 weeks following Week 17, to follow-up on concomitant medications and AEs, until their 
assigned MAD cohort has been opened.  
d) Symptom-directed physical examination. A neurologic assessment is also to be performed at Week 17. 
e) Platelet counts will be assessed by the local as well as the central laboratory. Local results should be available and within acceptable ranges to allow the IMP infusion. 
If a decreased platelet count is detected (value < LLN), a retest should be performed immediately in the local laboratory. If this retest confirms that the platelet count 
value is below LLN, the subject may NOT be dosed. For details see Section 7.11.2. If platelet clumping is observed in a local sample, the test should be repeated 
locally before IMP administration. In addition, a smear may be performed locally at the investigator’s discretion. If thrombocytopenia is reported, and if an IPF test 
is available at the local laboratory, IPF test results should be obtained in addition to the platelet count. The IPF is the ratio of immature platelets to the total number 
of platelets, indicating the percentage of young, so-called ‘reticulated’ platelets. 
f) 
All parameters that are not described in a separate assessment in this Trial Schedule are to be performed by the central laboratory, as specified in Section 6.2.2.2. 
g) Will be assessed by the central laboratory.  


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 27 of 100 
h) Will be assessed by the local laboratory only. 
i) 
Only applicable for female subjects of child-bearing potential. 
j) 
Blood samples for PK will be collected at 23 (Day 2), 47 (Day 3), and 167 hours (Day 8) after the end of infusion, and at 2 (Day 15) and 4 weeks (Day 29) post-dose, 
and monthly during the washout period. See also Section 6.2.3.1. 
k) At timepoints when platelets will be counted, a blood sample will be analyzed centrally for biochemistry and hematology. At timepoints without platelet count, only 
biochemistry samples will be analyzed centrally. 
 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 
Note: In case of early discontinuation, the subject should be encouraged to perform end-of-treatment assessments as detailed for the MAD Week 25 visit (excluding IMP 
administration). SAD subjects who discontinued prior to MAD part do not need to have a second muscle biopsy. If subjects agree, they will also have an EoT FU visit 3 months 
after their last IMP administration. 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 28 of 100 
4) MAD PART 
 
MAD PART 
Trial Period 
Multiple Dose Treatment Period a) b) 
Time Point: Day (D)/Week (W)  
MAD 
W1  
MAD 
W2 
MAD 
W3 
MAD 
W4 
MAD 
W5 
MAD 
W6 
MAD 
W7 
MAD 
W8 
MAD 
W9 
MAD 
W10 
MAD 
W11 
MAD 
W12 
D1 c) 
D2 
D4 
D8 
D11 
 
 
 
 
 
 
 
 
 
 
Time Window 
±1d 
±1d 
±1d 
±1d 
±1d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Administrative 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration (IV) d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical examination e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triplicate 12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (pulse rate, BP, RR, temperature, 
pulse oximetry) g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver ultrasound including hepatic 
elastography 
()g) h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet count f) g) i) 
 
 
k) 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory assessments f) g) j) 
l) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac troponin f) g) k) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complement assessments f) g) k) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation assessments f) g) m) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte sedimentation rate f) g) m) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (dipstick) g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test g) n) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect AEs/SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 29 of 100 
 
MAD PART 
Trial Period 
Multiple Dose Treatment Period a) b) 
Time Point: Day (D)/Week (W)  
MAD 
W1  
MAD 
W2 
MAD 
W3 
MAD 
W4 
MAD 
W5 
MAD 
W6 
MAD 
W7 
MAD 
W8 
MAD 
W9 
MAD 
W10 
MAD 
W11 
MAD 
W12 
D1 c) 
D2 
D4 
D8 
D11 
 
 
 
 
 
 
 
 
 
 
Time Window 
±1d 
±1d 
±1d 
±1d 
±1d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
PK Assessments 
 
Blood sample for PK 
o) 
 
 
 
 
 
 
 
 
 
 
 
 
 
o) 
Blood sample for anti-drug antibodies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for metabolic profiling  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p) 
24-hour urine collection for metabolic 
profiling  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
q) 
PD/Exploratory Efficacy Assessments  
 
Blood sample for biomarkers (optional) g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS and GAS questionnaires g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EAT-10 Dysphagia questionnaire g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory function g) r) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MyoGrip g) r) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MFM32 g) r) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; BP: blood pressure; EAT-10: Eating Assessment Tool; ECG: electrocardiogram; EoT: End of Treatment; FU: follow-up; GAS: Goal Attainment Scaling; 
IMP: investigational medicinal product; IPF: immature platelet fraction; IV: intravenous; MAD: multiple ascending dose; MFM: Motor Function Measure; PD: 
pharmacodynamics; PK: pharmacokinetics; PROMIS: Patient Reported Outcomes Measurement Information System; RR: respiratory rate; SAE: serious adverse event. 
a) Where possible, the visits in the MAD part will take place on the same day of the week as Day 1 (and of the SAD part, if applicable). A window of ±3 days is allowed 
for visits as of Week 3, with a minimum of 4 days between 2 subsequent infusions. Assessments of a single visit can be split over 2 consecutive days, if required. 
b) Replacement subjects starting in the MAD part should sign an ICF for participation in the MAD part, and their eligibility will be assessed (see Trial Schedule for the 
Screening Period) before the first IMP administration in the MAD part (MAD Week 1 Day 1). If needed (to be discussed with the sponsor), these subjects will have a 
run-in period before they can start in the MAD part (see Trial Schedule for Run-in Period). A DNA sample (optional) and a muscle biopsy should be taken before the 
first IMP administration. If needed, replacement subjects in MAD1 and MAD2 may have the second muscle biopsy taken after 6 to 12 weeks of MAD treatment, after 
discussion with the sponsor. 
c) All assessments need to be done pre-dose. 
d) Slow infusion over 1 hour; subjects will be monitored on site by qualified site personnel for a minimum of 1 hour after the infusion for safety. Platelet counts as 
determined by the local laboratory need to be within normal ranges before IMP administration. 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 30 of 100 
e) A symptom-directed physical examination (and measurement of body weight at MAD Week 1 Day 1) will be performed.  
f) 
During an unscheduled visit which will occur between 6 weeks and 7 days prior to the baseline visit for subjects for whom the last visit in the SAD part will be more 
than 3 months before the baseline visit in the MAD part. 
g) To be performed pre-dose. 
h) Only applicable if a liver ultrasound and/or hepatic elastography was not performed during the screening period. 
i) 
Platelet counts will be assessed by the local as well as the central laboratory. Platelet counts as determined by the local laboratory need to be within normal ranges 
before IMP administration. If a decreased platelet count is detected (value < LLN), a retest should be performed immediately in the local laboratory. If this retest 
confirms that the platelet count value is below LLN, the patient may NOT be dosed. For details see Section 7.11.2. If platelet clumping is observed in a local sample, 
the test should be repeated locally before IMP administration. In addition, smear may be performed locally at the investigator’s discretion. If thrombocytopenia is 
reported, and if an IPF test is available at the local laboratory, IPF test results should be obtained in addition to the platelet count. The IPF is the ratio of immature 
platelets to the total number of platelets, indicating the percentage of young, so-called ‘reticulated’ platelets.  
j) 
All parameters that are not described in a separate assessment in this Trial Schedule are to be performed by the central laboratory, as specified in Section 6.2.2.2. 
k) Will be assessed by the central laboratory.  
l) 
Blood samples for clinical laboratory assessments will be collected at 7, 23 (Day 2), 71 (Day 4), and 167 (Day 8) hours after end of infusion on Day 1. 
m) Will be assessed by the local laboratory only. 
n) Only applicable for female subjects of child-bearing potential. 
o) Blood samples for PK will be collected at MAD Week 1 pre-dose, at 30 minutes after start (during infusion), immediately after the end of infusion, and at 1, 3, 7, 23 
(Day 2), 71 (Day 4), and 167  (Day 8) hours post-dose (i.e. before infusion in Week 2) of MAD Week 1 Day 1 infusion, and at MAD Week 12 pre-dose, at 30 minutes 
after start (during infusion), immediately after the end of infusion, and at 1, 3, 7, 23 (Day 2), 71 (Day 4), and 167 (Day 8) hours after end of infusion (i.e. before infusion 
in Week 13) of MAD Week 12 Day 1 infusion.  
p) A sample will be taken at 1 and 167 hours after the end of infusion (i.e. before infusion in Week 13) in MAD Week 12 Day 1 infusion. 
q) Urine for PK (metabolic profiling) will be collected over a 24-hour interval. The window of collection will be based on the start of the infusion. 
r) 
Assessments should be performed in the order they are listed after all the questionnaires. 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 
Note: In case of early discontinuation, the subject should be encouraged to perform end-of-treatment assessments as detailed for the MAD Week 25 visit (excluding IMP 
administration). In addition, subjects will be encouraged to have the second muscle biopsy taken if the subject had at least 6 weeks of treatment during the MAD part of the trial 
and discontinued prior to having the Week 13 biopsy obtained. If subjects agree, they will also have an EoT FU visit 3 months after their last IMP administration. 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 31 of 100 
5) MAD EXTENSION PART   
 
MAD EXTENSION PART  
Trial Period 
Multiple Dose Treatment Period a) 
EoT/ED 
EoT FU  
Time Point: Week (W) 
MAD 
W13 
MAD 
W14 
MAD 
W15 
MAD 
W16 
MAD 
W17 
MAD 
W18 
MAD 
W19 
MAD 
W20 
MAD 
W21 
MAD 
W22 
MAD 
W23 
MAD 
W24 
MAD 
W25 
MAD Last 
dose + 
3 months b) 
Time Window 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Administrative 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration (IV) c) 
 
 
 
 
 
 
 
 
 
 
 
 
d) 
 
Safety Assessments 
 
Physical examination e) 
 
 
 
 
 
 
 
 
 
 
 
 
f) 
 
Triplicate 12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (pulse rate, BP, RR, 
temperature, pulse oximetry) f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet count f) g) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Clinical laboratory tests f) h) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac troponin f) i) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complement assessments f) i)  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation assessments f) j) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte sedimentation rate f) j) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (dipstick) f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test f) k) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect AEs/SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Assessments 
 
Blood sample for PK  
l) 
 
 
 
 
 
 
 
 
 
 
 
l) 
 
Blood sample for anti-drug antibodies f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 32 of 100 
 
MAD EXTENSION PART  
Trial Period 
Multiple Dose Treatment Period a) 
EoT/ED 
EoT FU  
Time Point: Week (W) 
MAD 
W13 
MAD 
W14 
MAD 
W15 
MAD 
W16 
MAD 
W17 
MAD 
W18 
MAD 
W19 
MAD 
W20 
MAD 
W21 
MAD 
W22 
MAD 
W23 
MAD 
W24 
MAD 
W25 
MAD Last 
dose + 
3 months b) 
Time Window 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Blood sample for metabolic profiling 
l) 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD/Exploratory Efficacy 
Assessments  
 
Blood sample for biomarkers 
(optional) f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS and GAS questionnaires f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-I and PGI-C questionnaires f) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EAT-10 Dysphagia questionnaire f) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory function f) m) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MyoGrip f) m) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MFM32 f) m) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Muscle biopsy m) 
n) 
 
 
 
 
 
 
 
 
 
 
 
()o) 
 
AE: adverse event; BP: blood pressure; CGI-I: Clinical Global Impression of Improvement; EAT-10: Eating Assessment Tool; ECG: electrocardiogram; ED: early 
discontinuation; EoT: End of Treatment; FU: follow-up; GAS: Goal Attainment Scaling; IMP: investigational medicinal product; IPF; immature platelet fraction; IV: 
intravenous; MAD: multiple ascending dose; MFM: Motor Function Measure; PD: pharmacodynamics; PGI-C: Patient Global Impression of Change; PK: pharmacokinetics; 
PROMIS: Patient Reported Outcomes Measurement Information System; RR: respiratory rate; SAE: serious adverse event. 
a) Where possible, the visits in the MAD extension part will take place on the same day of the week as MAD Week 1 Day 1. A window of ±3 days is allowed, with a 
minimum of 4 days between 2 subsequent infusions. Assessments of a single visit can be split over 2 consecutive days, if required. 
b) If a subject is NOT on treatment after the trial, the subject will return to the clinic 3 months after the last IMP administration, to follow-up on the subject’s status 
including abnormal laboratory test results, AEs, and concomitant medications. 
c) Slow infusion over 1 hour; subjects will be monitored on site by qualified site personnel for a minimum of 1 hour after the infusion for safety.  
d) The subject may continue to receive IMP weekly with clinic visits every 2 weeks with assessments as defined in the Trial Schedule for Follow-up post MAD Week 25. 
e) A symptom-directed physical examination (and measurement of body weight at MAD Week 13) will be performed. A neurologic assessment is also to be performed 
at the EoT/ED and EoT FU visit. 
f) 
To be performed pre-dose. 


DYN101-C101 Protocol (Non-substantial administrative correction) 
 
Dynacure 
Date: 01 December 2021, Final 
CONFIDENTIAL 
 
Page 33 of 100 
g) Platelet counts will be assessed by the local as well as the central laboratory. Platelet counts as determined by the local laboratory need to be within normal ranges 
before IMP administration. If a decreased platelet count is detected (value < LLN), a retest should be performed immediately in the local laboratory. If this retest 
confirms that the platelet count value is below LLN, the subject may NOT be dosed. For details see Section 7.11.2. If platelet clumping is observed in a local sample, 
the test should be repeated locally before IMP administration. In addition, smear may be performed locally at the investigator’s discretion. If thrombocytopenia is 
reported, and if an IPF test is available at the local laboratory, IPF test results should be obtained in addition to the platelet count. The IPF is the ratio of immature 
platelets to the total number of platelets, indicating the percentage of young, so-called ‘reticulated’ platelets.  
h) All parameters that are not described in a separate assessment in this Trial Schedule are to be performed by the central laboratory, as specified in Section 6.2.2.2. 
i) 
Will be assessed by the central laboratory.  
j) 
Will be assessed by the local laboratory, only. 
k) Only applicable for female subjects of child-bearing potential. 
l) 
Blood samples for PK and metabolic profiling at MAD Week 13 must be collected 167 hours after the end of infusion from MAD Week 12 Day 1 visit and before the 
infusion of MAD Week 13 visit. Blood sample for PK at MAD Week 25 must be collected 167 hours after the end of infusion from MAD Week 24 Day 1 visit and 
before the infusion of MAD Week 25 visit, where applicable.  
m) Assessments should be performed in the order they are listed after all the questionnaires. 
n) The muscle biopsy should be obtained after all muscle assessments have been performed. Platelet counts as determined by the local laboratory need to be within normal 
ranges before performing the muscle biopsy. In case general anesthesia is used for an open biopsy (see Section 6.2.6), there should be at least 24 hours between the 
muscle biopsy and the IMP administration. Consequently, platelet counts will need to be verified again before IMP administration (local assessment) only if previous 
platelet count is more than 3 days old. 
o) See note about early discontinuation assessments below. 
 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 
Note: In case of early discontinuation, the subject should be encouraged to perform end-of-treatment assessments as detailed for the MAD Week 25 visit (excluding IMP 
administration). In addition, subjects will be encouraged to have the second muscle biopsy taken if the subject had at least 6 weeks of treatment during the MAD part of the trial 
and discontinued prior to having the Week 13 biopsy obtained. If subjects agree, they will also have an EoT FU visit 3 months after their last IMP administration. 
 
 


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6) FOLLOW-UP POST MAD WEEK 25 
All subjects will remain on treatment with weekly IMP administrations and routine safety assessments performed as noted in the table below until 
the last MAD3 subject has completed the MAD Week 25 visit. All assessments are to be performed prior to IMP administration.  
12-week Follow-up Cycle Repeated After Week 25 
Time Point 
Weeks 1, 3, 5, 7, 9, 
and 11 
Weeks 2, 6, and 10 
Weeks 4 
and 8 
Week 12 
EoT 
EoT FU Visit 
Time Window a) 
±3d 
±3d 
±3d 
±3d 
±7d 
3 months after last IMP 
administration 
Administrative 
 
Concomitant medications 
 
 
 
 
 
 
IMP administration (IV) b) 
 
 
 
 
 
 
Safety Assessments 
 
Physical examination c) 
 
 
 
 
 
 
Triplicate 12-lead ECG 
 
 
 
 
 
 
Vital 
signs 
(pulse 
rate, 
BP, 
RR, 
temperature, pulse oximetry) d) 
 
 
 
 
 
 
Platelet count d) e) 
 
 
 
 
 
 
Clinical laboratory tests d) f) 
 
 
 
 
 
 
Cardiac troponin d) g) 
 
 
 
 
 
 
Complement assessments d) g) 
 
 
 
 
 
 
Coagulation assessments d) h) 
 
 
 
 
 
 
Erythrocyte sedimentation rate d) h) 
 
 
 
 
 
 
Urinalysis (dipstick) d) 
 
 
 
 
 
 
Urine pregnancy test d) i) 
 
 
 
 
 
 
Collect AEs/SAEs 
 
 
 
 
 
 
PK Assessments 
 
Blood sample for anti-drug antibodies d) 
 
 
 
 
 
 
PD/Exploratory Efficacy Assessments  
 
Blood sample for biomarkers (optional) d) 
 
 
 
 
 
 


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12-week Follow-up Cycle Repeated After Week 25 
Time Point 
Weeks 1, 3, 5, 7, 9, 
and 11 
Weeks 2, 6, and 10 
Weeks 4 
and 8 
Week 12 
EoT 
EoT FU Visit 
Time Window a) 
±3d 
±3d 
±3d 
±3d 
±7d 
3 months after last IMP 
administration 
PROMIS and GAS questionnaires d) 
 
 
 
 
 
 
CGI-I and PGI-C questionnaires d) 
 
 
 
 
 
 
EAT-10 Dysphagia questionnaire d) 
 
 
 
 
 
 
Respiratory function d) j) 
 
 
 
 
 
 
MyoGrip d) j) 
 
 
 
 
 
 
MFM32 d) j) 
 
 
 
 
 
 
Muscle biopsyd) j) 
 
 
 
 
 
 
AE: adverse event; BP: blood pressure; CGI-I: Clinical Global Impression of Improvement; EAT-10: Eating Assessment Tool; ECG: electrocardiogram; EoT: End of Treatment; 
FU: follow-up; GAS: Goal Attainment Scaling; IMP: investigational medicinal product; IPF: immature platelet fraction; IV: intravenous; MAD: multiple ascending dose; MFM: 
Motor Function Measure; PD: pharmacodynamics; PGI-C: Patient Global Impression of Change; PK: pharmacokinetics; PROMIS: Patient Reported Outcomes Measurement 
Information System; RR: respiratory rate; SAE: serious adverse event. 
a) Where possible, the visits in the MAD extension part will take place on the same day of the week as MAD Week 1 Day 1. A window of ±3 days is allowed, with a 
minimum of 4 days between 2 subsequent infusions. Assessments of a single visit can be split over 2 consecutive days, if required. 
b) Slow infusion over 1 hour; subjects will be monitored on site by qualified site personnel for a minimum of 1 hour after the infusion for safety.  
c) A symptom-directed physical examination and measurement of body weight. A neurologic assessment is also to be performed at EoT and EoT FU. 
d) To be performed pre-dose. 
e) Platelet counts will be assessed by the local laboratory only at weeks 2, 6, and 10 and both at the local and central laboratory at weeks 4, 8, and 12. Platelet counts as 
determined by the local laboratory need to be within normal ranges before IMP administration. If a decreased platelet count is detected (value < LLN), a retest should 
be performed immediately in the local laboratory. If this retest confirms that the platelet count value is below LLN, the subject may NOT be dosed. For details see 
Section 7.11.2. If platelet clumping is observed in a local sample, the test should be repeated locally before IMP administration. In addition, a smear may be performed 
locally at the investigator’s discretion. If thrombocytopenia is reported, and if an IPF test is available at the local laboratory, IPF test results should be obtained in 
addition to the platelet count. The IPF is the ratio of immature platelets to the total number of platelets, indicating the percentage of young, so-called ‘reticulated’ 
platelets.  
f) 
All parameters that are not described in a separate assessment in this Trial Schedule, as specified in Section 6.2.2.2, will be evaluated by the central laboratory at 
weeks 4, 8, and 12. Local results should be available and within acceptable ranges to allow the IMP infusion. If the local test result is abnormal, the test is to be repeated 
at the local laboratory immediately. If the repeat test is still abnormal, the test is to be repeated at the central laboratory at the next visit. 
g) Will be assessed by the central laboratory. 
h) Will be assessed by the local laboratory only. 
i) 
Only applicable for female subjects of child-bearing potential. 
j) 
Assessments should be performed in the order they are listed after all the questionnaires. 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 


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1. INTRODUCTION 
Centronuclear myopathies (CNMs) are a group of severe, debilitating, non-dystrophic, congenital 
myopathies, for which no effective therapy is currently available. CNMs are characterized by 
muscle weakness, fiber atrophy, predominance of type I fibers, and increased centralization of 
nuclei not secondary to muscle regeneration (Jungbluth et al., 2008; Romero and Bitoun, 2011). 
Three main forms of CNM have been characterized: 
• X-linked CNM (XLCNM), caused by mutations in the myotubularin 1 gene (MTM1) 
(Laporte et al., 1996);  
• Autosomal dominant CNM (ADCNM), caused by mutations in the dynamin 2 gene 
(DNM2) (Bitoun et al., 2005); 
• Autosomal recessive CNM (ARCNM), caused by mutations in the amphiphysin II 
gene (BIN1) (Nicot et al., 2007). 
The 3 genes with mutations causing CNM (MTM1, DNM2 and BIN1) are involved in membrane 
remodeling and membrane trafficking, and impairment of these processes could be a common 
CNM pathomechanism. 
Diagnosis of CNM is the same for all phenotypes: the presence of centrally placed nuclei on 
muscle biopsy in addition to clinical features and confirmative genotyping.  
Currently, there is no cure or disease-modifying therapy for CNM. Treatment of CNM is 
supportive. 
In this trial, the focus is on XLCNM and ADCNM as there are currently not enough BIN1 model 
data to support the inclusion of subjects with ARCNM. 
1.1 Condition Background and Current Treatment 
1.1.1 X-linked CNM 
XLCNM, also referred to as myotubular myopathy, is the best characterized form of CNM. 
Typically associated with congenital onset, profound muscle weakness, respiratory failure, and 
high mortality rates, it is considered to be the most severe form. The large majority of patients 
die within the first months of life, but a relatively small proportion of boys may be less affected 
in the neonatal period and survive into childhood and even adulthood (McEntagart et al., 2002). 
Many patients surviving through infancy usually remain severely impaired and require intensive 
physiotherapy and adapted rehabilitation (permanent ventilation, brace with head support, 
feeding tube) (Romero and Bitoun, 2011). Female carriers can also be affected to a variable 
degree (Jungbluth et al., 2003; Kristiansen et al., 2003). 
XLCNM is caused by mutations in the MTM1 gene, located on human chromosome Xq28. 
Myotubularin belongs to the large family of dual-specificity phosphatases, playing a role in the 
epigenetic regulation of signaling pathways involved in muscle growth and differentiation 
(Laporte et al., 1998). 
Currently, an incidence of 1 in 50,000 births has been reported for severe male XLCNM (Bertini 
et al., 2004; Laporte et al., 2001; Jungbluth et al., 2013), and pediatric point prevalence of CNM 
has been estimated to be < 1 in 100,000 (Biancalana et al., 2012; Fattori et al., 2015), both likely 
underestimate the current pool (Jungbluth et al., 2013; Verhaart et al., 2017a; Verhaart et al., 


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2017b). An integrated model utilizing available literature provides a prevalent patient pool of 
776 severe, 334 moderate and 1,542 mild XLCNM cases worldwide (Vandersmissen et al., 
2018). 
Data from 4 natural history studies (NHSs) evaluating XLCNM are currently available. 
(Annoussamy et al., 2016; Annoussamy et al., 2017; McEntagart et al., 2002; Amburgey et al., 
2017; Beggs et al., 2018). The data illustrate the substantial clinical and economic burden on 
XLCNM patients and their families. Increasing cumulative lifetime need for ventilation and 
tracheostomy with age place a substantial quality-of-life (QoL) burden on patients and their 
families, likely including cost, anxiety about the machines failing, difficulty communicating, and 
limitations on mobility and social activities. 
The overall median survival in XLCNM patients was 29 months (McEntagart et al., 2002). 
1.1.2 Autosomal Dominant CNM 
The clinical phenotypes of ADCNM range from mild and moderate forms in adult patients to 
severe forms in infants. In general, adolescent and young adult patients with moderate phenotype 
have moderate skeletal muscle weakness associated with ptosis and ophthalmoplegia and had 
delayed motor milestones as children. Pediatric patients usually have generalized weakness, 
hypotonia, moderate degree of facial weakness with open mouth, ptosis, and ophthalmoplegia 
(Romero and Bitoun, 2011). Many children with the disease also have stiff joints and sideways 
curvature of the spine (scoliosis). In childhood, as in the neonatal period, there is a risk of 
respiratory failure which can become life-threatening in serious situations (e.g. if the patient 
develops pneumonia). Adults may experience respiratory failure, which in turn may cause 
cardiac insufficiency. A significant portion of patients become wheelchair-dependent in their 
fifties (Bitoun et al., 2005; Verhaart et al., 2017a; Verhaart et al., 2017b; Voermans, 2017). 
ADCNM is caused by mutations in the DNM2 gene on chromosome 19p13.2 (Bitoun et al., 
2005). Dynamins are structurally complex proteins composed of 5 different domains. 
CNM-causing mutations identified to date mainly localize to the middle domain involved in 
protein self-assembly and centrosome localization. 
The incidence of ADCNM is currently unknown, although it has been reported to account for 
approximately 50% of CNM cases (Romero, 2010). The patient pool is estimated to have 
553 prevalent cases worldwide (Vandersmissen et al., 2018). No NHS data of ADCNM have 
been published to date. 
The prognosis of ADCNM is currently unknown. However, it appears to be quite heterogeneous, 
with some patients exhibiting a rapid deterioration and others a slow progressive loss of muscle 
function. 
1.2 RNA-targeted Therapeutic Concept 
Antisense oligonucleotide (ASO) technology represents a promising therapeutic approach for 
diseases caused by gain-of-function mutations. It either reduces expression of the mutant gene or 
induces the production of a functional or partially functional protein through a number of 
mechanisms including splicing modulation for loss-of-function genetic diseases. In 
neuromuscular diseases, this approach has been mainly applied to dystrophic muscle diseases 
where uptake may be facilitated by disruption of membrane integrity, or to diseases with nuclear 
accumulation of pathogenic RNA that favors RNase H1-dependent degradation of the targeted 
transcript (Wheeler et al., 2012). 


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As MTM1 and DNM2 are involved in membrane remodeling and membrane trafficking, 
impairment of these processes could be a common CNM pathomechanism. The physiological 
interplay is complex and not completely understood. MTM1 and DNM2 function in a common 
pathway, where either loss-of-function mutations in MTM1 or gain-of-function mutations in 
DNM2 lead to the CNM phenotype. MTM1 is a regulator of DNM2 in skeletal muscle in vivo 
(Cowling et al., 2014).  
Nonclinical data in mouse models of XLCNM and ADCNM have demonstrated a rescue of the 
CNM phenotype by reducing Dnm2 mRNA (Cowling et al., 2014;Tasfaout et al., 2017; Buono 
et al., 2018). 
Based on these nonclinical results, the sponsor has decided to develop DYN101, an ASO 
targeting reduction of human DNM2 mRNA, for subjects with mutations in MTM1 (XLCNM) 
and mutations in DNM2 (ADCNM).  
1.3 Investigational Medicinal Product Background 
 
  
Mutations in the DNM2 gene or genes upstream of DNM2 in the molecular pathway result in 
higher activity of DNM2 protein (either by activation or higher accumulation of the protein), 
which in turn plays a critical role in manifestation of CNM of different types in pediatric and 
adult patients (Cowling et al., 2014; Cowling et al., 2017; Buono et al., 2018). 
A summary of the experiments with DYN101 is provided below. For detailed information on 
DYN101, refer to the latest version of the Investigator’s Brochure (IB) (Dynacure). 
Compatibility of DYN101 200 mg/mL eq. sterile solution with the selected infusion solution and 
the selected infusion tubing for clinical study DYN101-C101, was evaluated in a compatibility 
study. The compatibility study mimicked the worst-case interaction of DYN101 200 mg/mL eq. 
sterile solution with tubing, infusion solution and infusion bag. 
The compatibility study evaluated both the physico-chemical and chemical stability of DYN101 
in the infusion solution after adding, after 6 hours and after 24 hours. Two infusion bags were 
prepared (3.5 mL DYN101 added to 250 mL sodium chloride 0,9%) and 20 mL samples were 
taken through the tubing at T0. The prepared infusion bags were stored at room temperature and 
at T6h (bag 1) and T24h (bag 2), a second 20 mL sample per bag is taken though the tubing. Test 
parameters were appearance, pH, viscosity, assay DYN101, chromatographic purity and 
osmolality, determined at time points 0, 6, and 24 hours. 
No physico-chemical or chemical degradation was observed in any of the samples tested in the 
compatibility/stability study. Based on the test results obtained in the study, it can be concluded 
that the proposed study set-up, using 1-mL or 3-mL syringes with luer lock, together with 0.9% 
sodium chloride infusion bags and the proposed infusion tubing is compatible with the DYN101 
solution. 


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1.3.1 Nonclinical Information 
Potency and efficacy of DYN101 were tested in vitro in human cell lines and in vivo in transgenic 
mice expressing human DNM2. Tolerability and safety were assessed in rodents (mice, rats) and 
in non-human primates (NHP). Single nucleotide polymorphism and off-target analysis was done 
in silico and in vitro. 
Proof-of-concept studies in mouse CNM disease models have demonstrated the efficacy of 
DNM2 mRNA targeting, DNM2 protein level reduction and disease improvement/stabilization. 
Reduction of DNM2 mRNA was already seen 1 week after dosing. In addition, 
pharmacology/tolerability and toxicity studies in mice, rats, and Cynomolgus monkeys have 
demonstrated the safe dosing of DYN101 up to/higher than the targeted human dose levels. 
In general, ASOs show a fast distribution (minutes to hours) into tissue, a rapid transmission into 
cells and long half-lives (2-4 weeks). In addition, pharmacokinetic (PK) properties of ASOs are 
similar across species (Yu et al., 2013) especially NHP PK data can be used to predict human PK 
behavior, including steady state in humans. Based on toxicokinetic results of a 13-week NHP 
study, DYN101 exposures increased in a dose-dependent manner with only moderate 
accumulation. As typical for ASOs, the subcutaneous (SC) administration of DYN101 exhibited 
a fast absorption (tmax=2 hours) with lower Cmax in comparison to the intravenous (IV) group and 
100% bioavailability based on AUC. After reaching Cmax, DYN101 concentration decreased in a 
biphasic manner with a fast-distributional half-life (t1/2) and a slower terminal elimination t1/2 of 
21 days (see Section 3.2.1 of the IB). A population PK modeling and simulation approach showed 
90% of steady state concentration will be reached with the planned dosing regimen (weekly 
administrations in MAD part), after 6 weeks, justifying a biopsy sample taken for early drop outs 
(see Section 3.1.2).  
1.3.2 Clinical Information 
No clinical studies have been conducted with DYN101 so far. 
1.4 Rationale for the Trial 
There are no available treatments aside from supportive care for patients with CNM. This 
first-in-human trial with DYN101 aims to assess the safety, tolerability, PK and 
pharmacodynamics (PD)/preliminary efficacy of DYN101 in subjects ≥ 16 years of age with 
CNM caused by mutations in DNM2 or MTM1. Targeted lowering of DNM2 is a novel 
therapeutic approach and is expected to benefit these patients. DNM2 protein is ubiquitously 
present in human cells and elevations in DNM2 protein levels or DNM2 function have been 
demonstrated in muscle tissue in preclinical models and in human tissue from CNM patients. 
Preclinical models of these mutations have shown the potential of reducing DNM2 mRNA to 
prevent and reverse the clinical status. 
 
 
A translation of similar 
changes in efficacy parameters in these knock-out mouse models to patients has been 
demonstrated by MTM1 gene therapy in an ongoing clinical trial conducted by Audentes 
Therapeutics in patients with XLCNM up to 4 years of age (ASPIRO trial, ClinicalTrials.Gov 
Identifier: NCT03199469). Moreover, an increased uptake of ASO was seen in muscle of 
diseased mice over their wild-type counterparts. This first-in-human trial for DYN101 will 
therefore be conducted in patients and not in healthy volunteers to assess safety, PK and dose 
selection based on PD/preliminary efficacy. 


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1.5 Risk/Benefit Considerations 
As this trial is investigational, there is no defined, expected benefit for subjects who participate 
in this trial except a better knowledge of their pathology, and the knowledge that they contribute 
to RNA-targeted therapy for CNM patients carrying MTM1 and DNM2 mutations. Should a clear 
benefit be shown, the sponsor will consider prolonging therapy for those who participated in the 
trial. 
Due to the encouraging results in animal models of the disease, the translation of changes in 
efficacy parameters from animals to humans seen in the ongoing gene therapy trial conducted by 
Audentes Therapeutics (see Section 1.4), and a minimum treatment duration of 24 weeks in this 
trial, it is possible that subjects may exhibit some clinical benefits during the multiple ascending 
dose (MAD) or MAD extension.  
The risks as described in the following paragraphs are considered to be potential risks to trial 
subjects, based on what is known about ASOs and the mechanism of action of DYN101. The 
choice of the eligibility criteria and assessments for this trial in relation to risk mitigation is 
explained in Section 3.2. 
Although this will be the first trial with an ASO specifically directed at lowering DNM2 mRNA, 
it can be expected that similar ASO-platform toxicities could occur (adverse events [AEs] of 
special interest, see Section 7.2):  
• A decrease in platelets to low levels resulting in bleeding has been observed with other 
ASOs. Subjects must have normal platelet levels upon entry into the trial, and will be 
monitored throughout the trial (see also Sections 4.1 and 7.11). In addition to central 
laboratory testing, platelet counts will be performed locally before investigational 
medicinal product (IMP) administration at the time points specified in the TRIAL 
SCHEDULES and before performing a muscle biopsy. 
• ASOs are generally directed to the liver, and transient elevation of liver enzymes may be 
observed as a result. Subjects will be excluded from this trial if they have clinically 
significant evidence of liver disease. In case any liver abnormalities are observed at 
baseline, there should be a medically plausible reason for these abnormalities, and a 
discussion with the medical monitor should occur in this situation before the subject may 
be dosed for the trial). Liver enzymes will be closely monitored throughout the trial (see 
also Sections 4.2 and 7.11). 
• ASOs are metabolized by cellular endonucleases and the metabolites are then excreted 
by the kidneys. Estimated glomerular filtration rate (eGFR) must be within normal range 
upon inclusion into the trial and will be monitored throughout the trial (see also 
Sections 4.1 and 7.11). Any abnormal results of these tests should have a medically 
plausible reason and should be discussed with the medical monitor before the subject may 
be screened and/or dosed for the trial. 
Infusion reactions after ASO administration have been known to occur, and are possibly related 
to complement activation, resulting in local inflammation at the injection site. The DYN101 
infusion will be given at a slow rate over 1 hour to minimize the potential of an infusion reaction. 
Additionally, complement factors will be assessed after each SAD infusion and repetitively 
during the MAD and extension phase (refer to TRIAL SCHEDULES).  


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Should there be significant infusion reaction symptoms, the infusion should be paused for 
30 minutes and then restarted at half the rate. If this is still followed by symptoms, the subject 
should be treated per local standard practice (e.g. a steroid bolus), or the infusion should be 
stopped altogether. 
In addition, several safety measures have been proposed to minimize risk to subjects, including: 
• 
Utilization of selection criteria which exclude subjects who may potentially be at higher risk 
of an AE (refer to Section 4). 
• 
Utilization of withdrawal criteria (refer to Section 4.5). Subjects withdrawn from IMP or 
from the trial (except when due to withdrawal of consent), will be encouraged to complete 
the assessments of the early discontinuation visit (refer to Section 6.1.5). 
• 
AEs assessed as “related” to IMP and all serious adverse events (SAEs) and AEs of special 
interest (regardless of their relationship to IMP) still ongoing after end of trial participation 
should be followed on a regular basis according to the investigator’s clinical judgment until 
the condition is stable (refer to Section 7.10). 
• 
Close monitoring and careful dose escalation as well as the implementation of an IDMC (see 
Sections 3.1.1 and 9.12). 
• 
The dosing schedule takes into account the possible side effect of Cmax exposures 
(tmax expected: 2-4 hours) and the observed high plasma exposures (during distribution 
phase) (see IB, Dynacure). The distribution phase lasts approximately 24-48 hours. 
Therefore, the medical monitor will review the 48-hour safety data of the first subject in a 
cohort before the next subject can be dosed, and there will be an interval of 7 days between 
dosing of the first and second subject in a cohort (see Section 3.1.1), to see if any delayed 
toxicities occur. In addition, any SAE data from the first subject received up until the 
moment of treatment of the second subject will be taken into account. 
• 
Safety evaluations will be done at several time points throughout the trial (refer to the TRIAL 
SCHEDULES). Blood samples for biochemistry and hematology (including platelet counts), 
coagulation tests, complement tests, and urine samples for urinalysis will be collected. Vital 
signs and triplicate 12-lead electrocardiograms (ECGs) will be recorded, as well as ECG 
monitoring which will be performed during the single dose infusion (see Section 6.2.2.5). 
Physical examinations will be performed. In addition, liver ultrasound including hepatic 
elastography will be performed. IMP can be stopped or interrupted at the investigator’s 
discretion (refer to Sections 4.5 and 7.11.2). 
• 
For all subjects, there are pre-specified rules that would result in pausing/stopping of IMP 
administration if predefined conditions occur, preventing exposure of further subjects to IMP 
until the IDMC has reviewed all safety data (refer to Section 7.11.1). 
• 
The blood sample collection scheme is designed to perform the safety, tolerability and PK 
(optional for biomarkers and DNA) assessments with a minimum number of blood samples 
being collected. The total blood volume to be collected is considered to be within the limits 
of standard blood donation (refer to Section 6.2.86.2.7). Blood samples will be collected by 
indwelling catheters to minimize discomfort and distress due to repeated venipunctures for 
blood sampling. 
• 
Pregnancy and breastfeeding are exclusion criteria. In addition, all subjects are required to 
use contraceptive methods, as detailed in Section 4.3. 


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More detailed information about the known and expected benefits and risks of DYN101 can be 
found in the IB for DYN101 (Dynacure). 
2. TRIAL OBJECTIVES AND HYPOTHESIS 
2.1 Primary Objective 
• To assess the safety and tolerability of 3 single ascending dose (SAD) levels and 3 MAD 
levels of DYN101. 
2.2 Secondary Objectives 
• To assess the PK of SAD and MAD of DYN101. 
• To explore target engagement in muscle of DYN101. 
2.3 Exploratory Objectives 
• To investigate the effect of DYN101 treatment on the clinical assessments in various 
affected domains (respiratory, muscle strength and function, dysphagia). 
• To explore the impact of CNM and its treatment on symptoms, functioning, and 
health-related QoL. 
• To assess the presence of anti-drug antibodies (ADA) against DYN101 by collecting 
blood samples. 
• To assess the metabolic profile of DYN101 by collecting blood and urine samples. 
• To contribute to the global understanding of CNM and its treatment by collecting 
blood and muscle samples for further exploratory biomarker/genetic research. 
2.4 Hypothesis 
As this trial is designed to provide descriptive information regarding safety and tolerability, no 
formal statistical hypothesis testing is planned. 
3. TRIAL DESIGN 
3.1 Overall Trial Design 
3.1.1 Overview of Trial Periods 
This is a first-in-human, Phase 1/2, open-label, multi-center trial to evaluate the safety, 
tolerability, PK, PD and preliminary efficacy of DYN101 after SAD and MAD in subjects 
≥ 16 years of age* with CNMs caused by mutations in DNM2 or MTM1 (*for Germany, the 
subject must be ≥ 18 years of age in accordance with local and national regulations).  
Sufficient subjects will be screened in order to ascertain that approximately 18 subjects will be 
dosed and finish the trial. Subjects may be recruited from an ongoing NHS (Nat-His-CNM Trial 
Protocol, 2017). 


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There will be stand-by subjects for replacement of subjects who discontinue the trial early, if 
needed. Stand-by subjects will perform run-in visits until the last MAD subject has completed 
Week 13, unless needed for replacement. 
The trial will consist of a pre-screening consent, a screening period, a run-in period (if 
applicable), a SAD part with 4 weeks of follow-up after IMP administration and a washout period 
of at least 12 weeks (followed by follow-up phone calls until the MAD part starts), a MAD part 
of 12 weeks, and a MAD extension part of 12 weeks. All subjects will participate in the SAD, 
MAD and MAD extension parts, unless they withdraw. End of Treatment (EoT) assessments will 
be performed after 24 weeks of MAD treatment have been completed, i.e. at the Week 25 visit. 
Subjects will return to the clinic 3 months after the last IMP administration, to follow-up on the 
subject’s status including abnormal laboratory results, AEs, and concomitant medications. The 
trial design is presented in Figure 1. 
 
 
Abbreviations: BL: baseline, EoT: End of Treatment, FU: follow-up, MAD: multiple ascending dose, SAD: single 
ascending dose, SCR: screening, W: week 
* All subjects will remain on treatment with weekly IMP administrations and bi-weekly (every 2 weeks) assessments 
until the last MAD3 subject has completed the MAD Week 25 visit. The data generated from these bi-weekly 
assessments will not be part of the statistical analysis for this trial (see Section 9.1). 
Figure 1: 
Trial Design: Trial Periods 
Subjects will give a ‘pre-screening’ consent to be entered as ‘pre-screened’ in the Interactive 
Response Technology (IRT) system. The pre-screening consent process can be managed 
remotely (please refer to the Site Operations Manual for more details). Subsequently, subjects 
will sign the main informed consent form (ICF) and screening will be performed to assess 
eligibility. Subjects who are participating in the NHS and have at least 2 data time points 
available from the NHS to assess their pre-trial condition do not require a mandatory run-in visit. 


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Subject screening should be performed within 6 weeks before the baseline visit. There should be 
a minimum of 3 data time points to assess their pre-trial condition. The screening visit can be the 
third data time point. 
Subjects who have not participated in the NHS or who do not have at least 2 data time points 
from the NHS will have a mandatory run-in period before continuing to the baseline visit. At 
least 1 run-in visit needs to be performed for these subjects in order to obtain 3 data time points 
to assess their pre-trial condition; screening can be the first data time point, baseline can be the 
third data time point. There should be a minimum of 28 days between screening and the first run-
in visit. Run-in visits may be repeated until the assigned cohort can start (see Section 6.1.2). The 
run-in period is optional for stand-by subjects who participated in the NHS and have at least 3 
data time points. 
At baseline, subjects will be enrolled into the trial (if all in- and exclusion criteria are still met) 
until recruitment in the last cohort is reached, including replacement subject(s) who were 
amongst the stand-by subjects. Stand-by subjects will perform run-in visits until the last MAD 
subject has completed Week 13, unless needed for replacement. 
In the SAD part, subjects will receive a single dose of IMP at Day 1. In the MAD part, subjects 
may receive the same or a different dose as in the SAD part, with weekly administrations of IMP 
for a period of 12 weeks, followed by a MAD extension part with an additional 12 weeks of 
treatment (weekly administrations). After Week 24, all subjects will remain on treatment with 
weekly IMP administrations and bi-weekly (every 2 weeks) assessments until the last MAD3 
subject has completed the MAD Week 25 visit. In order to avoid any overlaps, a given MAD 
cohort may not start before its corresponding SAD cohort is finished. 
Subjects will receive DYN101 in a low (1.5 mg/kg), middle (4.5 mg/kg), or high (up to 9 mg/kg) 
dose level in Cohorts 1, 2 and 3, respectively. In the MAD part, subjects may receive a different 
dose than what they received in the SAD part. In each cohort, there will be up to 6 subjects with 
a mutation in DNM2 (sub-cohort a) and up to 3 subjects with a mutation in MTM1 (sub-cohort 
b).  
Cohorts will be enrolled in a sequential, staggered approach, with an interval of at least 7 days 
between dose administration of the first and the next subject in a cohort, irrespective of their sub-
cohort. The first subject (i.e. the sentinel subject) in each cohort will be ≥ 18 years of age. The 
48-hour safety data from the first subject in a cohort will be reviewed by the medical monitor 
before the next subject can be dosed. In addition, any SAE data from the first subject received 
up until the moment of treatment of the second subject will be taken into account. 
Pausing/stopping rules will be applied in this trial (see Section 7.11). 
An IDMC will be established to monitor the safety data on a regular basis to ensure the continuing 
safety of the enrolled subjects. The IDMC may meet at any time based on emerging safety and 
tolerability data. At a minimum, the IDMC must meet after all subjects of a cohort have been 
dosed to advise to continue each MTM1 and/or DNM2 sub-cohort to the next dose level/or 
discontinue the MTM1 and/or DNM2 sub-cohort of the trial. Escalation of each MTM1 and/or 
DNM2 sub-cohort to the next increased dose level will not take place until the IDMC has 
reviewed the data of the previous sub-cohort (including subjects who have discontinued the trial). 
The data reviewed by the IDMC for dose escalation decisions will be as clean as possible prior 
to their review. The IDMC can recommend adjusting dose levels or stopping the dose escalation 
scheme for each MTM1 and/or DNM2 sub-cohort and/or individual subject based on the totality 
of available data (safety and tolerability data and/or level of target engagement). At each IDMC 
review, different decisions for the sub-cohorts (DNM2 vs MTM1) can be made based on the 


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emerging data. If needed, the IDMC review can be split over separate meetings for the sub-
cohorts, although the available data from the other sub-cohort will also be taken into account at 
each meeting.  
The IDMC will convene at least 4 times: 
• The trial will start with the enrollment of approximately 6 subjects in Cohort SAD1.  
• Cohort SAD2 can start after a favorable IDMC review of the 2-week safety and PK 
data of SAD1 (IDMC1). 
• Cohorts SAD3 and MAD1 can start after a favorable IDMC review of the 2-week 
safety and PK data of SAD2 (IDMC2). 
• Cohort MAD2 can start after a favorable IDMC review of the 2-week safety and PK 
data of SAD3, if available, as well as the 6-week safety and PK data of MAD1 
(IDMC3). 
• Cohort MAD3 can start after a favorable review of the 12-week safety and PK data 
of MAD1 and MAD2 as well as the MAD1 and MAD2 12-week PK and muscle 
biopsy data (IDMC4). In this meeting the IDMC will also recommend a starting dose 
for the pediatric DYN101-C102 study. 
Details of the IDMC review will be described in the IDMC charter (see Section 9.12). 
 
 
IDMC1: review of 2-week safety and PK data of SAD1; IDMC2: review of 2-week safety and PK data of SAD2; 
IDMC3: review of 2-week safety and PK data of SAD3, if available, and 6-week safety and PK data of MAD1; 
IDMC4: review of 12-week safety and PK data of MAD1 and MAD2, and 12-week PK and muscle biopsy data of 
MAD1 and MAD2. 
Figure 2: 
Trial Cohorts and IDMC Reviews 
Safety and tolerability will be evaluated throughout the trial from signing of the main ICF 
onwards until the last trial visit (i.e. EoT follow-up visit 3 months after the last IMP 
Cohort SAD1 
Low dose 
Cohort SAD2 
Middle dose 
Cohort SAD3 
High dose 
Cohort MAD1 
Low dose 
Cohort MAD2 
Middle dose 
Cohort MAD3 
High dose 
IDMC1 
IDMC2 
IDMC4 
IDMC3 
IDMC4 
IDMC3 
IDMC2 


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administration). Safety evaluations will include monitoring of SAEs/AEs, clinical laboratory 
tests, ECGs, vital signs, and physical examinations at specified time points. 
All enrolled subjects will undergo blood sampling for PK evaluations at specified time points. In 
addition, blood and/or urine samples will be collected for analysis of ADA and metabolic 
profiling. 
PD/exploratory efficacy parameters including respiratory function, muscle strength and function, 
and dysphagia will be assessed, and a muscle biopsy will be taken at specified time points.  
For subjects who provided a separate informed consent, blood samples will be collected for 
further exploratory research on blood biomarkers (including DNA). Participation in this part of 
the trial is optional and does not impact the subject’s eligibility for participation in the trial. 
Subjects may continue to participate in the trial if they refuse to provide a sample or if they 
withdraw their samples. 
The impact of CNM and its treatment (safety and efficacy) on QoL and health outcomes will be 
evaluated at specified time points, using questionnaires. 
For an overview of the safety, PK and PD/exploratory efficacy assessments, please refer to the 
TRIAL SCHEDULES. 
An interim analysis will be performed when all subjects in Cohorts 1 and 2 have completed 12 
weeks of MAD treatment or discontinued earlier, or if the sponsor deems a risk/benefit analysis 
necessary at any time point. The primary analysis will be performed when all subjects in all 
cohorts have completed 12 weeks of MAD treatment or discontinued earlier. The final analysis 
will be performed when all subjects have completed 24 weeks of MAD treatment (12 weeks in 
the MAD part + 12 weeks in the MAD extension part; Week 25 visit) or discontinued earlier. 
The duration of participation in the trial for an individual subject in any cohort, from screening 
(excluding run-in period) to the last trial visit, will be at least 60 weeks. 
The end of the trial is defined as the last visit of the last subject. 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
Manual, Pharmacy Manual). 
3.1.2 Replacement of Subjects 
Enrolled subjects who are withdrawn (see Section 4.5) can be replaced after discussion with the 
sponsor, the medical monitor and the investigator in the following circumstances:  
• Enrolled subjects who participated in the SAD part and drop out before the start of 
the MAD part can be replaced (for the MAD part).  
• Enrolled subjects who drop out and received less than 6 weeks of MAD treatment 
can be replaced.  
• Enrolled subjects who drop out but received between 6 and 12 weeks of MAD 
treatment and do not consent to a second muscle biopsy can be replaced. However, 
subjects will not be replaced if they received between 6 and 12 weeks of MAD 
treatment and consent to a second muscle biopsy, or if they received more than 
12 weeks of MAD treatment. 


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There will be stand-by subjects for replacement of subjects who discontinue the trial early, if 
needed. Stand-by subjects will perform run-in visits until the last MAD subject has completed 
Week 13, unless needed for replacement. 
Replacement subjects starting in the MAD part should sign an ICF for participation in the MAD 
part, and their eligibility will be assessed before the first IMP administration in the MAD part 
(MAD Week 1 Day 1). Replacement subjects may or may not need a run-in period, in 
consultation with the sponsor. A muscle biopsy and a DNA sample should be taken before the 
first IMP administration. If needed, replacement subjects in MAD1 and MAD2 may have the 
second muscle biopsy taken after 6 to 12 weeks of MAD treatment, after discussion with the 
sponsor. 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
Manual, Pharmacy Manual). 
3.2 Trial Design Rationale 
3.2.1 Rationale for Choice of Design 
Both XLCNM and ADCNM are ultra-rare diseases, and adult patients who are ambulatory 
comprise a very small proportion of the total population. A limited number of patients thus meet 
the criteria for eligibility into this Phase 1/2 trial. In these circumstances, ultra-orphan diseases 
often do not include a placebo arm in their first in human studies. 
The primary and secondary endpoints to this trial are safety/tolerability and PK/PD, with efficacy 
being a tertiary endpoint. An NHS that has been ongoing for several years has had safety 
parameters captured and it is intended to compare the AEs and SAEs in the Phase 1/2 trial to 
those recorded in the NHS. The PK/PD results do not need any comparison to placebo. 
The NHS is demonstrating that patients are very stable for all the assessment measures that are 
included in this Phase 1/2 trial (except for dysphagia which is a new parameter). These 
assessments were repeated 3 times and were shown to be reliable with little variability. In this 
Phase 1/2 trial, assessments will be repeated 3 times with an accepted variability of 10% for the 
recording of the best value, which is difficult to assign to a placebo effect. These tertiary results 
will only be used to strengthen the choice of a dose for pivotal trials that will be primarily based 
on the safety, tolerability, PK, ASO concentration and DNM2 mRNA reduction in muscle 
biopsies. 
3.2.2 Rationale for Choice of Eligibility Criteria 
As explained in Section 1.4, changes in efficacy parameters observed in mouse models can be 
translated to patients. This first-in-human trial for DYN101 will therefore be conducted in 
patients and not in healthy volunteers to assess safety, PK and dose selection based on PD and 
possibly efficacy. 
Subjects ≥ 16 years will be included in this Phase 1/2 trial. The metabolism of ASOs occurs via 
nucleases which are ubiquitously expressed at similar levels in children and adults (Wójcik et 
al., 2007). Thus, it could be expected that the dose for children will be the same as for adults on 
a mg per kg body weight basis. Inclusion of children at an early stage of clinical development 
(i.e. during dose finding) could be seen as subjecting them to unnecessary interventions 


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(e.g. muscle biopsies). Therefore, it is preferable to only dose children once an appropriate dose 
for lowering of DNM2 mRNA is achieved in adults and then used for children in subsequent 
trials.  
It is intended to include mild to moderately affected subjects in this trial, with clinical symptoms 
in at least 2 of the domains that will be investigated (respiratory function, muscle strength and 
function, and dysphagia). Due to the frequency of trial assessments at a site and associated travel, 
inclusion of ambulatory subjects will facilitate recruitment and retention. Furthermore, the 
possibility of seeing an efficacy signal in mild to moderately affected subjects will be greater due 
to the amount of recoverable muscle mass remaining. Ambulatory subjects can have more 
efficacy assessments carried out (upper and lower limbs) and are less prone to be affected by 
contractures that are very often seen in more severe subjects.  
ASO platform side effects include liver toxicity where a significant portion of administered drug 
accumulates. Furthermore, rare instances of peliosis hepatis have been reported in untreated 
XLCNM patients (Motoki et al., 2013; Wang et al., 2001). Moreover, some degree of liver 
dysfunction has been previously reported in long-term survivors (Herman et al., 1999). Recently, 
investigators for an ongoing clinical trial in children with XLCNM mention that >50% of subjects 
enrolled in the trial displayed some evidence of pre-existing hepatobiliary disease (Shieh et al., 
2020). Therefore, liver function tests, liver ultrasound, and hepatic elastography will be carried 
out to ensure that these are normal prior to entry. In case of slight liver function abnormalities, 
there should be a medically plausible reason for the elevation of these parameters outside of the 
normal range, and a discussion with the medical monitor should occur in this situation before the 
subject may be screened and/or dosed for the trial.  
ASOs are slowly metabolized to chain-shortened metabolites and excreted by the kidneys (Geary 
et al., 2009). Therefore, only subjects with normal kidney function will be included. 
Symptomatic decreases in platelet count have been reported for some other ASOs, and these were 
managed by implementation of monitoring of platelet count and cessation of treatment once they 
fell to a predetermined level. This mostly led to a normalization of platelet count with no further 
reports of untoward effects. As a result, only subjects with a platelet count > 150,000/µL will be 
included in this trial.  
3.2.3 Rationale for Choice of Safety Assessments 
Safety assessments are based on preclinical toxicology results, prior experience with platform 
safety of ASOs (see also Section 3.2.2), as well as the evaluation of potential on-target effects of 
decreasing DNM2 levels with the DYN101 ASO. 
Liver function tests, kidney function tests, platelet counts, coagulation tests, and complement 
testing will be monitored regularly in this trial. In addition to central laboratory testing, platelet 
counts will be assessed by the local laboratory and need to be within normal ranges before IMP 
administration and before performing a muscle biopsy.  
In a 9-month preclinical study with DYN101 in NHP, vasculitis which appeared to be associated 
with chronic complement activation with subsequent depletion and inflammation was observed. 
Therefore, subjects with any suspicion for vasculitis (vasculitis of any origin, including the 
complement pathway) will trigger a consult with an appropriate specialist for further 
investigation. 


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As there are no validated specific diagnostic markers to detect vasculitis, monitoring and 
assessment should be based on a high level of clinical awareness/suspicion and on physical 
examination and objective studies specific to the end organs that could be involved in 
drug-induced small or medium vessel vasculitis. These include, but are not limited to, the heart, 
kidney, lungs, liver, peripheral nervous system, and skin.  
3.2.4 Rationale for Choice of PD/Exploratory Efficacy Assessments 
An NHS is currently ongoing in subjects of all ages with CNM resulting from a mutation in the 
MTM1 and DNM2 genes. This study is assessing the natural history and functional status of these 
subjects by assessing, amongst others, respiratory function, motor function, muscle strength, 
cardiac function, liver function, kidney function, QoL and health outcomes. The aim is to include 
subjects mostly from this ongoing NHS into the current trial, although other subjects can also 
participate. Several of the aforementioned assessments have been performed at baseline and at 
several other time points in the NHS, which will allow to assess the validity and variability of 
the results at baseline as well as the individual subject’s course and inter-occasion variability for 
the various measurements prior to entry into the current trial for eventual comparative analyses. 
Subjects who are participating in the NHS and have at least 2 data time points available from the 
NHS to assess their pre-trial condition do not require a mandatory run-in visit. (see Section 6.1.2).  
Due to the extreme rarity, severity, and heterogeneity of CNM as well as the rapid benefit seen 
in mouse models and human studies, the set of exploratory efficacy assessments planned in this 
trial covers a wide range of areas affected by the disease and should allow for a decision on the 
most reliable and important endpoints for pivotal trials as well as potential efficacy signals for 
dose selection. 
The PD/exploratory efficacy assessments that will be performed in this trial will include QoL 
and health outcomes (by means of questionnaires), respiratory function tests, MyoGrip, Motor 
Function Measure (MFM), muscle biopsy, and dysphagia assessments. Details on these 
assessments are provided in Section 6.2.4.  
The sponsor intends to apply biomarker/genetic research across the DYN101 development 
program to explore how biomarker/genetic variations may affect the clinical parameters 
associated with and response to DYN101 (and any background products, comparators and 
concomitant medications), and potentially the basis of the indications under study in the protocol, 
in this case CNM. Collection of appropriate samples from populations with well described 
clinical characteristics may lead to improvements in the design and interpretation of clinical 
studies, biomarker-guided treatment strategies and a better understanding of disease etiology 
which may lead to new therapeutic approaches. 
Candidate biomarkers/genes which may be studied include those potentially related to the 
mechanism of action of DYN101 and comparators and concomitant medications as well as those 
potentially responsible for absorption, disposition, metabolism and excretion of DYN101 and 
comparators and concomitant medications. Future research may suggest other genes, gene 
categories, proteins etc. as candidates for influencing not only response to DYN101 and 
comparators and concomitant medications but also susceptibility to CNM for which DYN101 
may be evaluated. Thus, this additional biomarker/genetic research may involve the future study 
of additional unnamed genes or gene categories, but only as they relate to CNM and drug action. 


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3.2.5 Rationale for Choice of Doses, Route of Administration and Dosing 
Regimen 
Dose selection was based on the following data/assumptions: 
1. Safety profile of DYN101 derived from Cynomolgus monkey studies. 
2. Target knock-down: 30 to 50% knock-down of DNM2 mRNA resulted in a significant 
reduction of myopathic features in mice. It is assumed that a similar target knock-down 
level in humans would translate into clinically meaningful effects.  
3. Translatability of effective concentrations: the required effective concentration in human 
tissue (muscle) is expected to be the same as the observed effective concentration in 
transgenic mouse tissue expressing human DNM2. 
4. Translation of effective concentrations in humans into doses can be extrapolated from non-
human primate data. 
See the latest version of the IB for the supportive information on dose selection (Dynacure). 
The minimal recommended starting dose (MRSD) is 1.5 mg/kg (i.e. low dose level in this trial). 
This MRSD is selected based on the no observed adverse effect level (NOAEL) of 10 mg/kg 
from a Good Laboratory Practice (GLP), 13-week toxicity study with an 8-week recovery period 
in Cynomolgus monkeys. The most noteworthy finding during the 13-week treatment was a 
marked platelet reduction in two female monkeys at 30 mg/kg. This type of platelet change has 
occasionally been observed in monkeys treated with ASOs of similar chemistry, where a small 
proportion of individual animals appear to be susceptible to marked effects on platelet counts 
following ASO treatment. Platelet counts will be closely monitored in this trial to ensure subjects’ 
safety and mitigate the risk. In addition, recovery of platelet counts occurs after drug withdrawal 
and/or treatment with steroids. Moreover, sudden decreases in platelets have not been observed 
in humans so far with other constrained ethyl ASOs at dose levels of 1.5 mg/kg.  
In addition, a human dose of 1.5 mg/kg has the possibility to provide a beneficial effect 
(on-target) to patients with this life-threatening, rare disease. Since this first-in-human study will 
not be conducted in healthy volunteers, but in patients with a severely debilitating disease, a 
possible benefit also at the lowest dose level is desired if patients’ safety is ensured. Preclinical 
data in mouse models of XLCNM and ADCNM suggest that therapeutic efficacy might be seen 
at 15% target knock-down. Based on quadriceps tissue concentration data derived in NHP, this 
level of knock-down could be achieved after administration of 1.5 mg/kg in humans.  
The suggested middle dose level will be 4.5 mg/kg and the high dose level will be up to 9 mg/kg. 
These dose levels should be sufficient to achieve the target knock-down DNM2 mRNA levels of 
30% and 50%, respectively (based on animal data from quadriceps muscle tissue) (Table 1). The 
predicted DNM2 mRNA knock-down of 30% to 50% is anticipated to be efficacious in humans. 
Moreover, these target knock-down levels have not raised any safety concerns in nonclinical 
studies, as reduction of DNM2 mRNA and DNM2 protein by more than 80% in key tissues such 
as liver and skeletal muscle was safe and well tolerated in mice. In addition, 9 mg/kg is below 
the NOAEL of 10 mg/kg, as derived from the GLP, 13-week toxicity study with an 8-week 
recovery period in Cynomolgus monkeys. 


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Table 1: 
Calculated Weekly Human Dose*  
Level of mRNA Knock-down 
15% 
30% 
50% 
Muscle 
Concentration in NHP Muscle (µg/g) a) 
Human Dose (mg/kg) b) 
Quadriceps at 
25 mg/kg SC 
9.3±0.8 
1.9 
4.2 
9.7 
Quadriceps at 
30 mg/kg IV 
9.8±2.9 
2.1 
4.7 
11.1 
* Based on Kim, 2018. 
a) Data from a 12-week NHP study at 25 mg/kg SC (non-GLP; Kim, 2018) and a 13-week toxicity study with 
an 8-week recovery period in NHP at 30 mg/kg IV (). 
b) In a humanized, transgenic DNM2 mouse model, effective DYN101 concentrations in quadriceps muscle 
were 3.62, 1.55, and 0.7 µg/g, respectively at EC50, EC30, and EC15 on mRNA knock-down. These 
concentrations were used to calculate the human doses required to reach a level of KD of 50%, 30%, and 
15% respectively. 
Escalation to the next dose level will be done carefully and the decision will be made by an 
IDMC. To decide on dose escalation to the highest dose level, the IDMC will be allowed to adjust 
the dose level to a lower level, driven by the safety, tolerability and expected target engagement 
in quadriceps or biceps muscle. 
DYN101 will be administered via IV infusion over 1 hour. The most widely used route of 
administration for ASOs is SC injection; however, there are some limitations as follows. For SC 
administration, it is recommended not to exceed an injection volume of 2 mL due to the 
tolerability at the injection site. For instance, IV infusion accommodates for dosing up to 9 mg/kg, 
whereas the limit of 2 mL will be exceeded in the targeted population if SC administration is 
conducted. Moreover, injection site reactions are known to occur after SC injection of ASOs: 
this was reported by 79% of patients treated with weekly SC injections of 300 mg/1.5 mL 
volanesorsen in a pivotal clinical trial (FDA, 2018). 
The doses will be administered weekly in the MAD part of the trial. This dosing regimen was 
used to establish proof-of-concept in mice (see IB, Dynacure) and is an established regimen for 
other ASOs. Steady state will be reached after 12 weeks of weekly dosing, when the second 
muscle biopsy will be taken. This muscle biopsy will be used to determine DYN101 uptake in 
muscle and target engagement (see Section 6.2.6). 
3.3 Trial Endpoints 
3.3.1 Primary Endpoint 
• Comparison of adverse event (AE, SAE, AESI) frequency and severity by dose 
(cohort), for single or multiple administration, and by mutated gene (sub-cohort) and 
overall using the Safety Analysis Set following 12 weeks of MAD treatment and after 
24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD 
extension part; Week 25 visit) or discontinued earlier.    
3.3.2 Secondary Endpoints 
• Comparison of means for PK parameters of DYN101 in plasma (AUCτ, AUClast, 
AUC∞, Rac(AUC), Rac(Cmax), Cmax, Cav SS, CL, λz, t1/2, tmax, Vz) by dose (cohort), for 


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single or multiple administration, and by mutated gene (sub-cohort) and overall using 
the Pharmacokinetic Set. 
• Comparison of geometric means for PK parameters of DYN101 in plasma (Cmax and 
AUCs) by dose (cohort), for single or multiple administration, and by mutated gene 
(sub-cohort) and overall using the Pharmacokinetic Set. 
• Comparison of means on DNM2 mRNA levels and DYN101 concentrations using 
muscle biopsy data by dose (cohort), for single or multiple administration, and by 
mutated gene (sub-cohort) and overall using the Pharmacokinetic Set.  
• Comparison of means change from baseline in vital signs, laboratory data, and ECG 
by dose (cohort), for single or multiple administration, and by mutated gene (sub-
cohort) and overall. 
3.3.3 Exploratory Endpoints 
• Difference in mean change from baseline for clinical assessments in various affected 
clinical domains (respiratory, muscle strength and function, dysphagia) using the 
Pharmacokinetic Set by dose (cohort), for single or multiple administration, and by 
mutated gene (sub-cohort) at each post-baseline visit. The parameters to be analyzed 
for respiratory function are FVC (L), %FVC Predicted, FEV1 (L), %FEV1 Predicted, 
FEV1/FVC, MEP (cm H2O), %MEP Predicted, MIP (cm H2O), %MIP Predicted, 
Oxygen Saturation (%). The MyoGrip Test score will be used for analyzing muscle 
strength. The following parameters will be analyzed for muscle function; D1 Standing 
and transfers (%), D2 Axial and proximal motor function (%), D3 Distal motor 
function (%), Total MFM32 Score (%). Dysphagia will be assessed using the EAT-10 
total score.  
• Difference in mean change from baseline for PROMIS Questionnaire T-scores for the 
following domains (Anxiety, Depression, Fatigue, Pain Interference, Ability to 
Participate, and Physical Function) using the Pharmacokinetic Set by dose (cohort), 
for single or multiple administration, and by mutated gene (sub-cohort) at each post-
baseline visit. 
• Comparison of proportion of CGI-I responders (responders defined as responding 1 
or 2) using the Pharmacokinetic Set by dose (cohort), for single or multiple 
administration, and by mutated gene (sub-cohort) at each post-baseline visit. 
• Comparison of proportion of PGI-C responders (responders defined as responding 1 
or 2) using the Pharmacokinetic Set by dose (cohort), for single or multiple 
administration, and by mutated gene (sub-cohort) at each post-baseline visit. 
• Comparison of proportion of Goal Attainment Scaling (GAS) Questionnaire 
responders (responders defined as responding ‘YES – MUCH BETTER’, ‘YES – A 
LITTLE BETTER’) using the Pharmacokinetic Set by dose (cohort), for single or 
multiple administration, and by mutated gene (sub-cohort) at each post-baseline visit 
• Comparison of means of ADA against DYN101 using the Pharmacokinetic Set by 
dose (cohort), for single or multiple administration, and by mutated gene (sub-cohort) 
at each post-baseline visit. 


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• Comparisons of the metabolic profile of DYN101 in blood and urine using the 
Pharmacokinetic Set by dose (cohort), for single or multiple administration, and by 
mutated gene (sub-cohort) at each post-baseline visit. 
3.4 Sample Size 
Sufficient subjects will be screened to ascertain approximately 18 subjects who will be dosed 
and finish the trial. The target is approximately 6 subjects per dose level. In each dose level, the 
target will be up to 6 subjects with a DNM2 mutation and up to 3 subjects with an MTM1 
mutation. This sample size is deemed to be appropriate for safety and tolerability purposes and 
are not based on any power analysis (see Section 9.11). 
3.5 Sites and Regions 
This trial is planned to be conducted at 5 to 10 sites in Europe and the United States of America, 
with an estimation of 1 to 5 subjects per site. 
4. TRIAL POPULATION 
4.1 Inclusion Criteria 
The subject cannot be enrolled in the trial before all of the following inclusion criteria (including 
test results) are met: 
1. Male or female aged ≥ 16 years of age* on the date of signing the main ICF. The first 
subject (i.e. the sentinel subject) in each cohort will be ≥ 18 years of age. 
*for Germany, the subject must be ≥ 18 years of age in accordance with local and national 
regulations. 
2. Have a documented mutation in DNM2 or MTM1. 
3. Platelet count > 150,000/µL 
4. Have a symptomatic CNM in the opinion of the investigator, at least mild to moderately 
affected, i.e. showing clinical symptoms in at least 2 of the 4 relevant domains that will be 
investigated in this trial (respiratory function, muscle strength, muscle function, and 
dysphagia), and be ambulatory, i.e. being able to walk 10 steps, if needed with 
support/assisted. If a subject is non-ambulatory but highly functioning in the view of the 
investigator, he/she may be included following discussion with the sponsor. 
5. Have an understanding, ability, and willingness to fully comply with visit frequency, trial 
procedures and restrictions, including contraceptive requirements. 
6. Able to provide written, signed and dated informed consent/assent to participate in the 
trial. Parental consent (one or both parents) and an assent for subjects < 18 years may be 
required per local legislation.  


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4.2 Exclusion Criteria 
Subjects are excluded from the trial if any of the following exclusion criteria are met:  
1. Clinically significant liver disease.  
2. Clinically significant renal disease. 
3. Presence of significant co-morbidities or conditions other than CNM or clinically 
significant findings during screening of medical history, physical examination, laboratory 
testing, vital signs or ECG recording for which, in the opinion of the investigator and the 
medical monitor, participation would not be in the best interest of the subject 
(e.g. compromise the safety or well-being) or that could prevent, limit, or confound the 
protocol-specified assessments (e.g. taking a muscle biopsy). 
4. For female subjects of child-bearing potential: pregnant or breastfeeding or planning to 
become pregnant during the trial. 
5. Current or past abuse of alcohol or recreational/narcotic drugs (with the exception of 
caffeine and nicotine), which in the investigator’s opinion would compromise the subject’s 
safety and/or compliance with the trial procedures.  
6. Currently enrolled in any interventional trial or scheduled to participate in such a trial 
whilst participating in this trial. Subjects are allowed to participate in registry studies. 
7. Current or relevant history of physical or psychiatric illness, any medical disorder that 
may require treatment or make the subject unlikely to fully complete the trial, or any 
condition that presents undue risk from the IMP or procedures. 
8. Intake of any disallowed therapies as noted in Section 5.5 within 12 weeks before the 
planned first IMP administration.  
9. Known or suspected intolerance or hypersensitivity to IMP ingredients or closely-related 
compounds, or history of a significant allergic reaction to IMP ingredients as determined 
by the investigator, such as anaphylaxis requiring hospitalization.  
10. Legally incapacitated or have limited legal capacity. Lack of mental capacity to fully 
understand the protocol requirements and complete all trial required procedures.  
Note: Retesting of subjects should always be discussed with the sponsor and/or medical monitor. 
Retesting of laboratory values that lead to exclusion will be allowed once using an unscheduled visit 
during the screening period to assess eligibility. This visit should be at least 2 weeks later than the 
original screening visit.  
4.3 Reproductive Potential 
At screening, female subjects should be either: 
• Post-menopausal (12 consecutive months of spontaneous amenorrhea and  51 years 
of age), or 
• Surgically sterile (i.e. hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy, or otherwise be incapable of pregnancy) and at least 6 weeks 
post-sterilization, or 


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• Of child-bearing potential with a negative pregnancy test at screening AND prior to 
the first IMP administration and 
- not heterosexually active but agree to use acceptable contraception as defined 
below if they become sexually active during the trial and until at least 90 days 
after the last IMP administration in this trial.  
- heterosexually active and have a vasectomized partner (confirmed sterile) 
- heterosexually active and using or agree to use acceptable contraception as 
defined below throughout the trial and until at least 90 days after the last IMP 
administration. 
The following forms of contraception are considered highly effective and acceptable: 
• Use of a hormone-based contraceptive (oral, depot, patch, injectable, or vaginal ring) 
or an intrauterine device in combination with condoms. Hormonal contraceptives 
should be administered according to the package insert. 
• Intrauterine device or intrauterine hormone-releasing system used/administered in 
accordance with the package insert.  
Male subjects who did not have a vasectomy performed more than 1 year prior to screening and 
who are sexually active with a female partner of child-bearing potential must use condoms for 
sexual intercourse throughout the trial and until at least 90 days after the last IMP administration 
in this trial. Their female partner should be advised to use an acceptable form of contraception 
as stated above.  
4.4 Prohibitions and Restrictions 
Subjects must be willing and able to adhere to the following prohibitions and restrictions during 
the course of the trial to be eligible for participation: 
1. Female subjects of child-bearing potential must remain on a highly effective method of 
birth control consistent with local regulations (see Section 4.3) until at least 90 days 
following the last IMP administration in this trial. 
2. Female subjects are not allowed to breastfeed their child during this trial. 
3. Male subjects with a female partner of child-bearing potential must agree to use effective 
contraceptive methods (see Section 4.3) during the trial until at least 90 days following 
the last IMP administration in this trial. 
4. Strenuous activities should be avoided during the whole trial (from screening to the last 
visit in the extension period, or early discontinuation visit). 
5. Subjects are not allowed to take alcohol/recreational or narcotic drugs 24 hours before 
each IMP administration and should abstain from alcohol/recreational or narcotic drugs 
for 24 hours after dosing. During the treatment period, the subject must be willing to limit 
alcohol consumption to < 5 drinks per day for men and < 4 drinks per day for women. One 
drink is defined as 1 bottle (360 mL) of beer, 1 glass (120 mL) of wine, or 30 mL of liquor. 
The abstinence of the use of alcohol/recreational or narcotic drugs will be confirmed 
verbally by site personnel before infusion. 


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6. Subjects are asked to refrain from using tobacco or nicotine-containing products during 
the treatment period.  
7. Subjects are not allowed to take any new medication (including over-the-counter 
medication and herbal supplements) to treat CNM or that are known to affect DNM2 levels 
(see Section 5.5).  
8. Subjects should follow restrictions imposed in response to a pandemic closely (e.g. social 
distancing). 
9. Subjects should refrain from sharing information about the trial within a patient 
community, on social media, etc. until the last subject in the trial has completed treatment.  
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
Manual, Pharmacy Manual). 
4.5 Subject Withdrawal and Trial Termination 
It is the investigators responsibility to stop dosing a subject(s) at any stage if they deem it in the 
subjects’ best interest to do so and take any urgent safety measures required to safeguard the 
subject.  Such measures should be reported to the sponsor immediately and to the regulatory 
authorities or the Independent Ethics Committee/Institutional Review Board (IEC/IRB). 
Pausing/stopping rules (Section 7.11) should be taken into account. 
A subject may be withdrawn from the trial at any time, for any reason, without prejudice to their 
future medical care by his/her physician or at the institution. Subjects withdrawing from the trial 
will be encouraged to complete the assessments of the early discontinuation visit, see 
Section 6.1.5), particularly safety evaluations in the subject’s interest and to ensure that data can 
be recorded in the same way as for subjects who completed the trial. If subjects agree, they will 
also have the follow-up visit 3 months after their last IMP administration (see Section 6.1.4). 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
electronic case report form (eCRF).  
Reasons for withdrawal from the trial may include, but are not limited to: 
- For subject’s best interest 
- SAE 
- Any pausing/stopping rule for the trial (as described in Section 7.11) 
- Pregnancy 
- Protocol violation (except if related to a restriction imposed in response to a 
pandemic) 
- Withdrawal of consent by subject 
- Lost to follow-up 
In case of temporary IMP discontinuation, it should be discussed with the medical monitor 
whether continued participation is possible and whether any (pre-) treatment/therapy before 
resuming IMP administration can be considered useful in order to ensure subject safety. The 
withdrawal of a subject from IMP by the investigator should be discussed, where possible, with 
the medical monitor before the subject stops with the IMP. The reason for IMP discontinuation 
and date of stopping IMP must be recorded on the eCRF and source documents. The total amount 
of IMP received is registered on the drug accountability form. 


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Replacement of withdrawn subjects can occur under the circumstances described in 
Section 3.1.2.  
At least 3 documented attempts must be made to contact any subject lost to follow-up at any time 
point prior to the last scheduled contact (e.g. office visit or telephone contact). One of these 
documented attempts must include a written communication sent to the subject’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they return 
to the site for final safety evaluations. 
The sponsor has the right to terminate the trial at any time in case of safety concerns or if special 
circumstances concerning the IMP or the company itself occur, making further treatment of 
subjects impossible. In this event, the investigator(s) and relevant authorities will be informed of 
the reason for trial termination. 
If a subject withdraws his/her consent to continue with the trial, the analysis and reporting of 
samples collected to that point, cannot be withdrawn. 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
Manual, Pharmacy Manual). 
Withdrawal from the Use of Research Samples 
Subjects may withdraw their consent for storage of samples for additional research at any time 
(see Section 10.4.4), in which case the samples will be destroyed, and no further testing will take 
place.  
5. TRIAL TREATMENT 
5.1 Investigational Medicinal Product 
 
 
he dose levels will be 1.5 mg/kg (Cohort 1), 4.5 
mg/kg (Cohort 2), and up to 9 mg/kg (Cohort 3), unless the IDMC advises otherwise. Additional 
information is provided in the IB (Dynacure).  
5.2 Dosage and Administration 
The IMP will be prepared by the pharmacist or delegated qualified site personnel. The ideal body 
weight determined at SAD Day 1, MAD Week 1 Day 1, and MAD Week 13 will be used to 
calculate the applicable dose. In case the ideal body weight is higher than real body weight, real 
body weight will be used to calculate the applicable dose. Refer to the Pharmacy Manual for the 
exact calculations of the volume to be administered. The corresponding volume of IMP will be 
taken from the vial and diluted into a 0.9% sodium chloride solution (in an infusion bag), 
resulting in an IV solution with the respective concentration of the dose level. A substantial 
change (as judged by the investigator) in body weight will be reported as an AE, and it will be 
discussed with the sponsor whether the dose calculation should be adjusted. 
Detailed instructions for aseptic preparation of the applicable doses and all items related to IMP 
administration will be described in the Pharmacy Manual. 
The IMP will be dispensed IV using a validated infusion pump. Subjects will be dosed by 
qualified site personnel. A physician will be available on-site during infusions. 


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In each cohort, there will be an interval of at least 7 days between dose administration of the first 
and second subject in a cohort, irrespective of their sub-cohort. The 48-hour safety data from the 
first subject in a cohort will be reviewed by the medical monitor before the next subject can be 
dosed. In addition, any SAE data from the first subject received up until the moment of treatment 
of the second subject will be taken into account. 
In the SAD part, subjects will receive a single IV administration of IMP over approximately 
1 hour at a low (1.5 mg/kg), middle (4.5 mg/kg), or high (up to 9 mg/kg) dose level in Cohorts 
SAD1, SAD2, or SAD3, respectively (unless the IDMC advises otherwise).  
In the MAD part, subjects will receive weekly IV administrations of IMP over approximately 
1 hour for a period of 12 weeks, at the same or different dose level (low, middle, or high) as in 
their SAD cohort in Cohorts MAD1, MAD2, or MAD3, respectively (unless the IDMC advises 
otherwise).  
After MAD, subjects will continue on the IMP dose level of their assigned MAD cohort in the 
extension part of this trial for an additional 12 weeks (weekly IV administrations), unless the 
IDMC decides to change the dose for a (sub)-cohort. After Week 24, all subjects will remain on 
treatment with weekly IMP administrations until the last MAD3 subject has completed the MAD 
Week 25 visit. 
All subjects will be monitored on site by qualified site personnel for a minimum of 1 hour after 
the infusion for safety. The infusion time including pauses may not exceed 3 hours (unless the 
pauses are due to technical issues).  
The planned dose levels may be adjusted upon IDMC recommendation, based on emerging data 
(see Section 3.1), taking into account pre-specified pausing/stopping rules (refer to Section 7.11 
for details).  
5.3 Treatment Allocation 
Subjects will be assigned to a dose level (low, middle, or high), just before baseline, as detailed 
in the Cohort Management Plan.  
The target will be up to 6 subjects with DNM2 and up to 3 subjects with MTM1 mutation  in each 
cohort.  
The first subject in each cohort will be a ‘sentinel’ subject. The sentinel subject in each cohort 
will be ≥ 18 years of age. There will be an interval of at least 7 days between dose administration 
of the first and second subject in a cohort, irrespective of their sub-cohort. 
The aim is to allocate the NHS subjects to the cohorts as evenly and as balanced as possible, 
given the logistical constraints of the trial. 
Family members, including direct family and siblings, are allowed to participate. Family 
members will be allocated to different cohorts as often as possible, taking into account the 
logistical constraints of the trial. 
A temporary unique number will identify all subjects during their pre-screening. Re-screened 
subjects will retain the same temporary unique number for all assessments. A cohort-subject 
number which is the final unique identifier will be assigned once eligibility has been determined. 
Once a unique identifier has been assigned, that number must not be used again if, for example, 


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a subject is withdrawn from the trial. If a temporary or final number is allocated incorrectly, the 
monitor must be notified as soon as the error is discovered.  
5.4 Labeling, Packaging, Storage, and Handling 
5.4.1 Labeling and Packaging 
Labels containing trial information and packaging identification are applied to the IMP vial.  
The IMP will be labelled according to local requirements. All manufacturing, packaging, and 
labeling operations will be performed according to Good Manufacturing Practice for Medicinal 
Products and the relevant regulatory requirements. Further details will be provided in the 
Pharmacy Manual. 
5.4.2 Storage 
The investigator has overall responsibility for ensuring that IMP is stored in a secure, 
limited-access location. Responsibility will be delegated to the pharmacy; this delegation must 
be documented.  
IMP must be stored in accordance with labeled storage conditions (temperature range of +2°C to 
+8°C in the carton and protected from light). Temperature monitoring is required at the storage 
location to ensure that the IMP is maintained within an established temperature range (as defined 
in the Pharmacy Manual). The pharmacist is responsible for ensuring that the temperature is 
monitored throughout the duration of the trial and that records are maintained.  
5.4.3 Handling 
The pharmacist must keep an accurate account of the number of IMP vials delivered to the site 
used to prepare infusion bags for administration to trial subjects and stored at the site, during the 
trial. IMP must be administered to subjects only by an appropriately qualified person. 
Investigators will maintain records that document adequately that the subjects were administered 
the IMP dose specified by the protocol. The pharmacist will reconcile all IMP vials received at 
the site before final disposition.  
At the completion of the trial after the last monitoring, any empty vials and unused IMP will be 
returned to the sponsor or its designee or destroyed with the sponsor’s written permission. For 
the latter, a certificate of destruction will be provided. 
Details will be provided in the Pharmacy Manual. 
5.5 Prior and Concomitant Medication/Therapy 
5.5.1 Prior Medication/Therapy 
Prior medication/therapy includes medication/therapy (including herbal treatments, vitamins, 
non-pharmacological treatment such as psychotherapy or physiotherapy as appropriate) received 
within 5 times the half-live of the drug in question and discontinued prior to the date of first IMP 
administration. Prohibited medication/therapy is provided in Table 2.  
Prior medication/therapy information must be recorded on the appropriate eCRF page. 
Disease-specific therapy should be recorded regardless of date of therapy.  


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Table 2: 
Prohibited Medication and Washout Period  
Medication/Therapy 
Washout Period 
Drug  
Drugs affecting DNM2 levels 
8 weeks 
Tamoxifen 
5.5.2 Concomitant Medication/Therapy  
Concomitant medication/therapy is defined as any medication/therapy being continued by the 
subject at the date of signing of the main ICF, and any new medication/therapy received during 
the trial. Subjects may get breathing technique advice during the trial as long as it is started at or 
before screening. 
Concomitant medication/therapy taken must be recorded on the appropriate eCRF page. 
Treatments not listed in Table 2 above are considered allowable. 
New medications (including herbal treatment) for the treatment of CNM are not allowed to be 
started during the trial, unless for the management of concurrent illness or AEs. Medications 
already used for the treatment of CNM (e.g. Mestinon) may be continued if subjects are on a 
stable treatment regimen for at least 3 months and the dose will not be increased during the trial. 
Administered vaccines, including COVID-19 vaccines, should be reported as a concomitant 
medication. In case of a (planned) vaccination, the investigator should contact the medical 
monitor to discuss the optimal timing of the vaccination in relation to dosing of the IMP. 
5.6 Treatment Compliance and Drug Accountability 
Sites will be provided with sufficient amounts of the IMP and related materials for infusion 
(described in the Pharmacy Manual) to carry out this protocol for the agreed number of subjects. 
The investigator or designee will acknowledge receipt of the IMP by documenting shipment 
content and condition. Accurate records of all IMP dispensed, used, returned, and/or destroyed 
must be maintained.  
The investigator has the overall responsibility for administering the IMP. Where permissible, 
tasks may be delegated to a qualified designee (e.g. a pharmacist) who is adequately trained in 
the protocol and who works under the direct supervision of the investigator. This delegation must 
be documented in the applicable trial delegation of authority form. 
The investigator or designee (as documented by the investigator in the applicable trial delegation 
of authority form) will administer the IMP only to subjects included in this trial following the 
procedures set out in the trial protocol. Each subject will be given only the dose of IMP carrying 
his/her treatment assignment. All dispensing of IMP will be documented on the drug 
accountability form and infusion information will be entered in the eCRF. Refer to Section 7.4 
for details on overdose. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
Based on entries in the IRT and site drug accountability forms, it must be possible to reconcile 
IMP delivered with those used, unused and returned to sponsor or designee. All IMP must be 
accounted for, and all discrepancies must be investigated and documented to the sponsor’s 
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6. TRIAL SCHEDULE AND ASSESSMENTS 
6.1 Trial Schedule 
Refer to the TRIAL SCHEDULES for an overview of the frequency and timing and sequence of 
the trial measurements and procedures. Further details will be described in the site manuals 
(e.g. Laboratory Manual, Site Operations Manual). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.  
For subjects suffering from an intercurrent illness (e.g. viral or bacterial infection) that could 
interfere with the PD/exploratory efficacy assessments (see Section 6.2.4), these assessments 
should be postponed for at least a week until the subject has recovered. 
Subjects will be confined to the clinic for at least 7 hours after SAD dosing, the first dosing or a 
change of dosing) during MAD, for at least 4 hours during all other clinic visits during MAD, 
and may be confined to the clinic for any 24-hour urine collection. Additionally, the subject may 
be confined to the clinic for their convenience if assessments will be performed on consecutive 
days.  
6.1.1 Pre-screening and Screening Period 
Subjects will give a ‘pre-screening’ consent to be entered as ‘pre-screened’ in the IRT system. 
During this pre-screening, NHS participation and data, age and type of mutation will be 
confirmed. The pre-screening consent process can be managed remotely (please refer to the Site 
Operations Manual for more details). 
Subsequently, screening will be performed to assess eligibility. Subjects who are participating in 
the NHS and have at least 2 data time points available from NHS to assess their pre-trial condition 
do not require a mandatory run-in visit. For subjects not performing run-in visits, the screening 
visit should be performed within 6 weeks before the baseline visit. There should be a minimum 
of 3 data time points to assess their pre-trial condition. The screening visit can be the third data 
time point. Subjects who have not participated in the NHS or who do not have at least 2 data time 
points from the NHS will have a mandatory run-in period before continuing to the baseline visit 
(see Section 6.1.2). The run-in period is optional for stand-by subjects who participated in the 
NHS and have at least 3 data time points. Informed consent (and assent, if applicable) must be 
obtained before any trial procedures are performed. This applies to the main ICF and optional 
ICFs as applicable. 
Eligibility of subjects will be checked according to the in- and exclusion criteria (see Sections 4.1 
and 4.2). The screening assessments can be split over 2 consecutive days, if required; if more 
than 2 days are needed, approval is required from the medical monitor in advance. 
Retesting of subjects should always be discussed with the sponsor and/or the medical monitor. 
Retesting of laboratory values that lead to exclusion will be allowed once using an unscheduled 
visit during the screening period to assess eligibility. This visit should be at least 2 weeks later 
than the original screening visit.  
Screen failed subjects can be re-screened up to 2 times after discussion with the medical monitor. 
The screening procedures to be repeated in case of re-screening will depend on the reason for 
re-screening and the time passed between the initial screening and the re-screening. Therefore, 


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the screening procedures to be repeated will be determined following discussion with the medical 
monitor. Re-screened subjects will be prioritized in the cohort assignment queue. A re-screening 
can also be only due to timing issues (e.g. government/hospital restrictions or a pause in IMP 
administration). In all cases, there should be no more than 6 weeks between the acceptable 
re-screening and Pre-dose/Baseline assessments. Re-screened subjects will retain the same 
temporary unique number for all assessments.  
6.1.2 Run-in Period (if Applicable) 
Subjects who are participating in the NHS and have at least 2 data time points available from the 
NHS to assess their pre-trial condition do not require a mandatory run-in visit. For these subjects, 
screening should be performed within 6 weeks before the baseline visit. There should be a 
minimum of 3 data time points to assess their pre-trial condition. The screening visit can be the 
third data time point. Subjects who have not participated in the NHS or who do not have at least 
2 data time points from the NHS will have a mandatory run-in period before continuing to the 
baseline visit. Subjects will be asked to visit the site for run-in visits to assess their pre-trial 
condition. At least 1 run-in visit needs to be performed in order to obtain 3 data time points to 
assess their pre-trial condition; screening can be the first data time point, baseline can be the third 
data time point. Run-in visits should be repeated until the sponsor deems there are sufficient data 
time points for an individual subject, or until a cohort is declared open. Stand-by subjects will 
perform run-in visits until the last MAD subject has completed Week 13, unless needed for 
replacement. There should be a minimum of 28 days between screening and the first run-in visit. 
Thereafter, run-in visits may be performed every 12 weeks (±14 days), until the cohort is declared 
open. If there is only 1 run-in visit, there should be a minimum of 28 days between the run-in 
visit and the baseline visit. If there is more than 1 run-in visit, there should be 12 weeks 
(±14 days) in between the run-in visits unless it is known that the baseline visit can be scheduled 
within 14 days following a run-in visit; in that case, the last run-in visit should be dropped.  
In case the screening laboratory results (clinical laboratory assessments, including platelet count) 
became available more than 12 weeks before the baseline visit (due to a long run-in period), these 
laboratory tests should be repeated during the run-in period. 
Assessments of a single visit can be split over up to 2 consecutive days, if required. If more than 
2 days are needed, approval is required from the medical monitor in advance. 
The run-in period is optional for stand-by subjects who participated in the NHS and have at least 
3 data time points. 
6.1.3 Treatment Periods 
Assessments of a single visit can be split over up to 2 consecutive days, if required. If more than 
2 days are needed, approval is required from the medical monitor in advance. 
6.1.3.1 
Baseline Visit 
If needed, all assessments that need to be performed pre-dose can be done over 2 consecutive 
days (i.e. Day 0 or Day 1); any exceptions to doing over 2 consecutive days due to an open biopsy 
with general anesthetic must be discussed with the medical monitor in advance for approval. 
There must be at least 24 hours between the biopsy and IMP administration. The investigator is 


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to get approval from the medical monitor if additional time is required to perform all needed Pre-
dose/Baseline assessments. 
6.1.3.2 
Single Ascending Dose Part  
Subjects will receive a single IV administration of DYN101 on Day 1, after which they are 
followed for 4 weeks up to Day 29.  
There will be a subsequent washout period of at least 12 weeks: during Weeks 5-17, subjects will 
be asked to visit the site every 2 weeks for safety follow-up, even if they do not continue to the 
MAD part. Where possible, the visits will take place on the same day of the week as the visit on 
Day 1.  
Due to restrictions imposed in response to a pandemic that restrict subject visits, please contact 
the medical monitor to determine the strategy for continuing the subject in the trial. All efforts 
must be employed to maintain subject safety. Assessments, if feasible, must be collected during 
a phone call with the subject. The site should arrange the collection of the blood and urine 
samples, if at all possible. 
Every 2 weeks following the Week 17 visit, subjects will be contacted by phone by qualified site 
personnel to follow-up on concomitant medications and AEs, until their assigned MAD cohort 
has been opened. 
Subjects who participated in the SAD part will subsequently participate in the MAD part 
(provided the IDMC has given a favorable advice to proceed, see Section 3.1.1).  
6.1.3.3 
Multiple Ascending Dose Part 
For subjects for whom the last visit in the SAD part was more than 3 months before the baseline 
visit in the MAD part, there will be an unscheduled visit (physical examination and clinical 
laboratory parameters) which will occur between 6 weeks and 7 days prior to the MAD baseline 
visit. Liver ultrasound and hepatic elastography have to be performed before the baseline visit in 
the MAD part. The first IMP administration in the MAD part cannot be started before the liver 
ultrasound and hepatic elastography results are available. 
Subjects will receive weekly IV administrations of DYN101 for a period of 12 weeks, i.e. from 
MAD Week 1 to Week 12.  
Replacement of withdrawn subjects can occur under the circumstances described in 
Section 3.1.2. New subjects who did not participate in the SAD part should sign an ICF for 
participation in the MAD part, and the eligibility will be assessed (see Section 6.1.1) before the 
first IMP administration in the MAD part (MAD Week 1 Day 1). Replacement subjects may or 
may not need a run-in period, in consultation with the sponsor (see Section 6.1.2). A DNA sample 
(optional) and a muscle biopsy should be taken before the first IMP administration.  
6.1.3.4 
MAD Extension Part  
After completion of the MAD part, subjects will continue on the IMP dose level of their assigned 
MAD cohort for an additional 12 weeks with weekly IV administrations (MAD Weeks 13-24) 
(unless the IDMC advises otherwise). 
End-of-treatment assessments will be performed after 24 weeks of MAD treatment have been 
completed, i.e. at the Week 25 visit. 


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After Week 24, all subjects will remain on treatment with weekly IMP administrations and 
assessments every 2 weeks until the last MAD3 subject has completed the MAD Week 25 visit. 
Data collected during this period will be listed and tabulated in the clinical trial report but will 
not be included in the statistical modeling. 
6.1.4 End of Treatment Follow-up Visit 
If a subject is NOT continuing on IMP treatment after the trial, the subject will return to the clinic 
for an EoT follow-up visit 3 months after the last IMP administration, to follow-up on the 
subject’s status including abnormal laboratory results, AEs, and concomitant medications. The 
follow-up information will be recorded in the eCRF. 
6.1.5 Early Discontinuation 
In case subjects are withdrawn from IMP or from the trial, there will be a follow-up visit to query 
for AEs/SAEs and concomitant medications. In addition, safety, PK and PD/exploratory efficacy 
assessments may be performed at this early discontinuation visit. The assessments to be 
performed at this visit correspond to the assessments of the MAD Week 25 visit (excluding IMP 
administration) (refer to the TRIAL SCHEDULES). In addition, subjects participating in MAD 
are encouraged to have a second muscle biopsy taken if the subject had at least 6 weeks of 
treatment during the MAD part of the trial and discontinued prior to having the Week 13 biopsy 
obtained; SAD subjects do not need a second muscle biopsy.  
If subjects agree, they will also have an EoT follow-up visit 3 months after their last IMP 
administration. 
6.1.6 Additional Care of Subjects After the Trial 
The sponsor will consider providing IMP to subjects after the last visit in this trial, including 
stand-by subjects. 
6.2 Trial Evaluations 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
Manual, Pharmacy Manual). 
6.2.1 Demographic and Other Baseline Characteristics 
Demographic data such as age, gender, race and ethnicity, and other baseline characteristics 
including medical history will be recorded. 
6.2.2 Safety Evaluations 
The investigators, together with the medical monitor, will be responsible for the safety 
monitoring of the trial, and will pause IMP administration of further subjects in case any of the 
pre-specified pausing/stopping rules described in Section 7.11.1 occur.  
An IDMC will be appointed by the sponsor before the start of the trial to perform regular reviews 
of the emerging safety data during the trial. Details regarding the IDMC are provided in 
Section 9.12.  


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Abnormal results for any safety evaluations, which are unexpected or not explained by the 
subject’s clinical condition may be, at the discretion of the investigator or sponsor, repeated until 
confirmed, explained, or resolved as soon as possible. 
6.2.2.1 
Adverse Events 
At each trial visit, subjects will be questioned in a general way to ascertain if AEs have occurred 
since the previous visit (e.g. “Have you had any health problems since your last visit?”). AEs are 
collected from signing of the main ICF until the last trial visit.  
For definitions of AEs and SAEs, and procedures regarding reporting of SAEs refer to Section 7. 
Adverse events of special interest are defined in Section 7.2, and will be reported as AEs. 
6.2.2.2 
Clinical Laboratory Tests 
Clinical laboratory parameters should be monitored at the time points specified in the TRIAL 
SCHEDULES.  
In addition to testing of all parameters (except coagulation and erythrocyte sedimentation rate 
[ESR]) at the central laboratory, platelet counts will also be assessed locally prior to IMP 
administration and muscle biopsy. Platelet counts as determined by the local laboratory need to 
be within normal laboratory references ranges before IMP administration (at the time points 
specified in the TRIAL SCHEDULES), or before performing a muscle biopsy. The samples for 
platelet count verification cannot be older than 3 days. Any discrepancy between the results of 
the local and central laboratory should be discussed with the medical monitor before any further 
IMP administration. The coagulation panel and ESR will only be tested locally; they will NOT 
be repeated at the central laboratory. If thrombocytopenia is reported during the trial after the 
first IMP administration, and if an immature platelet fraction (IPF) test is available at the local 
laboratory, IPF test results should be obtained in addition to the platelet count. The IPF is the 
ratio of immature platelets to the total number of platelets, indicating the percentage of young, 
so-called ‘reticulated’ platelets. 
All clinical laboratory assays will be performed according to the local or central laboratory’s 
normal procedures. Normal reference ranges which are age- and gender-specific (as applicable) 
are supplied by the respective laboratories and used to assess the clinical laboratory data for 
clinical significance and out-of-range pathological changes. The investigator should assess out-
of-range clinical laboratory values for clinical significance, indicating if the value(s) is/are not 
clinically significant or clinically significant.  
 
 


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The following clinical laboratory assessments will be performed: 
Biochemistry: 
General 
Liver function tests Kidney function tests 
Other 
- sodium 
- AST 
- BUN 
Cardiac Safety  
- creatine kinase myocardial 
band (CK-MB) 
- potassium 
- ALT 
- creatinine 
- cardiac troponin  
- chloride 
- ALP 
- cystatin C 
 
- calcium 
- GGT 
- eGFR a) 
 
- magnesium 
- bilirubin: direct, 
indirect, and total 
 
 
- phosphorus 
- albumin 
 
Muscle injury 
- bicarbonate - total protein 
 
- creatine kinase  
- glucose 
- bile acids 
 
 
- CRP 
 
 
- IgG and IgM 
 
 
- LDH 
 
 
a) Calculation of eGFR will be done by the central laboratory. The same method of calculation must be 
maintained for an individual subject. 
Complement: 
- C3 
- C5a 
- CBb 
 
 
Hematology: 
- hemoglobin 
- WBC differential b) 
- hematocrit 
- neutrophils 
- red blood cell (RBC) count a) 
- lymphocytes 
- RBC parameters a): 
- monocytes 
- mean corpuscular hemoglobin 
- eosinophils 
- mean corpuscular hemoglobin concentration 
- basophils 
- mean corpuscular volume 
- platelet count c) 
- white blood cell (WBC) count b) 
- ESR 
a) RBC evaluation may include abnormalities in RBC count and/or RBC parameters and/or RBC 
morphology, which will then be reported by the laboratory. 
b) WBC evaluation may include any abnormal cells, which will then be reported by the laboratory. In 
addition, any other abnormal cells in a blood smear will also be reported 
c) If platelet clumping is observed in a local sample, the test should be repeated locally before IMP 
administration. In addition, a smear may be performed locally at the investigator’s discretion. 
 
Coagulation: 
- PT a) 
- INR 
- aPTT 
 
 
a) Depending on local laboratory’s routine practice Coagulation panel test result may or may not include PT. 
Urinalysis (dipstick): 
- proteinuria 
- hematuria 


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6.2.2.3 
Physical Examination  
A complete physical examination (including height, body weight and body systems) will be 
performed at screening. At all other time points, a symptom-directed physical examination will 
be performed. At baseline and after 24 weeks of MAD treatment (Week 25 visit), the symptom-
directed physical examination will include a neurologic assessment. Physical examination results 
will be reported as normal/abnormal. Abnormal results will include underlying disease 
abnormalities. A neurologic assessment will be performed at Screening, Day 1 for each SAD and 
MAD cohort, Week 17 for each SAD cohort, and Week 25/EoT for each MAD cohort and at EoT 
and EoT follow-up for any subject in the MAD extension. Further details will be described in the 
site manuals (e.g. Laboratory Manual, Site Operations Manual, Pharmacy Manual). 
Body weight will be measured at the indicated time points. A substantial change (as judged by 
the investigator) in body weight will be reported as an AE, and it will be discussed with the 
sponsor whether the dose calculation should be adjusted (see Section 5.2). 
Treatment of any abnormality observed during this examination has to be performed according 
to local medical practice outside this trial or by referral to an appropriate health care provider. 
Abnormalities identified at screening (compared to a healthy person) will be documented in the 
subject’s source documents and on the medical history eCRF. Worsening after screening will be 
captured as AEs on the AE eCRF page, when deemed clinically significant in the opinion of the 
investigator. 
6.2.2.4 
Vital Signs 
Vital signs (i.e. pulse rate, systolic and diastolic blood pressure, respiratory rate, pulse oximetry, 
and body temperature) will be assessed in a standardized manner. Pulse rate and blood pressure 
will be measured after 5 minutes in supine position. Blood pressure should be determined by cuff 
(using the same method, the same arm, and in the same position throughout the trial). Any 
deviations from baseline vital signs, which are deemed clinically significant in the opinion of the 
investigator, will be recorded as an AE. The vital signs monitoring during the infusion should be 
done every 5 minutes for the first 15 minutes and every 15 minutes until the infusion is 
completed. If the infusion is stopped for any reason and restarted, vital signs are to be taken 
according to this schedule until the infusion is completed. Pulse oximetry will measure the 
oxygen saturation level using a small device attached to the subject’s finger. The pulse oximetry 
device should remain in place throughout the IMP administration; any clinical findings during 
the continuous monitoring are to be reported. All vital signs will be noted as normal, abnormal 
not clinically significant, or abnormal clinically significant. Any abnormal clinically significant 
vital signs results are to be recorded as an AE. 
6.2.2.5 
Triplicate 12-Lead ECG and ECG Monitoring 
Triplicate 12-lead ECGs will be recorded and interpreted locally at the specified time points. On 
Day 1 (SAD), a triplicate 12-lead ECG will be performed, within 30 minutes before the start of 
the IMP administration and within 15 minutes after the end of the infusion, and ECG monitoring 
will be performed during the infusion (accompanied by oximetry and vital signs monitoring). 
Additional ECG monitoring may be done during treatment if, in the opinion of the investigator, 
this is clinically indicated.  
The subject will be instructed to rest in the supine position for 5 minutes before having an ECG 
assessment performed. If blood sampling or vital sign measurements are scheduled at the same 


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time point as the ECG recording, the procedures should preferably be initiated in the following 
order: ECG, vital signs and blood draw.  
Any deviations from baseline values, which are deemed clinically significant in the opinion of 
the investigator, will be recorded as an AE. 
6.2.2.6 Liver Ultrasound and Hepatic Elastography 
A liver ultrasound including hepatic elastography to assess hepatic peliosis and other structural 
abnormalities will be performed during the screening period, at the baseline visit of SAD (if the 
screening liver ultrasound and/or hepatic elastography is older than 12 months), or before the 
baseline visit in the MAD part (if not performed during the screening period). The liver 
ultrasound and hepatic elastography results should be available before IMP administration.   
Abnormalities identified at baseline will be documented in the subject’s source documents and 
on the medical history eCRF page.  
6.2.2.7 
Pregnancy Test 
A urine beta human chorionic gonadotropin (hCG) pregnancy test with a minimal sensitivity of 
25 mL/IU will be performed on all female subjects of child-bearing potential at the specified time 
points, in case pregnancy is suspected, and/or upon withdrawal of the subject from the trial. 
6.2.3 Pharmacokinetic Evaluations 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
Manual, Pharmacy Manual). 
6.2.3.1 
Collection of Blood Samples for PK Evaluations 
Blood samples for the determination of DYN101 levels in plasma will be collected by an 
indwelling catheter in the arm into vacuum tubes at the time points indicated in Table 3. A sample 
should be taken immediately after the end of the infusion. The following post-dose samples 
should be taken relative to the end of the infusion. 
Table 3: 
Pharmacokinetic Sampling Schedule 
Time Point 
Time Relative to Dosing on Day 1 (SAD/MAD) 
Sampling Window 
SAD and Washout 
 
 
Week 1, Day 1 
Pre-dose (0h) 
 
30 min after start of infusion (i.e. during infusion) 
±10 min 
Immediately after the end of infusion 
±10 min 
1h after the end of infusion 
±10 min 
3h after the end of infusion 
±10 min 
7h after the end of infusion 
±1h 
Week 1, Day 2 
23h after the end of infusion 
±3h 
Week 1, Day 3 
47h after the end of infusion 
±3h 
Week 2, Day 8  
167h after the end of infusion 
±1d 
Week 3, Day 15  
2 weeks post-dose 
±3d 
Week 5, Day 29  
4 weeks post-dose 
±3d 
Week 9 
8 weeks post-dose 
±3d 
Week 13 
12 weeks post-dose 
±3d 
Week 17 
16 weeks post-dose 
±3d 


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Time Point 
Time Relative to Dosing on Day 1 (SAD/MAD) 
Sampling Window 
MAD 
 
 
MAD Week 1, Day 1 
Pre-dose (0h) 
 
30 min post start of infusion (i.e. during infusion) 
±10 min 
Immediately after the end of infusion 
±10 min 
1h after the end of infusion 
±10 min 
3h after the end of infusion 
±10 min 
7h after the end of infusion 
±1h 
MAD Week 1, Day 2 
23h after the end of infusion 
±3h 
MAD Week 1, Day 4 
71h after the end of infusion 
±3h 
MAD Week 2 
Week 1, Day 1* 167h after the end of infusion 
±1d 
MAD Week 12, Day 1 
Pre-dose (0h) 
 
30 min after start of infusion (i.e. during infusion) 
±10 min 
Immediately after the end of infusion 
±10 min 
1h after the end of infusion 
±10 min 
3h after the end of infusion 
±10 min 
7h after the end of infusion 
±1h 
MAD Week 12, Day 2 
23h after the end of infusion 
±3h 
MAD Week 12, Day 4 
71h after the end of infusion 
±3h 
MAD Week 13  
Week 12, Day 1* (167h after the end of infusion) 
±1d 
MAD Week 25 
Week 24* (167h after the end of infusion) 
±1d 
* Sample to be taken before the next infusion (if applicable). 
6.2.3.2 
Collection of Samples for Exploratory Pharmacokinetics 
Collection of Blood Samples for Anti-Drug Antibodies 
Blood samples for determination of ADA will be taken in the MAD part and the MAD extension 
part at the time points specified in the TRIAL SCHEDULES.  
Collection of Blood Samples for Metabolic Profiling 
Blood samples for metabolic profiling of DYN101 will be taken in MAD Week 12 at 1 and 
167 hours post-dose (see Table 3).  
Collection of Urine for Metabolic Profiling 
Urine for metabolic profiling will be collected in MAD Week 12 in the following manner: 
• Subject should empty their bladder prior to, but as close as feasibly possible to, dose 
administration.  
• Urine will be collected over a 24-hour interval. The window of collection will be 
based on the start of the infusion (e.g. if infusion start is recorded as 13:00, then the 
collection window will end the following day at 12:59). 
Complete instructions on the collection of urine will be provided to the subject prior to the start 
of the collection. The subject may be confined to the clinic to collect this 24-hour urine sample. 
Further details will be described in the site manuals (e.g. Laboratory Manual, Site Operations 
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6.2.3.3 
Analytical Methods 
Plasma samples will be analyzed to determine concentrations of DYN101 using a validated, 
specific and sensitive method. 
DYN101 metabolites in plasma and urine will be identified and profiled in an exploratory 
manner. 
A validated ELISA method will be used to determine the presence and level of anti-DYN101 
antibodies in plasma. 
6.2.3.4 
PK Parameters 
The PK parameters of DYN101 will be derived using non-compartmental analysis methods with 
the plasma concentration-time data from all evaluable subjects. Actual sampling times, rather 
than scheduled sampling times, will be used in all computations involving sampling times. The 
following PK parameters will be calculated for plasma concentration values of DYN101. 
Parameter 
Definition 
AUCτ 
Area under the plasma concentration-time curve during a dosing interval 
AUClast 
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration 
AUC 
Area under the plasma concentration-time curve from time 0 to infinity 
Rac(AUC) 
Accumulation ratio based on AUCτ  
Rac(Cmax) 
Accumulation ratio based on Cmax 
Cmax 
Maximum plasma concentration 
Cav, SS 
Average plasma concentration during a dosing interval at steady state  
CL 
Clearance after IV administration 
z 
Terminal disposition phase rate constant 
t1/2 
Terminal disposition phase half-life 
tmax 
Time of first occurrence of Cmax 
Vz 
Apparent volume of distribution during the terminal disposition phase  
The effects of ADA on the PK parameters will be assessed. 
6.2.4 Pharmacodynamic/Exploratory Efficacy Evaluations 
The following PD/exploratory efficacy evaluations will be performed at specified time points as 
indicated in the TRIAL SCHEDULES. The questionnaires should be completed first, then the 
other assessments will be performed in the order listed: 
1) QoL and health outcome questionnaires 
2) EAT-10 Dysphagia questionnaire 
3) Respiratory function tests 
4) Muscle Strength and Function Tests: 
a. MyoGrip 
b. MFM32 


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All assessments, including their collection, management, and reporting, are described in detail in 
a separate Site Operations Manual. 
6.2.4.1 
Quality of Life and Health Outcome Questionnaires 
The following questionnaires will be assessed: 
• Patient Reported Outcomes Measurement Information System (PROMIS®) is a 
National Institutes of Health Initiative, created to assess patient–reported health status 
for physical, mental, and social well–being to reliably and validly measure 
patient-reported outcomes in chronic diseases for clinical research and practice. The 
PROMIS domains tested in this trial are Anxiety, Depression, Fatigue, Pain 
Interference, Ability to Participate, and Physical Function. 
• Clinical Global Impression of Improvement (CGI-I) is a 7-point scale ranging from 
(1) very much improved to (7) very much worse and is used to assess global changes 
in the subject’s condition compared to the condition before treatment. Wherever 
possible, the same clinician must complete the CGI-scale during the trial for the same 
subject. Results will be documented in the source documents. 
• Patient Global Impression of Change (PGI-C) is a scale similar to the CGI-I. It is a 
7-point scale ranging from (1) very much improved to (7) very much worse and needs 
to be completed independent of the investigator who completes the CGI-I, so neither 
party knows how the other has rated the scale. The subject (assisted by site personnel 
if needed) will complete PGI-C scale in the subject’s source documents. 
• Goal Attainment Scaling is an instrument that is intended for individual evaluation of 
an intervention. It allows subjects to set individual goals, together with their 
physician. The number of goals and the content of these goals may differ per subject, 
but the attainment of the goals is measured in a standardized way. This makes a 
standardized evaluation of an intervention possible, even when the subjects are all in 
a different stage of their disease. The physician selects objectives for each affected 
domain (respiratory, muscle strength and function, dysphagia) together with the 
subject, and records this in the eCRF. At the final assessment, the goal is evaluated 
on a 3-point scale by the physician and the subject. 
6.2.4.2 
Dysphagia Questionnaire 
Dysphagia is a relatively frequent problem in patients with CNM, particularly in those with 
XLCNM, and increases the risk of aspiration pneumonia, requiring the use of gastrostomy 
feedings. The Eating Assessment Tool (EAT-10) questionnaire will be used to assess swallowing 
difficulties and will be completed by the subject. 
6.2.4.3 
Respiratory Function Tests 
Assessment of the respiratory function will be performed with a handheld device, by qualified 
site personnel. To prevent air leaks, the nose will be blocked by a nose clip for every respiratory 
assessment. 


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For each parameter, the attempt should be repeated at least 3 times making sure that the subject 
has recovered between attempts. If, at each attempt, there is an improvement in the results, further 
tests can be conducted until the subject has achieved his/her best result. 
The following measurements will be performed: 
• Forced Vital Capacity (FVC): the maximum amount of air that a person can exhale 
as hard and as long as possible from the lungs after a maximum inspiration.  
• Forced Expiratory Volume (FEV1) in the first second of exhalation: FEV1 is the 
most frequently used index for assessing airway obstruction, bronchoconstriction or 
bronchodilatation. The ratio of FEV1 and FVC is the standard index (also called 
Tiffeneau index) for assessing and quantifying airflow limitation.  
• Maximum Expiratory and Inspiratory Pressures (MEP and MIP): these 
measurements assess the overall respiratory muscle strength. MIP reflects the strength 
of the inspiratory muscles, while MEP reflects the strength of the abdominal muscles 
and other expiratory muscles. This examination can detect early respiratory muscle 
weakness before the onset of a decrease in vital capacity. 
Measurements will be expressed as percent of predictive value. 
In addition, ventilation requirements will be recorded in the eCRF. 
6.2.4.4 
Muscle Strength and Function Tests 
All muscular testing will be done by a certified physiotherapist. 
The measurements will take place in a quiet and acclimatized room. All tests will be performed 
with the subject sitting in a regular chair or in their wheelchair facing a table, preferably 
adjustable in height with the forearm placed on the table or on the wheelchair shelf. Before each 
test, subjects will be given a description of the task, a demonstration of the expected movement 
and advice on the correct practice. If necessary, the correct body position will be manually 
guided. If standard upper limb position described in the assessment protocol (which will be 
provided to the sites) cannot be maintained because of contractures, an alternative position will 
be allowed.  
The subjects will perform the strength tests first (MyoGrip), followed by the functional tests 
(MFM32). To limit fatigue, only the subject’s dominant side will be tested, i.e. the hand preferred 
for fine motor skills such as writing. Each strength test must be repeated at least 3 times or 
repeated until the last attempt is less successful than the previous one. The retained value will be 
the maximal reproducible strength and should be within 10% of another attempt. Subjects will 
be given a 3-minute rest between each test. 
Functional tests will be video-recorded after signed consent to constitute a visual record of the 
subject’s ability. The subject or his/her representative have the right to refuse the video recording 
or request filming of only a specific frame (e.g. only the hand), a specific time period, or 
anonymization of the recording. In case the video will be used outside of the study team involved 
in the trial as a visual representation of the effect, the subject will be asked for a separate consent. 


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• MyoGrip is an extremely sensitive tool to measure muscle strength in severely 
disabled subjects where current tools are unable to measure changes or benefit 
(Servais et al., 2013). For disorders such as CNM, the ability to use the joystick of 
their electric wheelchair or other fine motor functions is important to the subject. 
These sensitive measures can also assist in detecting early signals of efficacy of an 
administered drug (Seferian et al., 2015). 
• Motor Function Measure (MFM) is classically used as a measure of functional 
capacities in subjects with neuromuscular disorders (Bérard et al., 2005). The MFM 
32-item list (MFM32) is a scale to enable an objective assessment of the motor 
abilities of subjects with neuromuscular diseases whatever the motor function 
deficiency. Three dimensions are taken into account: D1: standing position and 
transfers, D2: axial and proximal motor function, and D3: distal motor function.  
6.2.5 Collection of Optional Samples for Exploratory Research (Blood 
Biomarkers)  
Samples will be taken and stored from subjects who signed a separate ICF for further exploratory 
research (refer to Section 10.4.4). Blood-based biomarkers allow to explore how 
biomarker/genetic variations may affect the clinical parameters associated with the response to 
DYN101 and potentially the basis of CNM.  
If the subject is very light weight, anemic, or presenting with symptoms of fatigue, main study 
samples are to be taken first, exploratory samples may to be skipped due to the subject’s status. 
A blood sample for DNA will be taken only once at SAD baseline (or at MAD baseline for 
replacement subjects who did not participate in SAD) and blood samples for biomarkers will be 
taken at the time points defined in the TRIAL SCHEDULES. 
6.2.6 Muscle Biopsy 
Muscle biopsies will be performed at the time points defined in the TRIAL SCHEDULES. 
Details will be described in the Site Operations Manual. 
Muscle ultrasound imaging of both the vastus lateralis and biceps brachii will be performed at 
screening to determine which muscle should be biopsied. This imaging should not be older than 
6 months at baseline, otherwise it should be repeated. Muscle biopsies should be obtained from 
the vastus lateralis according to the site’s standard practice (open or needle biopsy) if sufficient 
muscle mass is identified after ultrasound imaging and muscle depth and location allow. In the 
event inadequate muscle tissue is identified in the vastus lateralis after ultrasound imaging, or it 
is determined that the location of a suitable vastus lateralis muscle is not easily accessible, a 
biopsy should be obtained from the biceps brachii (open or needle biopsy). For subjects 
undergoing an open muscle biopsy, general anesthesia can be applied. There should be 24 hours 
between the muscle biopsy and the IMP administration.  
Platelet counts need to be verified before a muscle biopsy is performed (the samples for 
verification of the platelet counts cannot be older than 3 days). The muscle biopsy should be the 
last assessment at the visit. Platelet counts will need to be verified again before IMP 
administration (local assessment) only if the previous platelet count is more than 3 days old. 


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The level of DNM2 mRNA as well as the concentration of DYN101 will be measured. This 
evaluation will allow for a measure of target engagement (i.e. the amount of decrease of DNM2) 
and will support the start of the MAD3 cohort and a dose selection for further clinical trials based 
on the PK/PD modelling, in addition to preclinical data, and results of some of the exploratory 
efficacy assessments.  
In addition, a section of the muscle will be prepared for histology.  
In case sufficient muscle biopsy material is left, the material will be stored for further exploratory 
research (see Section 10.4.4). 
6.2.7 Volume of Blood to be Drawn from Each Subject 
All blood samples will be collected via an indwelling catheter. The volume of blood to be drawn 
from each subject is presented in Table 4.  
Table 4: 
Volume of Blood to be Drawn from Each Subject  
Assessment 
Sample Volume 
(mL) 
Number of 
Samples a) 
Total Volume 
(mL) 
Safety samples – clinical laboratory tests 
Biochemistry (8.5 mL) 
8.5 
16 
136.0 
Biochemistry (5.0 mL) 
5.0 
19 
95.0 
Bile Acids 
3.5 
35 
122.5 
Complement  
5.0 
1 
5.0 
Hematology 
2.0 
31 
62.0 
Coagulation - local 
4.5 
31 
139.5 
Platelet count – local 
1.0 
31 
31.0 
Cardiac troponin 
2.5 
14 
35.0 
Erythrocyte sedimentation rate - local 
2.0 
30 
60.0 
PK samples b) 
PK evaluations 
4.0 
33 
132.0 
Anti-drug antibodies  
4.0 
5 
20.0 
Metabolic profiling 
4.0 
2 
8.0 
Blood biomarkers samples (optional) 
9.0 
6 
54.0 
DNA sample (optional) 
2.5 
1 
2.5 
Total Volume of Blood (mL) 
57.5 
 
902.5 
a) Not including any additional samples taken after MAD Week 25. 
b) If a catheter is used, the first 1 mL is to be discarded and 3 mL is taken into an appropriate tube for PK 
samples. Therefore, a total of 4 mL is indicated as the sample volume. 
Note: The above volume of blood to be taken for each assessment is an estimate. The volume of 
blood to be taken may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment. The estimated total blood volume does not include blood 
draws during unscheduled visits. When more than 1 blood assessment is to be done at the same 
time point/period, if they require the same type of tube, the assessments may be combined. 


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The total blood volume to be collected is considered to be within the limits of standard blood 
donation.  
6.2.8 Sample Management 
Samples will be labeled with the protocol number, the subject’s trial identification number and 
information related to the sample. No personal identifiers (e.g. date of birth, subject initials) will 
be recorded on the sample labels. Leftover samples may be used in the future for additional 
exploratory research. 
Sample collection and processing will be performed by qualified site personnel according to 
current versions of approved standard operating procedures. The Laboratory Manual contains 
further details regarding the collection, handling, labeling, and shipment of biological samples to 
the respective laboratories. 
7. SAFETY DEFINITIONS, REPORTING AND FOLLOW-UP 
7.1 Adverse Event Definitions 
An AE, an adverse drug reaction (ADR), and an SAE are defined according to the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Guideline E2A. 
An AE is any untoward medical occurrence in a subject administered the IMP and which does 
not necessarily have a causal relationship with this IMP or the IMP administration procedure. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the IMP including the IMP 
administration procedure. The definition also covers medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product. 
An ADR is an untoward and unintended response to the IMP related to any dose administered. 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if it was more severe) 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
o The hospitalization of a subject who decides to stay in the hospital overnight 
in advance or following IMP administration, for convenience based on 
personal choice or at the recommendation of the investigator without the 
presence of an AE warranting such hospitalization, is not considered an SAE.  
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 


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• Is judged medically important by the investigator (this refers to an event, not resulting 
in any of the outcomes listed above, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed) 
A suspected unexpected serious adverse reaction (SUSAR) is any suspected adverse reaction that 
is both serious and unexpected. 
The IB should be referenced for events that are considered expected. 
In the following situations events are not defined as an AE: 
• Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the trial that do not worsen. 
• Condition(s) for which pre-planned procedure(s) have been recorded at screening, 
including hospitalization(s), unless the condition(s) for which the procedure and/or 
hospitalization was planned has worsened from the first trial-related activity after the 
subject has signed the main ICF. 
• Concomitant illness identified during the screening procedures will be recorded as 
medical history. However, whenever symptoms for these condition(s) worsen and/or 
become serious, then these events must be reported as an AE or SAE, as applicable. 
7.2 Adverse Events of Special Interest 
The events described in this section will be reported as AEs, will be marked as AEs of special 
interest in the eCRF, and reported within 24 hours of the investigator becoming aware of the AE 
of special interest. 
Thrombocytopenia, impaired hepatic or kidney function are AEs of special interest, as they have 
been described with the use of ASOs previously, both in the preclinical and the clinical setting. 
Therefore, subjects experiencing reduced platelet counts or showing signs of impaired hepatic or 
kidney function, as evident by laboratory testing (see Section 7.11.2) should be examined by a 
physician as soon as possible and retested.  
Vasculitis is an AE of special interest as vasculitis which appeared to be associated with chronic 
complement activation with subsequent depletion and inflammation was observed in a 9-month 
preclinical study with DYN101 in NHP. Therefore, subjects with any suspicion for vasculitis 
(vasculitis of any origin, including the complement pathway) will trigger a consult with an 
appropriate specialist for further investigation. 
Although there is no clinical experience with DYN101 yet, some ASOs have been associated 
with an increased risk for thrombocytopenia. All subjects enrolled in clinical studies with 
DYN101 must be informed of the potential risk of severe thrombocytopenia.  
The investigator will diligently monitor each subject’s platelet count and must be in receipt of an 
interpretable platelet result before a scheduled IMP administration on the time points indicated 
in the TRIAL SCHEDULES. Investigators should ensure that subjects are queried about the 
possibility of spontaneous bleeding at routine study visits. 


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Subjects must also be instructed to urgently notify their doctor if they develop any symptoms 
consistent with thrombocytopenia or abnormal bleeding. It is recommended that subjects should 
be provided with an information leaflet describing these alert symptoms. These symptoms are as 
follows:  
• Nosebleed, bleeding from gums (either spontaneously or on brushing teeth), dark or 
bloody stools or blood in urine, vomiting blood, unusually heavy menstrual bleeding 
(period), or other unusual bleeding (for example prolonged bleeding after a cut or 
abrasion); 
• More frequent or easy bruising or bruising without injury; 
• Pinpoint-size red or purple spots on the skin, in the lining of the mouth, or the white 
of the eye; 
• Neck stiffness, unusual drowsiness, worsening headache, blurred or double vision; 
• Worsening abdominal pain. 
As there are no validated specific diagnostic markers to detect vasculitis, monitoring and 
assessment should be based on a high level of clinical awareness/suspicion and on physical 
examination and objective studies specific to the end organs that could be involved in 
drug-induced small or medium vessel vasculitis. These include, but are not limited to, the heart, 
kidney, lungs, liver, peripheral nervous system, and skin. In order to monitor for potential cases 
of vasculitis the following aspects need to be taken into account: 
• The physical examination performed by the investigator should include head, eyes, 
ears, nose, throat, heart, lungs, abdomen, extremities, examination of the skin for 
purpura, as well as neurological assessments for any new onset of paresthesia or 
dysesthesia. 
• Laboratory parameters, including cardiac troponin, complete blood count, clinical 
chemistry, liver and kidney function tests, urinalysis, and acute phase reactants like 
CRP and ESR have to be reviewed with the awareness of potential signals of end 
organs and non-specific markers of inflammation. 
In case of suspicion of vasculitis, refer to the Site Operations Manual for guidance on further 
work-up and consults with appropriate specialists. 
The investigator should also consider whether alternative explanations for the finding may be 
likely (e.g. recent antibiotic use when the subject presents with a rash) and how characteristic the 
finding is of vasculitis (e.g. a non-specific skin rash should be further investigated, but a purpuric 
rash should raise a higher level of suspicion, as it is more suggestive of vasculitis). 
7.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment, are 
not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology) or other abnormal (clinical trial-specific) assessments (e.g. ECG, vital signs) that 
require medical or surgical intervention, are associated with signs and/or symptoms, lead to IMP 


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interruption, modification, or discontinuation must be reported as an AE or SAE if they meet the 
definitions as described in Section 7.1. If the laboratory abnormality is part of a syndrome, the 
syndrome or diagnosis is to be reported (e.g. anemia instead of decreased hemoglobin). 
If a laboratory abnormality meets the criteria of a pausing stopping rule, appropriate action should 
be taken, as explained in Section 7.11. 
7.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of IMP to or by a 
subject, at a dose greater than 110% of the dosage  assigned to that individual subject according 
to the trial protocol.  
All cases of overdose (with or without associated AEs) will be documented in the eCRF. Cases 
of overdose without manifested signs or symptoms are not considered AEs. AEs associated with 
an overdose will be documented in the eCRF. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 7.7. 
In the event of overdose, the subject should be treated symptomatically. 
7.5 Adverse Event Assessment Definitions 
7.5.1 Severity 
The investigator should assess the severity of all AEs according to the following definitions: 
• Mild: A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual activities 
of daily living.  
• Moderate: A type of AE that is usually alleviated with specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research subject. 
• Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
For reporting of (S)AE related laboratory abnormalities, the severity (intensity) needs to be 
evaluated by the investigator in the accordance with the defined criteria for assessment of 
laboratory value abnormalities, following the CTCAE criteria (version 5, November 2017) (the 
investigator will be requested to provide the values for severity grades,). 
Note the distinction between seriousness and severity: the term severe is used to describe the 
intensity of the event and a severe event is not necessarily serious (e.g. a severe headache would 
probably not constitute an SAE; however, a mild myocardial infarction could constitute an SAE). 
The seriousness criteria serve as a guide for defining regulatory reporting obligations. 
If an AE changes severity over time, a new AE has to be reported with the new severity. 


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7.5.2 Relationship to Investigational Medicinal Product 
The investigator must assess the causal relationship of the IMP for each (S)AE. The investigator 
should decide whether, in his or her medical judgment, a possibility exists that the event may 
have been caused by the IMP. If there is a valid reason, even if undetermined or untested, for 
suspecting a cause-and-effect relationship between the IMP and the occurrence of the AE, then 
the AE should be considered ‘related’. If there is no valid reason for suggesting a relationship, 
i.e. when a relationship to IMP is excluded, then the AE should be classified as ‘not related’. The 
causality assessment must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Related 
Yes 
As a therapeutic dose has not yet been established for the IMP, at this time, 
all noxious and unintended responses to the IMP are considered to be related 
to the IMP unless they are reasonably attributed to another cause. There is 
a temporal relationship between the event and the administration of the 
IMP. 
Not Related 
No 
The event can be readily explained by other factors such as the concomitant 
therapy or accident and no plausible temporal or biologic relationship exists 
between the IMP and the event. In addition, this assessment can be used in 
cases where the subject did not receive any treatment with IMP. 
7.6 Reporting of Adverse Events 
All events meeting the definition of an AE must be reported from signing of the main ICF 
onwards until the last trial visit. Only medically qualified personnel (investigators) must assess 
AEs. 
AEs must be reported by the investigator in the source data and the eCRF. The diagnosis will be 
recorded, if available and applicable. If no diagnosis is available, each sign and symptom will be 
recorded as individual AEs in the eCRF. 
Recurring AEs with fluctuations in severity should be reported separately, i.e. with separate start 
date and time and stop date and time. Recurring AEs for which the severity is stable, could be 
reported as intermittent AEs, with the start date being the start of the first episode of the AE. If 
the severity changes, the intermittent AE should get a stop date, and a new AE with the new 
severity should be reported. 
Investigators will receive copies of initial and follow-up expedited safety reports (unexpected 
SAEs that are determined to be associated with the use of IMP) from the sponsor or designee. 
The investigator is responsible for fulfilling applicable local reporting requirements to their 
IEC/IRB. Investigators must forward copies of the IEC/IRB notification to the sponsor or 
designee. In the European Union (EU), the sponsor or designee is responsible for notifying the 
European Medicines Agency (EMA), IEC/IRB, and competent authorities. In regions/countries 
other than the EU, reporting of events to IEC/IRB or local authorities will be performed by the 
investigator/sponsor or designee and in accordance with local procedures/regulations. 


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7.7 Prompt Reporting of Serious Adverse Events  
All events meeting the definition of an SAE must be reported from signing of the main ICF 
onwards until the last trial visit. SAEs must be reported immediately to the sponsor as soon as 
the investigator determines that the event meets the protocol definition for that event. Further 
details will be described in the site manuals (e.g. Site Cohort Management Manual, Site 
Operations Manual). 
The information will be reported on the SAE eCRF and will include assessment of seriousness, 
severity, causal relationship to the IMP or trial procedures, outcome, and a narrative description 
of the course of the event. Additional information may be subsequently provided. 
All SAEs, regardless of causality, must be reported to the sponsor or designee (the contract 
research organization [CRO] responsible for Pharmacovigilance) within 24 hours of the first 
awareness of the event in the eCRF. In the event the eCRF system is unavailable, a paper back-up 
SAE form should be completed and submitted (see Emergency Contact Information). 
All relevant documents including but not limited to diagnostic procedures, hospital records, 
autopsy reports after redaction of all subject identification details must be faxed or e-mailed (see 
Emergency Contact Information). 
SAEs occurring in a subject after the subject has completed the clinical trial and for which a 
reasonable possibility of a causal relationship is assessed by the investigator should be reported 
by the investigator to the sponsor, if the investigator becomes aware of them regardless of the 
time that has elapsed (post-trial events). 
7.8 Regulatory Reporting Requirements for Serious Adverse Events and Other 
Events 
Prompt notification of SAEs by the investigator to the sponsor is essential, so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. This is particularly 
true for this trial as this involves the first use of DYN101 in humans; safety concerns drive the 
Pausing/Stopping rules for the trial (Section 7.11.1). Further details will be described in the site 
manuals (e.g. Site Cohort Management Manual, Site Operations Manual). 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. The sponsor will 
comply with the ICH/EMA and country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IEC/IRB, and investigators. 
Expedited reporting of SUSARs will be taking place within 7 or 15 days depending on fatal/life 
threatening status, seriousness, expectedness, and causality from all clinical trials globally 
(SUSAR reporting in EU). Any suspected adverse reaction that is both serious and unexpected 
according to the IB will be reported provided there is evidence to suggest a causal relationship 
between the IMP and the AE. 
Relevant follow-up information to a SUSAR will be submitted as soon as the information is 
available. 


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Information about SUSARs is also forwarded to the investigators and IEC/IRB. Additionally, 
safety information will be forwarded to Ionis Pharmaceuticals, Inc, owner of DYN101.   
An investigator who receives a SUSAR describing (an) SAE(s) or other specific safety 
information (e.g. summary or listing of SAEs) from the sponsor will file it with the IB, and will 
notify the IEC/IRB, if appropriate according to local requirements. 
In addition to submission of SAEs, an annual development safety update report will be prepared 
and submitted to the EMA (and locally, if applicable), according to the development international 
birth date. 
7.9 Reporting of Pregnancies 
Should a pregnancy occur in a female subject or female partner of a male subject, it will be 
recorded separately from AEs, but will be reported by the investigator in a manner identical to 
the reporting of SAEs (see Section 7.7), by completing the pregnancy eCRF. 
All attempts will be made to follow the pregnancy until the outcome of the pregnancy has been 
determined, and to capture information on the development of the infant in the period up till and 
including the age of 1 year. This information will only be collected if separate informed consent 
is given by the subject and the subject’s sexual partner. 
Any report of a congenital abnormality/birth defect is an SAE and should be reported as such. 
Any complication of a pregnancy occurring during this trial, including elective termination for 
medical reasons, must be reported in the pregnancy eCRF. 
In the event the eCRF system is unavailable, a paper back-up SAE form should be completed 
and submitted (see Emergency Contact Information). 
7.10 Follow-up on Adverse Events 
All AEs and SAEs should be followed until stable, resolved or they have reached a “final 
outcome” or the subject’s participation in the trial ends, whichever comes first. 
Adverse events assessed as “related” to IMP and all SAEs and AEs of special interest (regardless 
of their relationship to IMP) still ongoing after the end of trial participation (i.e. after the 
follow-up call) should be followed on a regular basis according to the investigator’s clinical 
judgment until the condition is stable. 
The outcome “recovering” can be used as the “final outcome” for events that are stabilized 
(i.e. no further worsening is expected) and expected by the investigator to resolve over time. 
The outcome “not recovered” can be used as the “final outcome” for events that are not expected 
to resolve over time (e.g. cancer). 
The outcome “unknown” can be used as the “final outcome” for events for which the outcome is 
not known. 
If a subject dies during the reporting period, attempts should be made to obtain muscle biopsy 
material to assess muscle histology, ASO concentration, and DNM2 mRNA.  


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Follow-up information received after the end of the trial should be sent to the sponsor. 
7.11 Pausing/Stopping Rules 
7.11.1 Pausing/Stopping Rules for the Trial 
The investigators, together with the medical monitor, will be responsible for the safety 
monitoring of the trial, and will pause IMP administration in case any of the pre-specified 
pausing/stopping rules have been met. The sponsor’s medical lead will be involved in all 
discussions and decisions. 
If any of the following events occur in any subject in any cohort who received at least one IMP 
administration in the trial (at any site), the investigator will pause the IMP administration of 
further subjects in all cohorts and will notify the medical monitor immediately. The medical 
monitor will inform all the other investigators to pause further IMP administration as well and 
will notify the IDMC immediately. 
• Death in any subject, considered related to IMP; OR 
• An anaphylactic reaction within 24 hours of the start of the infusion or the presence 
of generalized urticaria within 72 hours of the start of the infusion in any subject, 
considered related to IMP; OR 
• An SAE in any subject, considered related to IMP. 
Events which would not meet the hospitalization criterion to be reported as an SAE 
for this trial are: 
o Overnight stay for convenience based on the subject/caregiver personal choice 
o Overnight stay offered by the investigator based on non-clinical grounds 
o For observation of minor reactions which would not on their own warrant 
admission to hospital, but is preferred in this vulnerable population; OR 
• ALT or AST > 8 × ULN, considered related to IMP and confirmed by repeat testing.  
Subjects experiencing any of the events defined above will be permanently withdrawn from IMP 
administration and will discontinue the trial (see Section 4.5).  
Within 3 business days, the IDMC will convene to review the available safety data as outlined in 
the charter and to discuss further actions (e.g. continue either as planned or with modifications, 
or to stop the trial). In the event a stopping rule is met, the national authorities will be informed 
through a substantial amendment. The sites will be allowed to resume activities after the national 
authorities have received, reviewed, and approved the available safety data and any protocol 
amendment, if any, and upon receipt of a written notification from the sponsor to allow continued 
treatment and enrollment.  
In case the pause is lifted, withdrawn subjects can be replaced to maintain full enrollment within 
the sub-cohort under the circumstances described in Section 3.1.2. 
Subjects who were awaiting the start of their cohort and whose screening period is longer than 
the protocol-defined 6 weeks as a result of a pause in IMP administrations will be allowed to be 
re-screened in line with the re-screening procedures outlined in Section 6.1.1.  


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7.11.2 Individual Treatment Interruptions and Dose Adjustments 
As thrombocytopenia is a known side effect of ASOs, it is important to always check that the 
subject has a normal platelet count before dosing. If a decreased platelet count is detected (i.e. 
value < lower limit of normal [LLN]), a retest should be performed immediately in the local 
laboratory. If the retest confirms a platelet count value < LLN, the subject may NOT be dosed.  
Treatment interruptions will be considered in the event of any suspicion of vasculitis or in the 
event of any of the following situations that may occur, considered related to IMP: 
• Platelet count is between 75,000 and 150,000/µL; in that case the subject can be dosed 
as soon as the platelet count has returned to a value > LLN and dosing can resume at 
the same dose. 
• Platelet count is < 75,000/µL; in that case the subject can be dosed as soon as the 
platelet has returned to a value > LLN, however dosing should be resumed at 50% of 
the previous dose. 
• Platelet count is < LLN and a previous dose interruption had taken place because of 
decreased platelet values; in this case, the medical monitor should be contacted to 
discuss possible additional treatment interruptions and/or dose adjustments. 
Furthermore, treatment interruptions and/or dose adjustments for an individual subject should be 
considered in the event of any of the following events: 
• Elevation of AST and/or ALT > 3 × ULN  
• Elevation of bilirubin > 2 × ULN 
• Elevation of ALP > 1.5 × ULN 
• Elevation of ALT and/or AST in temporal association with nausea, vomiting, 
anorexia, abdominal pain, or fatigue 
• Clinically significant deteriorating kidney function during treatment 
• Any other clinically significant deterioration during treatment considered related to 
IMP. 
In these instances, the medical monitor should be contacted to discuss potential treatment 
interruptions and/or dose adjustments. 
In case a treatment interruption is needed for any safety reason for more than 4 consecutive 
weeks, or if there is a second treatment interruption on the initial or reduced dose level, the site 
should always contact the medical monitor to determine the best strategy for the subject, 
considering the individual risk-benefit ratio.  
Note: If treatment is interrupted for circumstances other than safety reasons, the site should also 
contact the medical monitor to determine whether it is allowed or possible to restart treatment, 
and if so, at what dose. 


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8. DATA MANAGEMENT 
8.1 Data Collection 
The investigators’ authorized site personnel must enter the information from the source data (see 
Section 10.2.3.2), as required by the protocol, in the eCRF (see Section 10.2.3.1). A monitor will 
visit each site in accordance with the monitoring plan and review the eCRF data against the 
source data for completeness and accuracy. Discrepancies between source data and data entered 
in the eCRF will be addressed by qualified site personnel. When a data discrepancy warrants 
correction, the correction will be made by authorized site personnel. Data collection procedures 
will be discussed with the site personnel at the site initiation visit and/or at the investigator’s 
meeting.  
8.2 Clinical Data Management 
Data are to be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections 
to the clinical database, and all corrections have to be documented in an auditable manner. 
9. STATISTICAL METHODS 
9.1 Statistical Analysis 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. Statistical 
analyses will be performed using Version 9.2 or higher of SAS® (SAS Institute, Cary, 
NC 27513). Details regarding the statistical methods and definitions will be provided in the 
Statistical Analysis Plan (SAP), and will include templates for the tables, figures and listings to 
be provided. The SAP will be finalized before the database lock; output for the IDMC will be 
finalized before the first subject receives the first dose of IMP. Any deviations from the SAP are 
to be justified in the clinical trial report. A general description of the statistical methods to be 
used to analyze the safety, PK, PD and preliminary efficacy data is outlined below. 
In general, descriptive statistics and/or frequency tabulations will be presented overall and by 
dose (cohort), for single or multiple administration, and by mutated gene (sub-cohort). Listings 
and figures presenting individual data will be generated as appropriate. 
Endpoints are described in Section 3.3.  
An interim analysis will be performed when all subjects in cohorts 1 and 2 have completed 
12 weeks of MAD treatment or discontinued earlier, or if the sponsor deems a risk/benefit 
analysis necessary at any time point.  
The primary analysis will be performed when all subjects in all cohorts have completed 12 weeks 
of MAD treatment or discontinued earlier.  


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The final analysis will be performed when all subjects have completed 24 weeks of MAD 
treatment (12 weeks in the MAD part + 12 weeks in the MAD extension part; Week 25 visit) or 
discontinued earlier.  
The interim, primary and final analyses will be performed on the Safety Analysis Set (see Section 
9.3) for the primary objective. Secondary and exploratory objectives will be conducted on the 
Pharmacokinetic Set. Safety analyses (AE, clinical laboratory tests, physical examination, vital 
signs, and ECG) will be performed on the Safety Analysis Set. Results from the interim, primary, 
and final analysis will be described in the clinical trial report. 
Note that after Week 24, all subjects will remain on treatment with weekly IMP administrations 
and bi-weekly (every 2 weeks) assessments until the last MAD3 subject has completed the MAD 
Week 25 visit. The data from this period for these subjects will be tabulated and listed in the 
clinical trial report but will not be taken into account in the statistical modeling. 
9.2 Planned Interim Analysis and Adaptive Design 
To allow robust data, an interim analysis will be performed when all subjects in Cohorts 1 and 2 
have completed 12 weeks of MAD treatment or discontinued earlier, or if the sponsor deems a 
risk/benefit analysis necessary at any time point.  
9.3 Selection of Subjects to be Included in the Analyses 
Pre-Screened Set – Subjects who have a signed pre-screening consent. 
Screened Set – Subjects who have signed main informed consent. 
Safety Analysis Set – Screened subjects who have received at least 1 IMP administration. 
Pharmacokinetic Set – Subjects in the Safety Analysis Set for whom the primary PK data are 
considered sufficient and interpretable. 
9.4 Subject Disposition 
Subjects in each analysis set as well as subjects who complete the trial or who discontinue from 
the trial will be summarized by sub-cohort using frequency tabulations. In addition, for subjects 
who discontinue from the trial, the reasons for discontinuation will be summarized by cohort. 
9.5 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be presented for the Safety Analysis Set. 
Continuous variables such as subject age, body weight, height and body mass index will be 
summarized using the number of observations, mean, standard deviation, median, minimum and 
maximum values. Categorical variables such as subject gender and race/ethnicity will be 
summarized using the number of observations and percentages for each category. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized using the number of observations and percentages of subjects reporting each 
category. 


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9.6 Investigational Medicinal Product Exposure 
Descriptive statistics for the duration of exposure to IMP will be calculated. The number of 
subjects receiving each dose and compliance rates will be summarized at each scheduled time 
point.  
9.7 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug dictionary and summarized using the number of observations and percentages of subjects 
reporting for each preferred drug name. 
9.8 Safety Analyses 
Safety analyses will be presented for the Safety Analysis Set. 
Baseline for all clinical laboratory tests, physical examination results, vital signs, liver ultrasound 
and hepatic elastography, and ECG will be defined as the last assessment prior to IMP 
administration. 
Safety data will be analyzed using descriptive statistics (arithmetic mean, geometric mean, SD, 
%CV, median, minimum and maximum values, including 95% confidence intervals (CIs), if 
applicable). 
Adverse Events 
AEs will be coded using the MedDRA version available at the start of the trial. The number of 
events as well as the incidence and percentage of subjects with treatment-emergent adverse 
events (TEAEs) will be calculated overall, by system organ class, and by preferred term. TEAEs 
will be further summarized by severity and relationship to IMP. AEs related to IMP, AEs of 
special interest, AEs leading to withdrawal, SAEs and deaths will be summarized or listed. 
Clinical Laboratory Tests 
Descriptive statistics of observed values and changes from baseline will be calculated for each 
laboratory analyte at each scheduled time point. The frequency counts and percentage of subjects 
with laboratory abnormalities will be tabulated at each scheduled time point. The laboratory 
abnormalities will be determined according to the CTCAE criteria (version 5, November 2017) 
and in accordance with the normal ranges of the clinical laboratory if no gradings are available. 
Potentially clinically important findings will also be summarized or listed. 
Physical Examination 
Physical examination abnormalities will be listed at each scheduled time point. 
Vital Signs and ECG 
Descriptive statistics of observed values and changes from baseline will be calculated for each 
vital signs and ECG parameter at each scheduled time point. The frequency counts and 
percentage of subjects with abnormalities for each parameter will be tabulated at each scheduled 
time point. 


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Liver Ultrasound and Hepatic Elastography 
The observed data for liver ultrasound and hepatic elastography assessments will be listed. 
9.9 Pharmacokinetics Analyses 
Plasma concentrations over each scheduled collection time and PK parameters of DYN101 will 
be summarized for each dose using descriptive statistics (arithmetic mean, SD, %CV, median, 
minimum and maximum). In addition, geometric mean and CV will be computed for Cmax and 
AUCs. 
To assess dose proportionality (as appropriate) following single or multiple doses in all cohorts, 
regression analysis of natural logarithm (log) transformed Cmax, AUClast and AUC∞ will be 
performed on log(dose). The power fit will be assumed as described by the following equation: 
 
log(PK parameter) = β0 + β1log(Dose) + ε 
Where β0 is the intercept and β1 is the slope. Dose will be the weight adjusted dose. 
The 90% CI of the slope estimate will be presented. Dose proportionality will be declared when 
the 90% CI for β1 lies entirely within the critical region: 
 
(1+log(0.8)/log(r)) < β1<(1+log(1.25)/log(r)) 
Where r is the ratio of the highest and the lowest dose in this trial. This criterion implies that the 
90% CI for the ratio of the central values of PK parameter of interest from the highest dose to 
the lowest dose is contained completely within the bioequivalence range of (0.80, 1.25). 
One-way analysis of variance will be performed for λz, with dose as a fixed effect to evaluate the 
effect of dose on λz. 
In addition, the impact of immunogenicity (ADA) on the PK of DYN101 will be explored. 
Furthermore, the metabolic profile of DYN101 will be described. 
Any additional analysis that is deemed necessary will be presented in the SAP.  
An exploratory population PK model might be developed, of which the results will be reported 
in a separate report. 
9.10 Pharmacodynamics/Exploratory Efficacy Analyses 
Descriptive statistics (arithmetic mean, geometric mean, SD, %CV, median, minimum and 
maximum) will be used to summarize the PD/exploratory efficacy data. Changes from baseline 
(where applicable) will also be tabulated. 
Advanced analyses and models will be used to summarize in a more effective way the potential 
effect of the treatment and are not aimed for inferential purposes since the trial is not powered 
for that purpose. 
For the respiratory function and the muscle strength and function tests data available from the 
NHS or the run-in period, an appropriate mixed effect model for repeated measurements will be 
applied to all the data to evaluate the evolution over time on a subject basis and to compute the 


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probability to observe the data under treatment assuming a normal disease progression. The 
model will include necessary covariates such as dose, demographic data, mutated gene, and 
biomarker values. Depending on the test, transformations may be applied to the results to ensure 
use of the appropriate model. For tests providing bounded scores, the normalized data between 
0 and 100% will be evaluated using a Beta sampling distribution. For unbounded scores, 
logarithmic transformations will be applied by default since these are strictly positive values. The 
selection of covariates such as demographic data and biomarker value will be made using quality 
of fit criteria such as Aikaike Information Criteria. 
The analysis of the blood biomarker data will be explorative and will not be performed as part of 
this trial. 
9.11 Sample Size Justification 
The sample size of 18 subjects treated with DYN101 is deemed to be appropriate to evaluate the 
safety and tolerability in a first-in-human trial. No power analysis was conducted to support the 
sample size. 
9.12 Independent Data Monitoring Committee 
An IDMC will be involved in the management of this trial. The purpose of the IDMC is to review 
the safety and tolerability and muscle biopsy data (where applicable) of the cohorts, before 
proceeding to the next dose level, as specified in Section 3.1.1. 
The committee will meet periodically (see Section 3.1 and Figure 2 for the 4 planned IDMC 
meetings) to monitor the safety data on a regular basis to ensure the continuing safety of the 
enrolled subjects. The IDMC may meet at any time based on emerging safety and tolerability 
data. At a minimum the IDMC must meet after all subjects of a cohort have been dosed to advise 
to continue each MTM1 and/or DNM2 sub-cohort to the next dose level/or discontinue the MTM1 
and/or DNM2 sub-cohort of the trial. Escalation of each MTM1 and/or DNM2 sub-cohort to the 
next increased dose level will not take place until the IDMC has reviewed the data of the previous 
(sub-)cohort (including subjects who have discontinued the trial). The data reviewed by the 
IDMC for dose escalation decisions will be as clean as possible prior to their review. The IDMC 
can recommend adjusting dose levels or stopping the dose escalation scheme for each MTM1 
and/or DNM2 sub-cohort and/or individual subject based on the totality of available data (safety 
and tolerability, level of target engagement and/or efficacy). At each IDMC review, different 
decisions for the sub-cohorts (DNM2 vs MTM1) can be made based on the emerging data. If 
needed, the IDMC review can be split over separate meetings for the sub-cohorts, although the 
available data from the other sub-cohort will also be taken into account at each meeting.  
The IDMC will review all available safety data on a rolling basis to allow emerging data to 
contribute to all decisions. An ad hoc IDMC meeting may be requested via the sponsor for any 
single event or combination of multiple events which are considered to jeopardize the safety of 
the subjects. 
Pausing/stopping rules will be applied in this trial (see Section 7.11). 
The IDMC will be appointed by the sponsor before the start of the trial. The IDMC will consist 
of at least 1 independent medical expert in the relevant therapeutic area and at least 1 independent 
statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
charter. Any safety reports/interim data from the cohorts in this trial reviewed by the IDMC and 
the recommendations of the IDMC will be shared with the local health authorities and the 
IEC/IRB. 


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Further details regarding the IDMC can be found in the IDMC charter, which will be available 
prior to the administration of DYN101. 
9.13 Missing Data 
Since efficacy concerns are only exploratory, no missing data imputations methods will be used. 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This trial will be conducted in accordance with the current applicable regulations, ICH GCP E6 
(R2) 
(https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R
2__Step_4_2016_1109.pdf), EU Directive 2001/20/EC and its updates (https://ec.europa.eu/ 
health/sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf), the Guideline 
on Strategies to Identify and Mitigate Risks for First-in-Human and Early Clinical Trials with 
Investigational Medicinal Products (20July2017EMEA/CHMP/SWP/28367/07 Rev), the 
guidelines of the Declaration of Helsinki, and local ethical and legal requirements. In the absence 
of data demonstrating developmental delay in subjects with CNM ≥ 16 years of age, apart from 
disease associated effect on muscles, these subjects will be treated as adults in this trial from a 
metabolic and PK perspective. And given that this disease has rare disease status, while the ICH 
11 Guideline, Clinical Investigation of Medical Products in the Pediatric Population 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/ICH_
E11_R1_Step_2_25Aug2016_Final.pdf), 
was 
reviewed, 
full 
compliance 
is 
not 
warranted/claimed.  
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety and well-
being of clinical trial subjects are protected, consistent with the principles that have their origin 
in the Declaration of Helsinki, and that the clinical trial data are credible. 
The name and address of each third-party vendor (e.g. CRO) used in this trial and the sponsor’s 
trial team members will be maintained in the investigator’s and sponsor’s files as appropriate. 
10.1 Sponsor’s Responsibilities 
10.1.1 Good Clinical Practice Compliance 
The sponsor and any third party to whom aspects of the trial management or monitoring have 
been delegated will undertake their assigned roles for this trial in compliance with the ICH GCP 
Guideline E6 (R2) as well as with applicable regulatory requirements in the countries where the 
trial will take place.  
The sponsor will provide the investigator with any new safety findings as soon as they are 
available.  
Representatives of the sponsor, and/or the company organizing/managing the research on behalf 
of the sponsor, conduct visits to sites to inspect trial data, subjects’ medical records, and eCRFs 
in accordance with current GCP and the respective local and (inter)national government 


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regulations and guidelines. Records and data may additionally be reviewed by auditors or by 
regulatory authorities. Any changes from standard agreed upon practices due to restrictions 
imposed in response to a pandemic will be communicated and agreed to by the sponsor. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
trial. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of IMP for 
shipment to the site. 
A ‘serious breach’ is defined as a breach likely to effect to a significant degree:  
• the safety or physical or mental integrity of the subjects of the trial; or 
• the scientific value of the trial.  
Making a judgment on whether a potential breach or non-compliance (or persistent non-
compliance) is ‘serious’ and requires reporting is the responsibility of the sponsor. The sponsor 
will notify the licensing authority in writing of any serious breach of:  
• the conditions and principles of GCP in connection with the trial; or  
• the protocol, as amended from time to time in accordance with local regulations, within 
7 days of becoming aware of that breach.  
10.1.2 Indemnity/Liability and Insurance 
The sponsor ensures that suitable clinical trial insurance coverage is in place prior to the start of 
the trial. An insurance certificate is supplied to the investigator and the IEC/IRB as necessary. 
The sponsor has obtained travel insurance to cover the subject’s and their caregiver’s travel to 
and from clinic visits.  
10.1.3 Public Posting of Trial Information 
The sponsor will assure that key design elements of this protocol will be posted in a publicly 
accessible database such as EudraCT and clinicaltrials.gov. In addition, upon trial completion 
and finalization of the trial report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. Information included in 
clinical trial registries may include participating investigators’ names and contact information. 
10.1.4 Submission of Summary of Clinical Trial Report to Competent Authorities 
of Member States Concerned and Independent Ethics 
Committees/Independent Review Boards 
The sponsor will provide a summary of the clinical trial report within 1 year of the end of the 
trial completion date to the competent authority of the member state(s) concerned as required by 
regulatory requirement(s) and to comply with the community guideline on GCP. The sponsor 
will provide the IECs/IRBs with a copy of the same summary. 


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10.1.5 Trial Suspension, Termination, and Completion 
The sponsor may suspend or terminate the trial or part of the trial at any time for any reason. If 
the trial is suspended or early terminated, the sponsor will ensure that applicable regulatory 
agencies and the IECs/IRBs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical trial, which has been posted to a designated public website, will be updated 
accordingly. 
Upon completion of the trial, the sponsor will make an end of trial declaration to the relevant 
competent authority as required by Article 10 (c) of Directive 2001/20/EC.  
10.2 Investigator’s Responsibilities 
10.2.1 Good Clinical Practice Compliance 
The investigator must agree to conduct the trial in accordance with ICH GCP Guideline E6 (R2), 
and applicable regulatory requirements and guidelines. Per the Guideline on Strategies to Identify 
and Mitigate Risks for First-in-Human and Early Clinical Trials with Investigational Medicinal 
Products (20July2017EMEA/CHMP/SWP/28367/07 Rev), the investigator should have 
immediate access to equipment and appropriately qualified staff for resuscitating and stabilizing 
individuals in an acute emergency including ready availability of intensive care unit and other 
hospital facilities. Procedures should be established between the clinical research unit and its 
nearby intensive care unit regarding the responsibilities and undertakings of each in the transfer 
and care of subjects. Further details will be described in the site manuals (e.g. Site Cohort 
Management Manual, Site Operations Manual, Pharmacy Manual). 
It is the investigator’s responsibility to ensure that adequate time and appropriate trained 
resources are available at the site prior to commitment to participate in this trial. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant trial-related tasks. Curriculum vitae for investigators and 
sub-investigators are provided to the sponsor (or designee) before starting the trial. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform him or her of the subject’s participation in the trial. 
A coordinating investigator is appointed to review the final clinical trial report for multi-center 
trials. Agreement with the final clinical trial report is documented by the signed and dated 
signature of the coordinating investigator, in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2 Protocol Adherence and Investigator Agreement 
The investigator and any sub-investigators must adhere to the trial protocol. The investigator is 
responsible for enrolling only those subjects who have met protocol eligibility criteria. The 
investigator agrees to promptly (i.e. immediately but in less than 24 hours) report any SAE in 
both sentinel and other subjects. Further details will be described in the site manuals (e.g. Site 


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Operations Manual, Site Cohort Management Manual). Investigators are required to sign an 
Investigator Agreement to confirm acceptance and willingness to comply with the trial protocol. 
The investigator is responsible for reporting protocol deviations. 
If the investigator terminates the trial at his or her site, the investigator will promptly inform the 
sponsor and the IEC/IRB and provide them with a detailed written explanation. The investigator 
will also return all IMP, containers, and other trial materials to the sponsor. Upon trial 
completion, the investigator will provide the sponsor, IEC/IRB, and regulatory authority with 
final reports and summaries as required by (inter)national regulations. 
Communication with the local IEC/IRB, to ensure accurate and timely information is provided 
at all phases during the trial, may be done by the sponsor, applicable CRO, investigator, or for 
multi-center trials, the coordinating investigator according to national provisions. 
Responsibilities for this communication will be documented in the Investigator Agreement. 
10.2.3 Documentation and Retention of Records 
10.2.3.1 
Electronic Case Report Forms 
Electronic CRFs are supplied by the CRO and should be handled in accordance with instructions 
from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records (see 
Section 10.2.3.2) from which accurate information is recorded onto eCRFs, which have been 
designed to record all observations and other data pertinent to the clinical investigation. The 
investigator will ensure the accuracy, completeness, legibility, and timelines of the data recorded 
in the eCRF, and of the provision of answers to data queries. All eCRF entries, corrections, and 
alterations must be made by the investigator or other authorized site personnel. The investigator 
will sign the completed eCRF. A copy of the completed eCRF will be sent to the sites for 
archiving.  
The monitor will verify the contents against the source data per the monitoring plan. If the data 
are unclear or contradictory, queries will be sent for corrections or verification of data. 
10.2.3.2 
Recording, Access, and Retention of Source Data and Trial Documents 
Original source data to be reviewed during this trial will include, but are not limited to the 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports, 
QoL and health outcome questionnaires, ECG, ICFs, and videos. 
All key data must be recorded in the subject’s medical records. 
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IEC/IRB, and auditors to inspect facilities and to have 
direct access to original source records relevant to this trial, regardless of media. Any access to 
original source records not possible due to restrictions imposed in response to a pandemic must 
be communicated to the sponsor and/or the company organizing/managing the research on behalf 
of the sponsor as soon as possible. All source records to be used in this trial will be explained to 
the subject in the ICF. 


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The monitor (and auditors, IEC/IRB or regulatory inspectors) may check the eCRF entries 
against the source documents. The ICF includes a statement by which the subject agrees to the 
monitor/auditor from the sponsor or its representatives, national or local regulatory authorities, 
or the IEC/IRB having access to source data (e.g. subject’s medical file, appointment books, 
original laboratory reports, X-rays etc.).  
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory authority (e.g. the US Food 
and Drug Administration [FDA], EMA, UK Medicines and Healthcare products Regulatory 
Agency [MHRA]) or an auditor) (in compliance with the General Data Protection Regulation 
(EU)2016/679 [27 April 2016]). 
The investigator should take all necessary measures to prevent accidental destruction of the 
essential documents. They must be maintained according to ICH GCP requirements, for at least 
15 years or longer if required by local regulatory requirements, and may not be destroyed without 
written permission from the sponsor. 
10.2.3.3 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this trial must be available for 
inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the MHRA, other regulatory authorities, the 
sponsor or its representatives, and the IEC/IRB for each site. 
10.3 Trial Documentation 
Before initiation of the trial, the following documents must be made available to the sponsor for 
each participating site: 
1) Curriculum vitae of the investigator and any sub-investigators (listed on the 1572 
form if applicable); 
2) A signed copy of the IEC/IRB approval notice for protocol and ICFs; 
3) A copy of the IEC/IRB-approved ICFs; 
4) Laboratory certification with a list of normal values for laboratory tests that will be 
conducted at local laboratories; 
5) Completed financial disclosure form for the Investigator and any sub-investigators 
(listed on the 1572 form if applicable); 
6) Authorization to conduct a Phase 1 trial as required per local regulation. 
Further details will be described in the site manuals (e.g. Site Cohort Management Manual, Site 
Operations Manual, Pharmacy Manual). 
10.4 Ethical Considerations 
10.4.1 Informed Consent 
It is the responsibility of the investigator, or designee, to obtain voluntary written informed 
consent and assent, where applicable from all subjects prior to any trial-related procedures 


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including screening assessments. All consent and assent documentation must be in accordance 
with the applicable regulations and GCP. The pre-screening consent process can be managed 
remotely (please refer to the Site Operations Manual for more details). Each subject or the 
subject’s legally-authorized representative as applicable is requested to sign ICFs after the 
subject has received and read the written subject information and received an explanation of what 
the trial involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed consent and 
assent documentation (i.e. a complete set of subject information sheets and fully executed 
signature pages) must be given to the subject or the subject’s legally-authorized representative 
as applicable. Signed consent forms including assent of under-age subjects must remain in each 
subject’s trial file and must be available for verification at any time. A subject will be required 
to be reconsent when a subject reaches the age of consent based on specific country requirements. 
If any new information is found during the trial that may affect whether a subject wants to 
continue to take part in the trial, the subject is to be given this information orally and in writing. 
The subject may be asked to sign a new consent form if this occurs. 
The subject will be provided with 24-hour contact information which can be used to report any 
safety concerns.  
Whenever the IEC/IRB is directly managed by the national coordinating investigator, he/she will 
provide the sponsor with a copy of the consent form which was reviewed by his/her IEC/IRB, 
and which received their favorable opinion/approval. A copy of the IEC/IRB written favorable 
opinion/approval of these documents must also be provided to the sponsor, prior to the start of 
the trial. Additionally, if the IEC/IRB requires modification of the subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor. 
Whenever the IEC/IRB is not managed by the investigator, the sponsor or its designee will 
provide the investigators with a copy of the consent form which was reviewed by the IEC/IRB, 
and which received their favorable opinion/approval. A copy of the IEC/IRB written favorable 
opinion/approval of these documents must also be provided to the investigator, prior to the start 
of the trial. 
10.4.2 Independent Ethics Committee/Independent Review Board 
The investigator (or authorized person) must submit the protocol and all the necessary documents 
(informed consent document and any materials provided to the subject) to the appropriate Ethics 
Committee (IEC/IRB), for review and approval, prior to any subject enrollment. Approval by 
IECs/IRBs is required for each participating site. Any changes from standard agreed upon 
submission to the IECs/IRBs due to restrictions imposed in response to a pandemic will be 
communicated and agreed to by the sponsor. 
The investigator (or authorized person) should notify the sponsor of the IEC/IRB’s approval date. 
The sponsor should receive a copy of the written and dated approval/favorable opinion signed by 
the Chairman with Ethics Committee (IEC/IRB) composition, prior to any investigational 
product drug shipment to the site. 


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Any substantial amendment to the protocol or any amendment to the ICFs should be submitted 
for approval to the Ethics Committee (IEC/IRB) prior to its implementation, unless there are 
overriding safety reasons. 
10.4.3 Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol or informed consent forms 
without a formal amendment by the sponsor. All protocol amendments must be issued by the 
sponsor and signed and dated by the investigator. Protocol amendments must not be implemented 
without prior IEC/IRB approval, or when the relevant competent authority has raised any grounds 
for non-acceptance, except when necessary to eliminate immediate hazards to the subjects, in 
which case the amendment must be promptly submitted to the IEC/IRB and relevant competent 
authority. Documentation of amendment approval by the investigator and IEC/IRB must be 
provided to the sponsor. When the change(s) involve(s) only logistic or administrative aspects of 
the trial, the IEC/IRB (where required) only needs to be notified. 
Substantial amendments have to be submitted to the IEC/IRB and competent authorities. Changes 
that are not substantial, which have no significant impact on the medical or scientific validity of 
the trial will be notified to the IEC/IRB and the competent authority, when required. 
During the course of the trial, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative. Except in emergency situations, this contact should be made before implementing 
any departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it. 
10.4.4 Long-term Retention of Samples for Additional Research (Optional) 
Samples collected in this trial may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand CNM. The research may begin 
at any time during the trial or the post-trial storage period. All samples will be pseudo 
anonymized to prevent unnecessarily associating the sample with a specific subject.  
Subjects will be asked to consent voluntarily for their samples to be stored for other research 
studies that may be done after this trial is completed. Participants for whom such consent is not 
given can participate in the trial without having their samples stored for future testing. In such 
case, their samples will be destroyed after all the trial assessments have been concluded (as 
agreed by the sponsor). Any results already generated on the samples will not be removed from 
any analyses that have already been performed. 
Samples for genetic (DNA) research and biomarkers may be taken from subjects who provide 
separate informed consent for these samples to be collected and for their samples to be stored for 
other research studies.  
Subjects may withdraw their consent for storage of samples for additional research at any time. 
In such case, their samples will be destroyed, and no further testing will take place. 


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The sponsor, sponsor’s representatives, bio-repositories, and any specialty laboratories will be 
blinded to the subject’s identity.  
Results of the genetic analyses may contribute to the global understanding of CNM and its 
treatment and may be used internally to help support the design of additional studies, form part 
of scientific publication, or be made known to the regulatory authorities as part of a new drug 
application. Any results generated will be for exploratory research purposes only and will not be 
made available unless required by law (i.e. to regulatory authorities). Additionally, as any 
potential analysis does not form part of pre-defined analysis within the protocol, any results will 
be reported separately to the main clinical trial report. Subjects can request results of any analysis 
on their samples. 
10.5 Privacy and Confidentiality 
All EU-based sites, sponsors and laboratories or entities providing support for this trial must, 
where applicable, comply with the General Data Protection Regulation (EU)2016/679 (27 April 
2016) and EU data protection regulations No. 45/2001 (18 December 2001). 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the trial, the sponsor and/or its representative 
reviews their medical records and data collected during the trial. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market DYN101; national or local regulatory authorities; and the IECs/IRBs, which gave 
approval for the trial to proceed. Additionally, the sponsor and/or its representatives may share 
the data with others confidentially relative to the further development of DYN101. The sponsor 
and/or its representatives, and Ionis Pharmaceuticals, Inc., owner of DYN101, accessing the 
records and data will ensure precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects' identities. 
Subjects are assigned a unique identifying number. However, age and birth year will be collected 
and used to assist the sponsor to verify the accuracy of the data, for example, to confirm that 
laboratory results have been assigned to the correct subject. 
The results of the trials – containing subjects’ unique cohort-subject identifying number, relevant 
medical records, and possibly age and birth year – will be recorded. They may be transferred to, 
and used in, other countries that may not afford the same level of protection that applies within 
the countries where this trial is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the trial 
results, or to answer questions asked by regulatory or health authorities. 
10.6 Publication Policy 
All manuscripts, abstracts, or other modes of presentation arising from the results of the trial 
must be reviewed and approved in writing by the sponsor, in advance of submission. The review 
is aimed at protecting the sponsor’s proprietary information either existing at the date of the 
commencement of the trial or generated during the trial. Authorship will follow the guidelines 


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established by the International Committee of Medical Journal Editors. The publication policy 
with respect to the investigator and site will be further detailed in a separate document. 
11. ADMINISTRATIVE ASPECTS 
Please refer to the trial contact list in the investigator site file. 


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Annoussamy et al., 2016. Baseline data from patients with myotubular myopathy enrolled in a 
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Beggs et al., 2018. A multicenter, retrospective medical record review of X-linked myotubular 
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Bérard et al., 2005. A motor function measure for neuromuscular diseases. Construction and 
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Bertini et al., 2004. 118th ENMC international workshop on advances in myotubular myopathy. 
26-28 September 2003, Naarden, The Netherlands. (5th workshop of the international consortium 
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Biancalana et al., 2012. Clinical utility gene card for: Centronuclear and myotubular myopathies. 
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Bitoun et al., 2005. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. 
37(11): 1207-1209. 
Buono et al., 2018. Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear 
myopathy. Proc Natl Acad Sci U S A. 115(43): 11066-11071. 
NatHis-CNM Trial Protocol: Prospective, longitudinal study of the natural history and functional 
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Cowling et al., 2014. Reducing dynamin 2 expression rescues X-linked centronuclear myopathy. 
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Cowling et al., 2017. Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle 
maturation. J Clin Invest. 127(12): 4477-4487.  
DYN101 Investigator’s Brochure. Edition 1. Dynacure, December 2018 (draft). 
Fattori et al., 2015. Centronuclear myopathies: genotype–phenotype correlation and frequency 
of defined genetic forms in an Italian cohort. J Neurol. 262(7): 1728-1740. 
FDA, 2018. Endocrinologic and Metabolic Drugs Advisory Committee Meeting, May 10, 2018. 
Briefing Document for NDA 210645, volanesorsen. 
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Biochem Pharmacol. 78(3): 284-291. 


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Herman et al., 1999. “Medical complications in long-term survivors with X-linked myotubular 
myopathy.” J Pediatr. 134(2):206-14. 
Hocquigny, 2019. 13-Week Intravenous (Infusion) or Subcutaneous Administration Toxicity 
Study in the Monkey Followed by an 8-Week Recovery Period. TOX0001, GLP Toxicity Study 
Report, Covance Laboratories Ltd. Draft interim report. 
Jungbluth et al., 2003. Early and severe presentation of X-linked myotubular myopathy in a girl 
with skewed X-inactivation. Neuromuscul Disord. 13(1): 55-59. 
Jungbluth et al., 2008. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis. 3: 26. 
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(myotubular) myopathies, 31st May - 2nd June 2013, Naarden, The Netherlands. Neuromuscul 
Disord. 23(12): 1033-1043. 
Kim, 2018. A 12-week repeat subcutaneous dose toxicity study of Dynamin II ASOs in 
Cynomolgus 
monkeys. 
DynaminII-RS01, 
non-GLP 
Toxicity 
Study 
Report, 
Ionis 
Pharmaceuticals. 
Kristiansen et al., 2003. X-inactivation patterns in carriers of X-linked myotubular myopathy. 
Neuromuscul Disord. 13(6): 468-471. 
Laporte et al., 1996. A gene mutated in X-linked myotubular myopathy defines a new putative 
tyrosine phosphatase family conserved in yeast. Nat Genet. 13(2): 175-182. 
Laporte et al., 1998. Genomic organization of the MTM1 gene implicated in X-linked 
myotubular myopathy. Eur J of Hum Genet. 6(4): 325-330. 
Laporte et al., 2001. The myotubularin family: from genetic disease to phosphoinositide 
metabolism. Trends Genet. 17(4): 221-228. 
McEntagart et al., 2002. Genotype-phenotype correlations in X-linked myotubular myopathy. 
Neuromuscul Disord. 12(10): 939-946. 
Motoki et al., 2013. Fatal hepatic hemorrhage by peliosis hepatis in X-linked myotubular 
myopathy: a case report. Neuromuscul Disord. 23(11): 917-921. 
Nicot et al., 2007. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and 
cause autosomal recessive centronuclear myopathy. Nat Genet. 39(9): 1134-1139. 
Romero, 2010. Centronuclear myopathies: a widening concept. Neuromuscul Disord. 
20(4): 223-228.  
Romero and Bitoun, 2011. Centronuclear myopathies. Semin Pediatr Neurol. 18(4): 250-256. 
Seferian et al., 2015. Upper limb strength and function changes during a one-year follow-up in 
non-ambulant patients with Duchenne Muscular Dystrophy: an observational multicenter trial. 
PLoS One. 10(2): e0113999.  


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Date: 01 December 2021, Final 
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Servais et al., 2013. Innovative methods to assess upper limb strength and function in 
non-ambulant Duchenne patients. Neuromuscul Disord. 23(2): 139-148. 
Shieh et al., 2020. “Re: “Moving Forward After Two Deaths in a Gene Therapy Trial of 
Myotubular Myopathy” by Wilson and Flotte”. Hum. Gene Ther. 31(15-16):787-787. 
Tasfaout et al., 2017. Antisense oligonucleotide-mediated Dnm2 knockdown prevents and 
reverts myotubular myopathy in mice. Nat Commun 8:15661. 
Vandersmissen et al., 2018. An integrated modelling methodology for estimating the prevalence 
of centronuclear myopathy. Neuromuscul Disord. 28(9): 766-777. 
Verhaart et al., 2017a. A multi-source approach to determine SMA incidence and research ready 
population. J Neurol. 264(7): 1465-1473. 
Verhaart et al., 2017b. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular 
atrophy - a literature review. Orphanet J Rare Dis. 12(1): 124. 
Voermans, 2017. Personal communication at the Dynacure Scientific Advisory Board, St Malo, 
October 2017. 
Wang et al., 2001. Hepatic rupture caused by peliosis hepatis. J Pediatr Surg. 36(9): 1456-1459. 
Wheeler et al., 2012. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. 
Nature. 488: 111-115. 
Wójcik et al., 2007. Nucleotide pyrophosphatase/phosphodiesterase 1 is responsible for 
degradation of antisense phosphorothioate oligonucleotides. Oligonucleotides. 17(1): 134-145. 
Yu et al., 2013. Clinical pharmacokinetics of second-generation antisense oligonucleotides. 
Expert Opin Drug Metab Toxicol. 9(2): 169-182. 

SAP_001.pdf: 
 
 
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Statistical Analysis Plan 
 
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Statistical Analysis Plan 
Title: A Phase 1/2 trial on the safety, tolerability, pharmacokinetics, 
pharmacodynamics and exploratory efficacy of DYN101 in patients ≥ 16 years of 
age with centronuclear myopathies caused by mutations in DNM2 or MTM1 
Protocol Number: DYN101-C101 
 
Version: 3.0 
Issue Date: 17-AUG-2022 
Author: 
 
 
 
Previous Versions 
Version 1.0 / 16-DEC-2019, Version 2.0 / 29-SEP-2020 
 
 


 
 
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SAP Amendments before database lock 
 
Version  Issue Date 
Section 
Revision/Addition 
Rationale 
0.1 
12-SEP-2019 
 
 
First draft for internal 
review 
0.2 
26-SEP-2019 
 
 
Draft version for sponsor 
review 
0.3 
04-OCT-2019 
 
 
Draft version for IDMC 
organizational meeting 
0.4 
14-NOV-2019 
 
 
Version including 
updates based on 
comments. 
1.0 
16-DEC-2019 
 
 
Version 1.0 
2.0 
29-SEP-2020 
1 
 
 
1, 6.4 
 
 
6.13.5 
6.14.2 - 
6.14.6 
 
Updated to the latest 
protocol amendment.  
 
Added COVID-19 
summaries. 
 
Shift table to be 
presented from BL to the 
worst recorded result in 
each trial period (not by 
each visit). 
To use the latest protocol 
amendment. 
 
Requirement to report 
impact of COVID-19. 
 
Shift table for each visit 
separately would get too 
big. 
3.0 
17-AUG-2022 
1 
 
 
 
 
 
 
4 
 
 
5 
 
 
 
Added note that only 
abbreviated CSR will be 
done due to study 
termination. Updated to 
the latest protocol and 
IDMC charter version. 
 
Sample size updated. 
 
 
Dosing information 
updated. 
 
To get updated with 
latest document versions. 
 
 
 
 
 
Updated per the latest 
protocol. 
 
Updated per the latest 
protocol. 
 


 
 
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6.2.6 
 
 
6.2.13 
 
 
6.4 
 
 
6.10 
 
 
6.13.2, 
6.13.3 
 
 
 
6.13.4 
 
 
6.13.5, 
6.13.6 
 
 
6.14.2 
 
 
 
8 
 
 
9 
 
 
10 
 
 
 
 
Added details for partial 
date imputations. 
 
Added information about 
the data collection. 
 
Small clarifications in 
disposition section. 
 
Added summary of doses 
received. 
 
Summary of categorical 
data using frequency 
tables not descriptive 
statistics. 
 
Added collected data 
categories. 
 
Clarified what will be 
reported for abbreviated 
CSR. 
 
Added data normalization 
for lab data. 
 
 
Updated primary analysis 
and final analysis section. 
 
Updated IDMC analysis. 
 
 
Added note for the 
changes from planned 
protocol analyses. 
 
 
Clarification for data 
derivation. 
 
General clarifications. 
 
 
To update readability. 
 
 
New summary due to 
many interruptions. 
 
To use better method 
summarizing data. 
 
 
 
To help understand 
underlying data. 
 
General clarification. 
 
 
 
To make lab parameters 
comparable across 
different labs. 
 
Updated to match the 
study termination. 
 
Per the latest IDMC 
charter. 
 
Updated to match the 
study termination. 
 
 
 


 
 
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12 
Removed tables that are 
not done for the 
abbreviated CSR. 
Updated to match the 
study termination. 
 
 


 
 
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Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 8 
1 
INTRODUCTION .............................................................................................11 
2 
STUDY OBJECTIVES .....................................................................................11 
2.1 
Primary Objective ......................................................................................................... 11 
2.2 
Secondary Objectives.................................................................................................... 11 
2.3 
Exploratory Objectives ................................................................................................. 11 
3 
ENDPOINTS .....................................................................................................12 
3.1 
Primary Endpoint .......................................................................................................... 12 
3.2 
Secondary Endpoints .................................................................................................... 12 
3.3 
Exploratory Endpoints .................................................................................................. 12 
4 
SAMPLE SIZE ..................................................................................................13 
5 
RANDOMIZATION .........................................................................................14 
6 
PLANNED ANALYSES ...................................................................................14 
6.1 
Analysis Sets ................................................................................................................. 14 
6.2 
Derived Data ................................................................................................................. 15 
6.2.1 
Age .......................................................................................................................... 15 
6.2.2 
Race......................................................................................................................... 15 
6.2.3 
Baseline ................................................................................................................... 15 
6.2.4 
Early Terminations Assessments ............................................................................ 15 
6.2.5 
Duration/Study Day/Time ....................................................................................... 15 
6.2.6 
Conventions for Missing and Partial Dates ............................................................ 15 
6.2.7 
Exposure to Study Drug .......................................................................................... 17 
6.2.8 
Treatment Compliance ............................................................................................ 17 
6.2.9 
Inexact Values ......................................................................................................... 17 
6.2.10 
Electrocardiogram Data .......................................................................................... 17 
6.2.11 
Unscheduled Visits ................................................................................................. 18 
6.2.12 
PK Parameters ......................................................................................................... 18 
6.2.13 
Pharmacodynamic data ........................................................................................... 18 
6.2.14 
Cumulative information for IDMC meetings ......................................................... 19 
6.3 
Conventions .................................................................................................................. 19 
6.3.1 
Decimal Places ........................................................................................................ 20 
6.4 
Subject Disposition ....................................................................................................... 21 


 
 
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6.5 
Protocol Deviations ....................................................................................................... 21 
6.6 
Baseline Comparability ................................................................................................. 21 
6.7 
Medical History Related to CNM ................................................................................. 22 
6.8 
Medical History Unrelated to CNM ............................................................................. 22 
6.9 
Prior and Concomitant Medications ............................................................................. 22 
6.10 
Exposure to Study Drug ................................................................................................ 23 
6.11 
Treatment Compliance .................................................................................................. 23 
6.12 
Pharmacokinetic Analyses ............................................................................................ 23 
6.12.1 
Analysis of dose proportionality ............................................................................. 24 
6.12.2 
Anti-Drug Antibodies ............................................................................................. 24 
6.12.3 
Metabolic Profiling blood/urine .............................................................................. 24 
6.13 
Pharmacodynamic and Exploratory Efficacy Analyses ................................................ 25 
6.13.1 
PROMIS Questionnaire .......................................................................................... 25 
6.13.2 
CGI-I Questionnaire................................................................................................ 25 
6.13.3 
PGI-C Questionnaire ............................................................................................... 25 
6.13.4 
GAS Questionnaire ................................................................................................. 26 
6.13.5 
Respiratory Function Tests ..................................................................................... 26 
6.13.6 
Muscle Strength and Function Tests ....................................................................... 27 
6.13.7 
Dysphagia Questionnaire ........................................................................................ 27 
6.13.8 
Muscle Biopsy ........................................................................................................ 28 
6.13.9 
Biomarker and DNA samples ................................................................................. 28 
6.13.10 Exploratory Bayesian Analyses .............................................................................. 28 
6.14 
Safety Analyses ............................................................................................................. 29 
6.14.1 
Adverse Events ....................................................................................................... 29 
6.14.2 
Laboratory Data ...................................................................................................... 30 
6.14.3 
Coagulation Data .................................................................................................... 31 
6.14.4 
Complement Data ................................................................................................... 31 
6.14.5 
Vital Signs ............................................................................................................... 32 
6.14.6 
Electrocardiogram Data .......................................................................................... 32 
6.14.7 
Physical Examination.............................................................................................. 33 
6.14.8 
Liver Ultrasound and Hepatic Elastography ........................................................... 33 
7 
INTERIM ANALYSIS ......................................................................................33 
8 
PRIMARY AND FINAL ANALYSIS ..............................................................33 
9 
INDEPENDENT DATA MONITORING COMMITTEE ANALYSIS ...........33 


 
 
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9.1 
IDMC Open Session / Closed Session .......................................................................... 34 
10 CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................34 
11 REFERENCES ..................................................................................................35 
12 LIST OF TABLES, FIGURES AND LISTINGS FOR THE IDMC, PRIMARY 
ANALYSIS AND FINAL ANALYSIS ..................................................................36 
13 APPENDIX........................................................................................................43 
13.1 
PROMIS Scoring Tables............................................................................................... 43 
13.1.1 
ABILITY TO PARTICIPATE IN SOCIAL ROLES AND ACTIVITIES ............. 43 
13.1.2 
ANXIETY ............................................................................................................... 45 
13.1.3 
DEPRESSION ........................................................................................................ 46 
13.1.4 
FATIGUE ............................................................................................................... 47 
13.1.5 
PAIN INTERFERENCE ......................................................................................... 48 
13.1.6 
PHYSICAL FUNCTION ........................................................................................ 49 
 
 
 


 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA  
anti-drug antibodies 
ADCNM  
autosomal dominant centronuclear myopathy 
ADR  
adverse drug reaction 
AE  
adverse event 
AESI  
adverse event of special interest 
ALT  
alanine aminotransferase 
ARCNM  
autosomal recessive centronuclear myopathy 
ASO  
antisense oligonucleotide 
AST  
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
area under curve 
BIN1  
amphiphysin II 
BLQ 
below the limit of quantitation 
BMI  
body mass index 
BUN  
blood urea nitrogen 
CGI-I  
Clinical Global Impression of Improvement 
CI  
confidence interval 
CL 
Clearance 
CNM  
centronuclear myopathy 
COVID-19 
coronavirus disease 2019 
CRO  
contract research organization 
CS  
clinically significant 
CSR 
clinical study report 
%CV 
coefficient of variation 
DNM2  
dynamin 2 
EAT-10  
Eating Assessment Tool 
ECG  
Electrocardiogram 
eCRF  
electronic case report form 
eGFR  
estimated glomerular filtration rate 
ELISA  
enzyme-linked immunosorbent assay 
EMA  
European Medicines Agency 
EU  
European Union 
FDA  
Food and Drug Administration 
FEV  
forced expiratory volume 
FVC  
forced vital capacity 
GAS 
Goal Attainment Scaling 


 
 
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GCP  
Good Clinical Practice 
GGT  
gamma glutamyltransferase 
GLP  
Good Laboratory Practice 
hCG  
human chorionic gonadotropin 
IB  
Investigator’s Brochure 
ICF  
informed consent form 
ICH  
International Council for Harmonization (previously International 
Conference on Harmonization) 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
IMP  
investigational medicinal product 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
IV  
intravenous(ly) 
MAD  
multiple ascending dose 
MedDRA  
Medical Dictionary for Regulatory Activities 
MEP  
maximum expiratory pressure 
MFM  
Motor Function Measure 
MHRA 
Medicines and Healthcare products Regulatory Agency (UK) 
MIP 
maximum inspiratory pressure 
mRNA 
Messenger ribonucleic acid 
MRSD 
minimal recommended starting dose 
MTM1 
myotubularin 1 
NCS 
not clinically significant 
NHP 
non-human primate(s) 
NHS 
natural history study 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PGI-C 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QoL 
quality-of-life 
RBC 
red blood cell 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
standard deviation 


 
 
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SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
WBC 
white blood cell 
WHO 
World Health Organization 
XLCNM 
X-linked centronuclear myopathy 
 
 


 
 
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1 INTRODUCTION 
This document details the planned statistical analyses for the Dynacure, protocol “DYN101-
C101” study titled “A Phase 1/2 trial on the safety, tolerability, pharmacokinetics, 
pharmacodynamics and exploratory efficacy of DYN101 in patients ≥ 16 years of age with 
centronuclear myopathies caused by mutations in DNM2 or MTM1”. 
The proposed analyses are based on the contents of the amended version 8.0 (incorporating 
Amendment 5) of the Protocol (dated 15-SEP-2021) and IDMC Charter version 3.0 (dated 19-
JAN-2022). 
The trial will consist of a pre-screening consent, a screening period, a run-in period (if 
applicable), a SAD part with 4 weeks of follow-up after IMP administration and a washout 
period of at least 12 weeks (followed by follow-up phone calls until the MAD part starts), a 
MAD part of 12 weeks, and a MAD extension part of 12 weeks. All subjects will participate in 
the SAD, MAD and MAD extension parts, unless they withdraw. 
This SAP describes analyses for both the IDMC deliverables and final CSR deliverables. 
Impact of COVID-19 will be evaluated in the subject disposition section. 
NOTE: The study was terminated early but this SAP includes all protocol planned analyses. 
However, only abbreviated CSR will be produced and not all planned analyses will be 
performed. Detailed list of the analyses included is given in Section 12 of this document. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
 To assess the safety and tolerability of 3 single ascending dose (SAD) levels and 3 MAD 
levels of DYN101. 
2.2 Secondary Objectives 
 To assess the PK of SAD and MAD of DYN101. 
 To explore target engagement in muscle of DYN101. 
2.3 Exploratory Objectives 
 To investigate the effect of DYN101 treatment on the clinical assessments in various 
affected domains (respiratory, muscle strength and function, dysphagia). 


 
 
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 To explore the impact of CNM and its treatment on symptoms, functioning, and health-
related QoL. 
 To assess the presence of anti-drug antibodies (ADA) against DYN101 by collecting 
blood samples. 
 To assess the metabolic profile of DYN101 by collecting blood and urine samples. 
 To contribute to the global understanding of CNM and its treatment by collecting blood 
and muscle samples for further exploratory biomarker/genetic research. 
3 ENDPOINTS 
3.1 Primary Endpoint 
 Comparison of adverse event (AE, SAE, AESI) frequency and severity by dose (cohort), 
for single and multiple administration, and by mutated gene (subcohort) and overall using 
the Safety Analysis Set following 12 weeks of MAD treatment and after 24 weeks of 
MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD extension part; 
Week 25 visit) or discontinued earlier. 
3.2 Secondary Endpoints 
 Comparison of means for PK parameters of DYN101 in plasma (AUCτ, AUClast, AUC∞, 
Rac(AUC), Rac(Cmax), Cmax, Cav SS, CL, λz, t1/2, tmax, Vz) by dose (cohort), for single and 
multiple administration, and by mutated gene (subcohort) and overall using the 
Pharmacokinetic Set. 
 Comparison of geometric means for PK parameters of DYN101 in plasma (Cmax and 
AUCs) by dose (cohort), for single and multiple administration, and by mutated gene 
(subcohort) and overall using the Pharmacokinetic Set. 
 Comparison of means on DNM2 mRNA levels and DYN101 concentrations using 
muscle biopsy data by dose (cohort), after multiple administration, and by mutated gene 
(subcohort) and overall using the Pharmacokinetic Set. 
 Comparison of mean change from baseline in vital signs, laboratory data and ECG by 
dose (cohort), for single andr multiple administration, and by mutated gene (subcohort) 
and overall using the Safety Analysis Set. 
3.3 Exploratory Endpoints 


 
 
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 Difference in mean change from baseline for clinical assessments in various affected 
clinical domains (respiratory, muscle strength and function, dysphagia) using the 
Pharmacokinetic Set by dose (cohort), for single or multiple administration, and by 
mutated gene (subcohort) at each post-baseline visit. The parameters to be analyzed for 
respiratory function are FVC (L), %FVC Predicted, FEV1 (L), %FEV1 Predicted, 
FEV1/FVC, MEP (cm H2O), %MEP Predicted, MIP (cm H2O), %MIP Predicted, 
Oxygen Saturation (%). The MyoGrip Test score will be used for analyzing muscle 
strength. The following parameters will be analyzed for muscle function; D1 Standing 
and transfers (%), D2 Axial and proximal motor function (%), D3 Distal motor function 
(%), Total MFM32 Score (%). Dysphagia will be assessed using the EAT-10 total score. 
 Difference in mean change from baseline for PROMIS Questionnaire T-scores for the 
following domains (Anxiety, Depression, Fatigue, Pain Interference, Ability to 
Participate and Physical Function) using the Pharmacokinetic Set by dose (cohort), for 
single and multiple administration, and by mutated gene (subcohort) at each post-baseline 
visit. 
 Comparison of proportion of CGI-I responders (responders defined as responding 1 or 2) 
using the Pharmacokinetic Set by dose (cohort), for single and multiple administration, 
and by mutated gene (subcohort) at each post-baseline visit. 
 Comparison of proportion of PGI-C responders (responders defined as responding 1 or 2) 
using the Pharmacokinetic Set by dose (cohort), for single and multiple administration, 
and by mutated gene (subcohort) at each post-baseline visit. 
 Comparison of proportion of Goal Attainment Scaling (GAS) Questionnaire responders 
(responders defined as responding ‘YES – MUCH BETTER’, ‘YES – A LITTLE 
BETTER’) using the Pharmacokinetic Set by dose (cohort), for single and multiple 
administration, and by mutated gene (subcohort) at each post-baseline visit. 
 Comparison of means of ADA against DYN101 using the Pharmacokinetic Set by dose 
(cohort), for single and multiple administration, and by mutated gene (subcohort) at each 
post-baseline visit. 
 Comparisons of the metabolic profile of DYN101 in blood and urine using the 
Pharmacokinetic Set by dose (cohort), for single and multiple administration, and by 
mutated gene (subcohort) at each post-baseline visit. 
4 SAMPLE SIZE 


 
 
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Sufficient subjects will be screened to ascertain approximately 18 subjects who will be dosed and 
finish the trial. The target is approximately 6 subjects per dose level. In each dose level, the 
target will be up to 6 subjects with a DNM2 mutation and up to 3 subjects with an MTM1 
mutation. This sample size is deemed to be appropriate for safety and tolerability purposes and 
are not based on any power analysis. 
5 RANDOMIZATION 
This study is not randomized. 
Subjects will receive DYN101 in a low (1.5 mg/kg), middle (4.5 mg/kg) or high (9 mg/kg) dose 
level in Cohorts 1, 2 and 3, respectively. In the MAD part, subjects may receive a different dose 
than what they received in the SAD part. In each cohort, there will be up to 6 subjects with a 
mutation in DNM2 (sub-cohort a) and up to 3 subjects with a mutation in MTM1 (sub-cohort b). 
Cohorts will be enrolled in a sequential, staggered approach, with an interval of at least 7 days 
between dose administration of the first and second subject in a cohort, irrespective of their 
subcohort. The 48-hour safety data from the first subject in a cohort will be reviewed by the 
medical monitor before the next subject can be dosed. In addition, any SAE data from the first 
subject received up until the moment of treatment of the second subject will be taken into 
account. 
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive 
and the final clinical study report (CSR) may contain additional tables or statistical tests if 
warranted by the data obtained. The justification for any such additional analyses will be fully 
documented in the final CSR. 
6.1 Analysis Sets 
Pre-Screened Set – Subjects who have signed pre-screening consent. 
Screened Set – Subjects who have signed main informed consent. 
Safety Analysis Set – Screened subjects who have received at least one Investigational 
Medicinal Product (IMP) administration. 
Pharmacokinetic Set – Subjects in the Safety Analysis Set, for whom the primary PK 
parameters can be calculated. 


 
 
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Subjects excluded from the analysis sets and the reason for their exclusion will be listed in 
Appendix 16.2 of the CSR. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Age 
Year of birth and age at the time of informed consent is collected in the CRF. 
6.2.2 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories. 
6.2.3 
Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives the first dose of study drug. The same baseline will be used for all SAD, 
MAD and MAD extension parts using the last available records before first dose of study drug in 
SAD part. 
6.2.4 
Early Terminations Assessments 
For the analysis early withdrawal visits will be assigned to the next scheduled visit where the 
relevant variable would have been assessed. For example subjects withdrawing after MAD week 
5 will have their withdrawal visit assigned as follows: vital sign data assigned to MAD week 6 
but laboratory data assigned to MAD week 9. 
6.2.5 
Duration/Study Day/Time 
Study day will be calculated as the number of days from first dose of SAD part. 
 date of event – date of first dose of study drug + 1, for events on or after first dose 
 date of event – date of first dose of study drug, for events before first dose. 
6.2.6 
Conventions for Missing and Partial Dates 


 
 
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It is not expected that there will be any missing dates, however in the rare case that an AE start 
date or time is missing and it is unclear whether the AE is treatment emergent or not then a 
conservative approach will be taken and it will be assumed that the AE occurred after first dosing 
(earliest date of all doses during the whole study). 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the subject has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the subject’s end 
of study visit 
 If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 
 If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the subject’s last clinic visit 
in which case the date of subject’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug. 
 If the stop date occurs before the start of study drug, the start date of the event / 
concomitant medication will be imputed as the subject’s screening date or the stop date of 
the event / concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) will be imputed as follows: 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date 
will be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
 If the stop date occurs before the start of study drug, the start date of the event / 
concomitant medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) will be imputed as follows: 


 
 
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 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month 
and year unless this partial start date is in same month as the first dose of study drug in 
which case the date of first dose of study drug will be used. 
 If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
All dates presented in the individual subject listings will be as recorded on the eCRF. 
6.2.7 
Exposure to Study Drug 
Exposure to study drug will be calculated separately for SAD and MAD + MAD Extension parts. 
SAD part: exposure will be set to 1 if subject was dosed. 
MAD + MAD Extension part: date of last MAD dosing - date of first MAD dosing + 1. 
The exposure calculation will not take into account breaks in therapy. 
6.2.8 
Treatment Compliance 
Treatment compliance is calculated by visit and overall for SAD part and MAD + MAD 
Extension parts. 
Treatment compliance at each visit will be calculated as 
100 × 𝐴𝑐𝑡𝑢𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 (𝑚𝐿)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑇𝑜𝑡𝑎𝑙 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
. 
Overall treatment compliance for MAD + MAD Extension parts will be calculated as 
100 × 𝑆𝑢𝑚 𝑜𝑓 𝑎𝑐𝑡𝑢𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 (𝑚𝐿)
𝑆𝑢𝑚 𝑜𝑓 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑇𝑜𝑡𝑎𝑙 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
. 
6.2.9 
Inexact Values 
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value 
of x will be taken for analysis purposes. 
6.2.10 
Electrocardiogram Data 


 
 
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For ECG data recorded on continuous scales, if more than one value is recorded at a time point, 
the mean value rounded to the integer will be presented. For overall interpretation if more than 
one value is recorded, the most severe (worst case) of the respective readings will be taken. 
6.2.11 
Unscheduled Visits 
Only scheduled post-baseline laboratory and vital signs values will be tabulated. Post-baseline 
repeat/unscheduled assessments will be disregarded, although these post-baseline assessments 
will be listed in the relevant appendices to the CSR. 
6.2.12 
PK Parameters 
The following PK parameters will be calculated for DYN101: 
AUCτ 
Area under the plasma concentration-time curve during a dosing interval 
AUClast 
Area under the plasma concentration-time curve from time 0 to time of the 
last quantifiable concentration 
AUC∞ 
Area under the plasma concentration-time curve from time 0 to infinity 
Cmax 
Maximum plasma concentration 
CL 
Clearance after IV administration 
λz 
Terminal disposition phase rate constant 
t1/2 
Terminal disposition phase half-life 
tmax 
Time of first occurrence of Cmax 
Vz 
Apparent volume of distribution during the terminal disposition phase 
6.2.13 
Pharmacodynamic data 
Patient-Reported Outcomes Measurement Information System (PROMIS) Questionnaire 
Summary T-score for each domain (Anxiety, Depression, Fatigue, Pain Interference, Ability to 
Participate and Physical Function) will be calculated. Scoring is done by calculating total raw 
scores for each domain by summing subject’s answers. Missing values are not allowed and if any 
data missing for a domain then total raw score will not be calculated. After raw scores are 
calculated a scoring table will be used to translate the total raw score into a T-score for each 
subject. Scoring tables are shown in the Appendix of this document. 


 
 
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For Physical Function, NHS part of the study utilized different PROMIS scale. First question 
was ‘Can you walk 25 feet on a level surface (with or without support)?’. If subject answered 
‘Yes’ then he/she filled all the following 12 questions. If subject answered ‘No’ then only 6 
further questions were filled. 
Respiratory Function Tests 
For each parameter, the attempt should be repeated at least 3 times making sure that the subject 
has recovered between attempts. If, at each attempt, there is an improvement in the results, 
further tests can be conducted until the subject has achieved his/her best result. For summary 
tables the best result will be selected. 
For respiratory function tests ratio of FEV1/FVC will be calculated for each subject and visit and 
rounded to 1 decimal place. 
6.2.14 
Cumulative information for IDMC meetings 
The IDMC will review cumulative safety and PK and efficacy study data for all previously dosed 
subjects. 
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS 
(Version 9.4 or higher)2. 
Summary tables will be presented by treatment group. Treatment group includes information 
about dose (cohort) and mutated gene (subcohort). 
PK data listings, summaries, figures, and statistical analyses will be generated using Phoenix™ 
WinNonlin® (Version 6.4 or higher) or SAS (Version 9.4 or higher). PK concentration data will 
be summarized by analyte, treatment group (cohort, subcohort) at each nominal sample time. PK 
parameter data will be summarized by analyte and treatment group (cohort, subcohort). 
Treatment group (cohort, subcohort) labels will be displayed as follows: 
1.5 mg/kg DNM2 
1.5 mg/kg MTM1 
1.5 mg/kg Overall 
4.5 mg/kg DNM2 
4.5 mg/kg MTM1 
4.5 mg/kg Overall 


 
 
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9 mg/kg DNM2 
9 mg/kg MTM1 
9 mg/kg Overall 
Overall 
Summary tables will be presented by the above groups. Overall group will not be displayed in 
the PK tables. 
Listings will be sorted in the following order treatment group (cohort, subcohort), subject, 
parameter, and visit unless otherwise stated. All data will be listed. 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, minimum and maximum values. Summaries for PK concentrations and AUCs 
and Cmax will be including additionally %CV, geometric mean, geometric SD and geometric 
%CV. 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented. 
6.3.1 
Decimal Places 
Decimal places for derived data described in section 6.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal 
places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the 
minimum and maximum will be displayed to the same number of decimal places as reported in 
the derived data. Percentages will be displayed with one decimal place. CV% will be reported to 
1 decimal place. 


 
 
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P-values will be quoted to 4 decimal places. P-values < 0.001 will be presented as p<0.001. 
Where this value is less than 0.05, 0.01 or 0.001, attention will be drawn to this fact using the 
conventional “*”, “**” or “***” annotation, respectively. 
6.4 Subject Disposition 
Subject disposition will be summarized by treatment group (cohort, subcohort) and overall. 
Subject disposition will be summarized as follows: 
 Screening failures: The number of subjects who failed screening and the reasons for 
failure will be tabulated for all subjects. 
 Analysis sets: The number of subjects in Pre-Screened Set, Screened Set, Safety Analysis 
Set, Pharmacokinetic Set. 
 Enrollment by region, country and clinical investigator: The number of subjects enrolled 
in each region, country and clinical investigator. 
 Cumulative proportion of information: The number of subjects completing each visit. 
 Subject disposition: The number of subjects completing study and early withdrawals 
including reason for withdrawal and time to withdrawal. 
 Inclusion/exclusion criteria: The number of subjects not meeting all inclusion/exclusion 
criteria. 
 The impact of the COVID-19 will be evaluated as follows: 
o Screening failures related to COVID-19 
o Early withdrawals related to COVID-19 
o Visits/Assessments Affected by COVID-19. 
If needed, the impact of COVID-19 will be further evaluated based on the above summaries. 
This might include more detailed summaries how COVID-19 affected visits/assessments and 
study endpoints. 
All disposition data will be listed. 
6.5 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2. 
6.6 Baseline Comparability 


 
 
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The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 
Standard continuous (n, mean, SD, median, min, max) or categorical (frequencies and 
percentages) variable summaries will be presented by treatment group (cohort, subcohort) for the 
following variables based on the Safety Analysis Set: 
 Age in years 
 Gender 
 Race 
 Ethnicity 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2) 
 Fertility status for female subjects. 
All baseline data will be listed. 
6.7 Medical History Related to CNM 
Separate tabulations of medical history related to CNM disease at screening will be presented by 
treatment group (cohort, subcohort) and overall for the Safety Analysis Set. Conditions will be 
presented by Medical Dictionary of Regulated Activities (MedDRA) primary system organ class 
and preferred term in descending order in overall group and then alphabetically. 
All medical history data will be listed. 
6.8 Medical History Unrelated to CNM 
Separate tabulations of medical history not related to CNM disease at screening will be presented 
by treatment group (cohort, subcohort) and overall for the Safety Analysis Set. Conditions will 
be presented by Medical Dictionary of Regulated Activities (MedDRA) primary system organ 
class and preferred term in descending order in overall group and then alphabetically. 
All medical history data will be listed. 
6.9 Prior and Concomitant Medications 


 
 
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Separate tabulations will be produced for prior and concomitant medications presented by 
treatment group (cohort, subcohort) and overall for the Safety Analysis Set. Prior medications 
are defined as all medications ending before the date of first dose of study drug. Concomitant 
medications are defined as medications taken on or after the date of first dose of study drug. 
Concomitant medications will be summarized using ATC Level 2 and preferred term in 
descending order in overall group and then alphabetically. 
All medication data will be listed. 
6.10 Exposure to Study Drug 
Extent of exposure (number of days of exposure to study drug) will be presented by treatment 
group (cohort, subcohort) for the Safety Analysis Set and separately for SAD and MAD parts. 
Additionally, number of doses will be summarized. 
All dosing information will be listed. 
6.11 Treatment Compliance 
Treatment compliance will be presented by treatment group (cohort, subcohort) for the Safety 
Analysis Set and separately for SAD and MAD parts. 
All dosing information will be listed. 
6.12 Pharmacokinetic Analyses 
Blood samples for determination of plasma concentrations of DYN101 will be collected 
according to pharmacokinetic sampling schedule in the study protocol. 
Concentration-time data will be tabulated by nominal time, analyte, and treatment group (cohort, 
subcohort) using descriptive statistics. For presentation of the individual data and summary 
statistics, concentrations below the limit of quantitation (BLQ) will be set to zero for pre-dose 
records and to BLQ for records after study drug dosing. 
Individual subject and mean plasma concentration-time data will be presented graphically on 
linear and semi-logarithmic scales. Mean data will be plotted using nominal sample times, and 
individual data will be plotted using actual times. 
PK parameters for DYN101 will be calculated as described in section 6.2.12. 
PK parameters will be summarized by analyte and treatment group (cohort, subcohort) using 
descriptive statistics (n, mean, SD, median, min, max, %CV, geometric mean, geometric SD, 
geometric %CV). 


 
 
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Geometric mean will be calculated as 
𝜇𝑔= √𝑥1𝑥2𝑥3 … 𝑥𝑛
𝑛
, 
where n is the number of observations and xi are the observed data. 
Geometric SD will be calculated as 
𝜎𝑔= exp (√∑
(ln 𝑥𝑖−ln 𝜇𝑔)
2
𝑛
𝑖=1
𝑛
), 
where the square root is the arithmetic standard deviation of logarithmic data. 
Geometric CV % is calculated as 
%𝐶𝑉𝑔= 100 ∙√𝑒(ln 𝜎𝑔)
2
−1100 × 𝜎𝑔
1 𝜇𝑔
⁄
. 
All concentration and PK parameter data will be listed. 
6.12.1 
Analysis of dose proportionality 
The dose proportionality will be assessed by comparing dose-normalized Cmax and dose-
normalized AUClast or AUC∞. single or multiple doses in all cohorts, where possible.  
6.12.2 
Anti-Drug Antibodies 
The impact of immunogenicity (anti-drug antibodies, ADA) on the PK of DYN101 will be explored. 
Blood samples for determination of ADA will be taken in the MAD part and the MAD extension 
part at the time points specified in the Trial Schedules. 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values will be presented 
by treatment group (cohort, subcohort) and visit for each parameter. 
All data will be listed. 
6.12.3 
Metabolic Profiling blood/urine 
Blood samples for metabolic profiling of DYN101 will be taken in MAD Week 12 at 2 and 168 
hours post-dose. 
Urine for metabolic profiling will be collected in MAD Week 12 by collecting urine over a 24-
hour interval starting at the same time with the infusion. 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values will be presented 
by treatment group (cohort, subcohort) and visit for each parameter. 


 
 
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All data will be listed. 
6.13 Pharmacodynamic and Exploratory Efficacy Analyses 
6.13.1 
PROMIS Questionnaire 
Patient-Reported Outcomes Measurement Information System (PROMIS®) is a National 
Institutes of Health Initiative, created to assess patient–reported health status for physical, 
mental, and social well–being to reliably and validly measure patient-reported outcomes in 
chronic diseases for clinical research and practice. The PROMIS domains tested in this trial are 
Anxiety (8 items), Depression (8 items), Fatigue (8 items), Pain Interference (8 items), Ability to 
Participate (8 items) and Physical Function (10 items). 
Descriptive statistics (n, mean, SD, median, min, max) for observed values and changes from 
baseline in T-scores will be presented by treatment group (cohort, subcohort) at each visit for 
each domain score. 
All data, including responses to questionnaire items and T-scores, will be listed. 
6.13.2 
CGI-I Questionnaire 
Clinical Global Impression of Improvement (CGI-I) is a 7-point scale ranging from (1) very 
much improved to (7) very much worse and is used to assess global changes in the subject’s 
condition compared to the condition before treatment. 
Frequency tables for observed values will be presented by treatment group (cohort, subcohort) at 
each visit. As the questionnaire collects information in relation to the condition before treatment, 
there is no need to summarize change from baseline. 
Additionally, CGI-I responders will be summarized where responder is defined as subject 
responding ‘Very Much Improved’ or ‘Much Improved’. 
All CGI-I data will be listed. 
6.13.3 
PGI-C Questionnaire 
Patient Global Impression of Change (PGI-C) is a scale similar to the CGI-I. It is a 7-point scale 
ranging from (1) very much improved to (7) very much worse and needs to be completed 
independent of the investigator who completes the CGI-I. 
Frequency tables for observed values will be presented by treatment group (cohort, subcohort) at 
each visit. As the questionnaire collects information in relation to the condition before treatment, 
there is no need to summarize change from baseline. 
Additionally, PGI-C responders will be summarized where responder is defined as subject 
responding ‘Very Much Improved’ or ‘Much Improved’. 


 
 
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All PGI-C data will be listed. 
6.13.4 
GAS Questionnaire 
Goal Attainment Scaling is an instrument that is intended for individual evaluation of an 
intervention. It allows subjects to set individual goals, together with their physician. The number 
of goals and the content of these goals may differ per subject, but the attainment of the goals is 
measured in a standardized way. This makes a standardized evaluation of an intervention 
possible, even when the subjects are all in a different stage of their disease. 
Frequency tables for observed values ('YES - MUCH BETTER', 'YES - A LITTLE BETTER', 
'YES - AS EXPECTED', 'NO - PARTIALLY ACHIEVED', 'NO - SAME AS BASELINE', 'NO 
- WORSE') will be presented by treatment group (cohort, subcohort) at each visit. 
Additionally, GAS responders will be summarized where responder is defined as subject 
responding ‘YES – MUCH BETTER’, ‘YES – A LITTLE BETTER’). 
All GAS data will be listed. 
6.13.5 
Respiratory Function Tests 
Assessment of the respiratory function will be performed with a handheld device. 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline (continuous data) will be presented by treatment group (cohort, subcohort) and visit for 
each parameter. For summary tables the best result will be selected. All collected data will be 
included in the listings. 
Continuous parameters: 
 FVC (L) 
 %FVC Predicted 
 FEV1 (L) 
 %FEV1 Predicted 
 FEV1/FVC 
 MEP (cm H2O) 
 %MEP Predicted 
 MIP (cm H2O) 
 %MIP Predicted 
 Oxygen Saturation (%). 
For the abbreviated CSR reporting only FVC and MIP will be included. 


 
 
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Respiratory function (Normal; Abnormal NCS, Abnormal CS) will be summarized by treatment 
group (cohort, subcohort) and period in a shift table from baseline to the worst recorded result in 
each trial period. 
All data, including details of clinically significant findings will be listed. 
6.13.6 
Muscle Strength and Function Tests 
MyoGrip 
MyoGrip is an extremely sensitive tool to measure muscle strength in severely disabled subjects 
where current tools are unable to measure changes or benefit. For disorders such as CNM, the 
ability to use the joystick of their electric wheelchair or other fine motor functions is important to 
the subject. These sensitive measures can also assist in detecting early signals of efficacy of 
administered drug. 
For MyoGrip reporting only the best strength test result will be summarized. Descriptive 
statistics (n, mean, SD, median, min, max) of the observed values and percent change from 
baseline will be presented by treatment group (cohort, subcohort) and visit for each parameter. 
All data, including all strength test repeats, will be listed. 
Motor Function Measure (MFM) 
Motor Function Measure (MFM) is classically used as a measure of functional capacities in 
subjects with neuromuscular disorders. The MFM 32-item list (MFM32) is a scale to enable an 
objective assessment of the motor abilities of subjects with neuromuscular diseases whatever the 
motor function deficiency. Three dimensions are taken into account: D1: standing position and 
transfers, D2: axial and proximal motor function, and D3: distal motor function. 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline will be presented by treatment group (cohort, subcohort) and visit for the following 
parameters: 
 D1 Standing and transfers (%) 
 D2 Axial and proximal motor function (%) 
 D3 Distal motor function (%) 
 Total MFM32 Score (%). 
For the abbreviated CSR reporting only Total MFM32 Score will be included. 
All data, including responses to questionnaire items and total scores, will be listed. 
6.13.7 
Dysphagia Questionnaire 


 
 
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Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline will be presented by treatment group (cohort, subcohort) and visit for the EAT-10 score. 
All data, including responses to questionnaire items and total scores, will be listed. 
6.13.8 
Muscle Biopsy 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline will be presented by treatment group (cohort, subcohort) and visit. 
All data will be listed. 
6.13.9 
Biomarker and DNA samples 
Samples for genetic (DNA) research and biomarkers may be taken from subjects who provide 
separate informed consent for these samples to be collected and for their samples to be stored for 
other research studies. This data will not be reported in this study. 
6.13.10 Exploratory Bayesian Analyses 
The MFM 32, continuous respiratory measures and continuous strength measures (in absolute 
values) will also be analyzed in an exploratory manner using Bayesian statistical modeling. 
Bayesian methods are used as they allow for an easy construction of the predictive distributions. 
These distributions will be used to assess whether deviations from the natural course of the 
disease as observed from the run-in and the natural history data are observed after administration 
of the IMP. 
A hierarchical model will be fitted to each of the responses using Bayesian methods. Only non-
informative priors will be considered. The data used for the modeling consist of the NHS data or 
the run-in for patients who did not participate in the NHS. This hierarchical model will contain a 
random slope and intercept for each subject. The other covariates of the model will be time in 
months and treatment group. The baseline is at time 0. These models will be performed for each 
mutation separately.  
Using the posterior distributions of the different parameters of the model fitted using NHS or 
run-in data only, the predictive distributions at future time points of interest in the current study 
will be generated. Then the predictive probability that an observation would have occurred given 
the natural course of each patient’s disease will be computed. This predictive probability under 
the assumption of the natural evolution of the disease will also be considered as an additional 
endpoint or transformation of the clinical endpoint to evaluate the potential effect of the IMP.  


 
 
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The appropriate distribution or transformation to be applied on the observed endpoints will be 
justified to reflect the nature of the data. For example, the Beta distribution may be used for 
bounded scales or a logistic transformation for percentages.  
These assessments will only be realized at the end of the study and will not be conducted for 
IDMC purposes. 
Theses Analyses will be conducted by PharmaLex Belgium using SAS v9.4. Bayesian 
estimations will be realized with the proc MCMC procedure. 
6.14 Safety Analyses 
The safety analyses (AE, clinical laboratory tests, physical examination, vital signs and ECG) 
will be presented by the treatment received for the Safety Analysis Set. 
6.14.1 
Adverse Events 
Adverse events will be reported separately for SAD and MAD + MAD Extension parts. 
A pre-therapy AE is defined as any AE that starts before the first dose of study drug. 
A treatment emergent adverse event (TEAE) is defined as: 
 Any AE that has an onset on or after the first dose of study drug and before last dose of 
study drug + 28 days. 
 Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
and before the last dose of study drug + 28 days. 
A treatment-related AE is defined as an AE as being related to the study drug. If an AE has 
missing relationship it is assumed to be related to the study drug for analysis purposes. 
Maximum severity will be assumed for an AE with missing severity. 
The following tables will be presented for AEs: 
 Summary of All Adverse Events, incidence and the number of events. 
 Pre-therapy AEs by system organ class and preferred term, incidence and number of 
events 
 TEAEs by system organ class and preferred term, incidence and number of events 
 Treatment-related TEAEs by system organ class and preferred term, incidence and 
number of events 


 
 
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 Serious TEAEs by system organ class and preferred term, incidence and number of 
events 
 TEAEs leading to treatment withdrawal by system organ class and preferred term, 
incidence and number of events 
  All AEs of special interest by system organ class and preferred term, incidence and 
number of events 
 TEAEs by system organ class, preferred term and maximum severity, incidence 
 Treatment related TEAEs by system organ class, preferred term and maximum severity, 
incidence 
 TEAEs by system organ class, preferred term and study drug relationship, incidence 
 Listing of Deaths (presented in the Table section of the appendices) 
 Listing of Serious TEAEs (presented in the Table section of the appendices) 
All AEs will be listed. 
6.14.2 
Laboratory Data 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline (continuous data) will be presented by treatment group (cohort, subcohort) and visit for 
each hematology, chemistry and urinalysis parameter. 
Each measurement (continuous data) will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. Shift tables in relation to the normal range from 
baseline to the worst recorded result in each trial period will be presented. 
In addition to central laboratory, platelet counts will be analyzed in local laboratory. This local 
laboratory data will be reported as part of the laboratory tables describe above. 
All laboratory data will be listed. 
Some laboratory samples are analyzed in local laboratory instead of central laboratory. If data 
from same sample is available from both central and local laboratory then the records from 
central laboratory will be used. Local laboratory might use different units and/or normal ranges 
to central laboratory and this need to be taken into account as described below. 
For shift tables (low/normal/high) local lab data will use the original units and normal ranges. 
For descriptive statistics, local laboratory results are normalized using location-scale 
normalization or scale normalization to be comparable to central lab results. These methods are 
described by Karvanen (2003). 


 
 
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Result Normalization 
Location-scale normalization is used when both central lab and local lab have both lower and 
upper limits for normal specified in the data: 
𝑠location-scale = 𝐿𝑆+ (𝑥−𝐿𝑋) (𝑈𝑆−𝐿𝑆)
(𝑈𝑋−𝐿𝑋) 
If location-scale normalization reaches negative value for a parameter then for that parameter 
scale normalized value will be used instead (giving priority for value using upper normal limit). 
Scale normalization is used when either central lab or local lab have and only lower or upper 
limits for normal specified in the data (or location-scale normalization reaches negative value): 
𝑠scale(upper) = 𝑥𝑈𝑆
𝑈𝑥
 
or 
𝑠scale(lower) = 𝑥𝐿𝑆
𝐿𝑥
The notation in the above formulas are as follows: 
 
s 
normalized result 
x 
local laboratory result 
LX 
lower normal limit in local lab 
UX 
upper normal limit in local lab 
LS 
lower normal limit in central lab 
US 
upper normal limit in central lab. 
As a result of normalization the normalized values will be comparable to central lab results and 
are using the same units and normal ranges. 
6.14.3 
Coagulation Data 
Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline (continuous data) will be presented by treatment group (cohort, subcohort) and visit for 
each parameter. 
Shift tables in relation to the normality (Normal, Abnormal NCS, and Abnormal CS) from 
baseline to the worst recorded result in each trial period will be presented. 
All data, including details of any abnormalities, will be listed. 
6.14.4 
Complement Data 


 
 
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Descriptive statistics (n, mean, SD, median, min, max) of the observed values and change from 
baseline (continuous data) will be presented by treatment group (cohort, subcohort) and visit for 
each parameter. 
Each measurement (continuous data) will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. Shift tables in relation to the normal range from 
baseline to the worst recorded result in each trial period will be presented. 
6.14.5 
Vital Signs 
Descriptive statistics (n, mean, SD, median, min, max) for observed values and changes from 
baseline in the following vital signs will be presented by treatment group (cohort, subcohort) at 
each visit: 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
 Pulse rate (bpm)  
 Respiration rate (breath/min) 
 Body temperature (degrees Celsius) 
 Pulse Oximetry (SpO2) 
 Body weight (kg) 
 BMI (kg/m2) 
All vital sign data will be listed. 
6.14.6 
Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be tabulated by treatment group (cohort, subcohort) at each visit: 
 Heart rate (bpm) 
 PR interval (ms) 
 RR interval (ms) 
 QRS duration (ms) 
 QT interval (ms) 
 QTc interval (ms) 
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal CS) 
from baseline to the worst recorded result in each trial period will be presented. 


 
 
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All ECG data, including details of any abnormalities, will be listed. 
6.14.7 
Physical Examination 
All data, including details of clinically significant findings will be listed. 
At baseline and after 24 weeks of MAD treatment (Week 25 visit), the symptom-directed 
physical examination will include a neurological assessment. Neurological examination will be 
presented similarly to physical examination. 
6.14.8 
Liver Ultrasound and Hepatic Elastography 
The observed data for liver ultrasound and hepatic elastography assessments will be listed only. 
7 INTERIM ANALYSIS 
Not applicable. Study was terminated before the interim analysis. 
8 PRIMARY AND FINAL ANALYSIS 
The study was terminated early and therefore planned primary and final analyses will not be 
performed. Reporting will include only same set of outputs as was delivered for the IDMC 
meetings (full safety analyses) and selected key efficacy endpoints. Section 12 of this SAP is 
updated to highlight which outputs are excluded from the planned. 
9 INDEPENDENT DATA MONITORING COMMITTEE ANALYSIS 
The purpose of the IDMC is to review study data of the cohorts, before proceeding to the next 
dose level. Further details about Independent Data Monitoring Committee (IDMC) meetings and 
deliverables are described in IDMC Charter. IDMC will be reviewing data at least 4 time during 
the study: 
1. Organizational Meeting. 
2. First Data Review Meeting 
 When last subject from SAD1 has completed study visit SAD1 W3 (Day 15). 
3. Second Data Review Meeting 
 When last subject from SAD2 has completed study visit SAD2 W3 (Day 15) 
4. Third Data Review Meeting 
 When at least two subjects in each sub cohort have passed study visit MAD1 W6 
and all available SAD3 data available at the time of the meeting (SAD3 dosing is 
optional for this IDMC meeting) 


 
 
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5. Fourth Data Review Meeting 
 When last subject from MAD1 has completed study visit MAD1 W13 and last 
subject from MAD2 has completed study visit MAD2 W13 
9.1 IDMC Open Session / Closed Session 
Separate outputs will be delivered for IDMC open and closed sessions. 
Open session tables will be including only overall treatment group. Closed session reports will 
be including treatment groups (cohort, subcohort) and overall as defined in section 6.3 of this 
document. 
10 CHANGES TO PLANNED PROTOCOL ANALYSIS 
Additional exploratory Bayesian analyses for MFM 32, continuous respiratory measures and 
continuous strength measures were added in section 6.13.10. 
The study was stopped and the final reporting will be including only the IDMC outputs and 
selected efficacy parameters (FVC, MIP, Total MFM32 Score and PGI-C). 
 
 


 
 
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11 REFERENCES 
1. Phoenix™ WinNonlin® (Version 6.4, Pharsight Corporation) 
2. SAS Institute Inc., Cary, NC, 27513, USA 
3. Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information 
Journal, Vol. 37, pp. 101–107, 2003, 0092-8615/2003 
 
 
 


 
 
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12 LIST OF TABLES, FIGURES AND LISTINGS FOR THE IDMC, 
PRIMARY ANALYSIS AND FINAL ANALYSIS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods 
maybe used: 
 Independent programming of numbers and manual review of format (IP) 
 Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
 Manual review (MR) 
 Code review (CR) 
Note: Strikethrough tables are ones that were originally planned for primary and final analysis 
but will be excluded from the abbreviated CSR because of the termination of the study. 
 
Table 
Number 
Table Title 
Included 
in 
IDMC 
meetings 
Validation 
Method 
Shell 
Number (if 
repeat) 
Items in bold are not table titles but references to the section headings within eCTD. 
14.1 
Demographic Data 
 
 
 
14.1.1.1 
Subject Enrollment – Screened Set 
1-4 
IP 
 
14.1.1.2 
Screen Failures – Screened Set 
1-4 
IP 
 
14.1.1.3 
Inclusion/Exclusion Criteria – Screened Set 
1-4 
IP 
 
14.1.1.4 
Analysis Sets – Pre-Screened Set 
1-4 
IP 
 
14.1.1.5 
Cumulative proportion of information – Safety Analysis 
Set 
1-4 
IP 
 
14.1.1.6 
Subject Disposition – Safety Analysis Set 
1-4 
IP 
 
14.1.1.7 
Subject Disposition by Country – Safety Analysis Set 
1-4 
IP 
14.1.1.6 
14.1.1.8 
Visits/Assessments Affected by COVID-19 – Safety 
Analysis Set 
 
IP 
 
14.1.2.1 
Demographics – Safety Analysis Set 
1-4 
IP 
 
14.1.3.1 
Medical History Related to Centronuclear Myopathy 
(CNM) – Safety Analysis Set 
1-4 
IP 
 
14.1.3.2 
Medical History Unrelated to Centronuclear Myopathy 
(CNM) – Safety Analysis Set 
1-4 
IP 
14.1.3.1 
14.1.4.1 
Prior Medications – Safety Analysis Set 
1-4 
IP 
 
14.1.4.2 
Concomitant Medications – Safety Analysis Set 
1-4 
IP 
14.1.4.1 
14.1.5.1 
Treatment Exposure – Safety Analysis Set 
1-4 
IP 
 
14.1.5.2 
Treatment Compliance – Safety Analysis Set 
1-4 
IP 
 
14.2 
Pharmacodynamics and Exploratory Efficacy 
 
 
 


 
 
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Table 
Number 
Table Title 
Included 
in 
IDMC 
meetings 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.1.1 
PROMIS Questionnaire, Descriptive Statistics – 
Pharmacokinetic Set 
 
IP 
 
14.2.2.1 
CGI-I Questionnaire, Frequency Table – Pharmacokinetic 
Set 
 
IP 
 
14.2.2.2 
CGI-I Questionnaire, Responders – Pharmacokinetic Set 
 
IP 
14.2.2.1 
14.2.3.1 
PGI-C Questionnaire, Frequency Table – Pharmacokinetic 
Set 
 
IP 
14.2.2.1 
14.2.3.2 
PGI-C Questionnaire, Responders – Pharmacokinetic Set 
 
IP 
14.2.2.1 
14.2.4.1 
GAS Questionnaire, Frequency Table – Pharmacokinetic 
Set 
 
IP 
14.2.2.1 
14.2.4.1 
GAS Questionnaire, Responders – Pharmacokinetic Set 
 
IP 
14.2.2.1 
14.2.5.1 
Respiratory Function Tests, Descriptive Statistics – 
Pharmacokinetic Set 
4 
IP 
14.2.1.1 
14.2.5.2 
Respiratory Function Tests, Shift Table – Pharmacokinetic 
Set 
4 
IP 
 
14.2.5.3 
Explorative Bayesian Analysis for Respiratory Function 
Tests – Pharmacokinetic Set 
 
Stat IP 
 
14.2.6.1 
MyoGrip, Descriptive Statistics – Pharmacokinetic Set 
4 
IP 
14.2.1.1 
14.2.6.2 
Explorative Bayesian Analysis for MyoGrip – 
Pharmacokinetic Set 
 
Stat IP 
14.2.5.3 
14.2.7.1 
MFM32, Descriptive Statistics – Pharmacokinetic Set 
4 
IP 
14.2.1.1 
14.2.7.2 
Explorative Bayesian Analysis for MFM32 – 
Pharmacokinetic Set 
 
Stat IP 
14.2.5.3 
14.2.8.1 
Dysphagia Questionnaire, Descriptive Statistics – 
Pharmacokinetic Set 
4 
IP 
14.2.1.1 
14.2.9.1 
Muscle Biopsy, Descriptive Statistics – Pharmacokinetic 
Set 
4 
IP 
14.2.1.1 
14.3 
Safety Data 
 
 
 
14.3.1 
Displays of Adverse Events 
 
 
 
14.3.1.1.1 
Overall Summary of Adverse Events – Safety Analysis Set 
1-4 
IP 
 
14.3.1.2.1 
Pre-Therapy AEs by System Organ Class and Preferred 
Term – Safety Analysis Set 
1-4 
IP 
 
14.3.1.2.2 
TEAEs by System Organ Class and Preferred Term – 
Safety Analysis Set 
1-4 
IP 
14.3.1.2.1 
14.3.1.2.3 
Treatment Related TEAEs by System Organ Class and 
Preferred Term – Safety Analysis Set 
1-4 
IP 
14.3.1.2.1 
14.3.1.2.4 
Serious TEAEs by System Organ Class and Preferred Term 
– Safety Analysis Set 
1-4 
IP 
14.3.1.2.1 
14.3.1.2.5 
TEAEs Leading to Treatment Withdrawal by System 
Organ Class and Preferred Term – Safety Analysis Set 
1-4 
IP 
14.3.1.2.1 
14.3.1.2.6 
All AEs of Special Interest by System Organ Class and 
Preferred Term – Safety Analysis Set 
1-4 
IP 
14.3.1.2.1 


 
 
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Table 
Number 
Table Title 
Included 
in 
IDMC 
meetings 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.3.1.3.1 
TEAEs by System Organ Class, Preferred Term and 
Maximum Severity – Safety Analysis Set 
1-4 
IP 
 
14.3.1.3.2 
Treatment Related TEAEs System Organ Class, Preferred 
Term and Maximum Severity – Safety Analysis Set 
1-4 
IP 
14.3.1.3.1 
14.3.1.4.1 
TEAEs by System Organ Class, Preferred Term and 
Strongest Study Drug Relationship – Safety Analysis Set 
1-4 
IP 
 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events 
 
 
 
14.3.2.1 
Listing of Deaths – Safety Analysis Set 
1-4 
IP 
 
14.3.2.2 
Listing of Serious TEAEs – Safety Analysis Set 
1-4 
IP 
14.3.2.1 
14.3.3 
Narratives of Deaths, Other Serious and Certain Other 
Significant Adverse Events 
 
 
 
 
Not Applicable 
 
 
 
14.3.4 
Abnormal Laboratory Values 
 
 
 
14.3.4.1.1 
Listing of Abnormal Laboratory Values 
1-4 
IP 
 
14.3.5 
Laboratory Data 
 
 
 
14.3.5.1.1 
Hematology Data, Descriptive Statistics – Safety Analysis 
Set 
1-4 
IP 
14.2.1.1 
14.3.5.1.2 
Hematology Data, Shift Table – Safety Analysis Set 
1-4 
IP 
14.2.5.2 
14.3.5.2.1 
Serum Chemistry Data, Descriptive Statistics – Safety 
Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.5.2.2 
Serum Chemistry Data, Shift Table – Safety Analysis Set 
1-4 
IP 
14.2.5.2 
14.3.5.3.1 
Urinalysis Data, Frequency Table – Safety Analysis Set 
1-4 
IP 
 
14.3.5.4.1 
Coagulation Data, Descriptive Statistics – Safety Analysis 
Set 
1-4 
IP 
14.2.1.1 
14.3.5.4.2 
Coagulation Data, Shift Table – Safety Analysis Set 
1-4 
IP 
14.2.5.2 
14.3.5.5.1 
Complement Data, Descriptive Statistics – Safety Analysis 
Set 
1-4 
IP 
14.2.1.1 
14.3.5.5.2 
Complement Data, Shift Table – Safety Analysis Set 
1-4 
IP 
14.2.5.2 
14.3.6 
Vital Signs 
 
 
 
14.3.6.1 
Vital Signs, Descriptive Statistics – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.7 
ECG 
 
 
 
14.3.7.1 
ECG Data, Descriptive Statistics – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.7.2 
ECG Data, Shift Table – Safety Analysis Set 
1-4 
IP 
14.2.5.2 
14.3.8 
Physical Examination 
 
 
 
 
Not Applicable 
 
 
 
14.4  
Pharmacokinetics 
 
 
 
14.4.1.1 
Pharmacokinetic Concentrations – Pharmacokinetic Set 
1-4 
IP 
 
14.4.2.1 
Pharmacokinetic Parameters – Pharmacokinetic Set 
4 
IP 
14.4.1.1 
14.4.2.2 
Analysis of Dose Proportionality – Pharmacokinetic Set 
 
Stat IP 
 
14.4.2.3 
Analysis of Terminal Disposition Phase Rate Constant λz – 
Pharmacokinetic Set 
 
Stat IP 
 


 
 
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Table 
Number 
Table Title 
Included 
in 
IDMC 
meetings 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.4.3.1 
Anti-Drug Antibodies, Descriptive Statistics – 
Pharmacokinetic Set 
 
IP 
14.2.1.1 
and/or 
14.2.2.1 
14.4.4.1 
Metabolic Profiling (Blood), Descriptive Statistics – 
Pharmacokinetic Set 
 
IP 
14.2.1.1 
14.4.4.2 
Metabolic Profiling (Urine), Descriptive Statistics – 
Pharmacokinetic Set 
 
IP 
14.2.1.1 
 
 


 
 
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Figure 
Number 
Figure Title 
Included 
in IDMC 
meetings 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.2.1.1 
PGI-C Questionnaire, Mean Profiles – Pharmacokinetic Set 
 
IP 
 
14.2.1.2 
PGI-C Questionnaire, Individual Profiles – Pharmacokinetic 
Set 
 
IP 
 
14.2.2.1 
Respiratory Function Tests, Mean Profiles – 
Pharmacokinetic Set 
 
IP 
14.2.1.1 
14.2.2.2 
Respiratory Function Tests, Individual Profiles – 
Pharmacokinetic Set 
 
IP 
14.2.1.2 
14.2.3.1 
MFM32, Mean Profiles – Pharmacokinetic Set 
 
IP 
14.2.1.1 
14.2.3.2 
MFM32, Individual Profiles – Pharmacokinetic Set 
 
IP 
14.2.1.2 
14.3.5.1.1 
Hematology, Mean Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.5.1.2 
Hematology, Individual Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.2 
14.3.5.2.1 
Serum Chemistry, Mean Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.5.2.2 
Serum Chemistry, Individual Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.2 
14.3.5.4.1 
Coagulation Data, Mean Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.5.4.2 
Coagulation Data, Individual Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.2 
14.3.5.5.1 
Complement Data, Mean Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.5.5.2 
Complement Data, Individual Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.2 
14.3.6.1.1 
Vital Signs, Mean Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.6.1.2 
Vital Signs, Individual Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.2 
14.3.7.1.1 
ECG, Mean Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.1 
14.3.7.1.2 
ECG, Individual Profiles – Safety Analysis Set 
1-4 
IP 
14.2.1.2 
14.4.1.1 
Pharmacokinetic Concentrations, Mean Profiles on Linear 
and Semi-Logarithmic Scales – Pharmacokinetic Set 
1-4 
IP 
 
14.4.1.2 
Pharmacokinetic Concentrations, Individual Profiles on 
Linear and Semi-Logarithmic Scales – Pharmacokinetic Set 
1-4 
IP 
 
 
 


 
 
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Listing 
Number 
Listing Title 
Included 
in IDMC 
meetings 
Validation 
Method 
Shell 
Number 
(if 
repeat) 
16.2 
Subject Data Listings 
 
 
 
16.2.1 
Discontinued Subjects 
 
 
 
16.2.1.1 
Screen Failures – Screened Set 
1-4 
IP 
 
16.2.1.2 
Inclusion/Exclusion Criteria – Screened Set 
1-4 
IP 
 
16.2.1.3 
Study Completion – Safety Analysis Set 
1-4 
IP 
 
16.2.1.4 
COVID-19 Summary – Screened Set 
 
IP 
 
16.2.1.5 
COVID-19 Visit Log – Screened Set 
 
IP 
 
16.2.2 
Protocol Deviations 
 
 
 
16.2.2.1 
Protocol Deviations – Screened Set 
 
IP 
 
16.2.3 
Subjects Excluded From The Efficacy Analyses 
 
 
 
16.2.3.1  
Analysis Sets – Pre-Screened Set 
1-4 
IP 
 
16.2.4 
Demographic Data 
 
 
 
16.2.4.1 
Informed Consent – Safety Analysis Set 
 
IP 
 
16.2.4.2 
Demographics – Safety Analysis Set 
1-4 
IP 
 
16.2.4.3 
Medical History Related to CNM – Safety Analysis Set 
1-4 
IP 
 
16.2.4.4 
Medical History Unrelated to CNM – Safety Analysis Set 
1-4 
IP 
 
16.2.4.5 
Prior and Concomitant Medications – Safety Analysis Set 
1-4 
IP 
 
16.2.4.6 
Prior and Concomitant Non-Drug Therapies and Procedures – 
Safety Analysis Set 
 
IP 
 
16.2.5 
Compliance and/or Drug Concentration Data 
 
 
 
16.2.5.1 
Exposure and Compliance – Safety Analysis Set 
1-4 
IP 
 
16.2.5.2 
Infusion Interruption / Infusion Rate Change – Safety Analysis 
Set 
1-4 
IP 
 
16.2.5.3 
Pharmacokinetic Concentrations – Safety Analysis Set 
1-4 
IP 
 
16.2.5.4 
Pharmacokinetic Parameters – Safety Analysis Set 
4 
IP 
 
16.2.6 
Individual Efficacy Response Data 
 
 
 
16.2.6.1 
PROMIS – Pharmacokinetic Set 
 
IP 
 
16.2.6.2 
CGI-I Questionnaire – Pharmacokinetic Set 
 
IP 
 
16.2.6.3 
PGI-C Questionnaire – Pharmacokinetic Set 
 
IP 
 
16.2.6.4 
GAS Questionnaire – Pharmacokinetic Set 
 
IP 
 
16.2.6.5 
Respiratory Function Tests – Pharmacokinetic Set 
4 
IP 
 
16.2.6.6 
MyoGrip – Pharmacokinetic Set 
4 
IP 
 
16.2.6.7 
MFM32 – Pharmacokinetic Set 
4 
IP 
 
16.2.6.8 
Dysphagia Questionnaire – Pharmacokinetic Set 
4 
IP 
 
16.2.6.9 
Muscle Biopsy – Pharmacokinetic Set 
4 
IP 
 
16.2.7 
Adverse Event Listings 
 
 
 
16.2.7.1 
Adverse Events – Safety Analysis Set 
1-4 
IP 
 
16.2.8 
Individual Laboratory Measurements and Other Safety 
 
 
 
16.2.8.1 
Hematology – Safety Analysis Set 
1-4 
IP 
 
16.2.8.2 
Serum Chemistry – Safety Analysis Set 
1-4 
IP 
 
16.2.8.3 
Urinalysis – Safety Analysis Set 
1-4 
IP 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 42 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
Listing 
Number 
Listing Title 
Included 
in IDMC 
meetings 
Validation 
Method 
Shell 
Number 
(if 
repeat) 
16.2.8.4 
Coagulation Data – Safety Analysis Set 
1-4 
IP 
 
16.2.8.5 
Complement Data – Safety Analysis Set 
1-4 
IP 
 
16.2.8.6 
Vital Signs – Safety Analysis Set 
1-4 
IP 
 
16.2.8.7 
Pregnancy Test – Safety Analysis Set 
 
IP 
 
16.2.8.8 
ECG – Safety Analysis Set 
1-4 
IP 
 
16.2.8.9 
Physical Examination – Safety Analysis Set 
1-4 
IP 
 
16.2.8.10 
Neurological Examination – Safety Analysis Set 
1-4 
IP 
 
16.2.8.11 
Anti-Drug Antibodies – Safety Analysis Set 
 
IP 
 
16.2.8.12 
Metabolic Profiling (Blood) – Safety Analysis Set 
 
IP 
 
16.2.8.13 
Metabolic Profiling (Urine) – Safety Analysis Set 
 
IP 
 
16.2.8.14 
Liver ultrasound Including Hepatic Elastography – Safety 
Analysis Set 
 
IP 
 
16.2.9 
Abnormal Safety Results 
 
 
 
16.2.9.1 
Abnormal Laboratory, ECG and Vital Sign Results – Safety 
Analysis Set 
2-4 
IP 
 
 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 43 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13 APPENDIX 
13.1 PROMIS Scoring Tables 
13.1.1 
ABILITY TO PARTICIPATE IN SOCIAL ROLES AND 
ACTIVITIES 
Ability to Participate Social Roles and Activities 
4a 
Adult version 
Raw Score 
Scale Score 
4 
27.5 
5 
31.8 
6 
34.0 
7 
35.7 
8 
37.3 
9 
38.8 
10 
40.5 
11 
42.3 
12 
44.2 
13 
46.2 
14 
48.1 
15 
50.0 
16 
51.9 
17 
53.7 
18 
55.8 
19 
58.3 
20 
64.2 
 
Ability to Participate Social Roles and Activities 
8a 
Adult version 
Raw Score 
Scale Score 
8 
25.9 
9 
29.7 
10 
31.3 
11 
32.6 
12 
33.6 
13 
34.5 
14 
35.3 
15 
36.2 
16 
36.9 
17 
37.7 
18 
38.5 
19 
39.3 
20 
40.2 
21 
41.1 
22 
42.0 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
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Effective Date: 05-Sep-2017 
 
Confidential 
 
Ability to Participate Social Roles and Activities 
8a 
Adult version 
Raw Score 
Scale Score 
23 
43.0 
24 
44.0 
25 
45.0 
26 
46.0 
27 
47.0 
28 
48.0 
29 
48.9 
30 
49.9 
31 
50.8 
32 
51.7 
33 
52.7 
34 
53.6 
35 
54.6 
36 
55.7 
37 
56.8 
38 
58.2 
39 
60.2 
40 
65.4 
 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 45 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13.1.2 
ANXIETY 
Anxiety 
8a 
Adult v1.0 
Raw Score 
Scale Score 
8 
37.1 
9 
43.2 
10 
45.9 
11 
47.8 
12 
49.4 
13 
50.8 
14 
52.1 
15 
53.2 
16 
54.3 
17 
55.4 
18 
56.4 
19 
57.4 
20 
58.4 
21 
59.4 
22 
60.4 
23 
61.4 
24 
62.5 
25 
63.5 
26 
64.5 
27 
65.6 
28 
66.6 
29 
67.7 
30 
68.7 
31 
69.8 
32 
70.8 
33 
71.9 
34 
73.0 
35 
74.1 
36 
75.4 
37 
76.7 
38 
78.2 
39 
80.0 
40 
83.1 
 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 46 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13.1.3 
DEPRESSION 
Depression 
8a 
Adult v1.0 
Raw Score 
Scale Score 
8 
38.2 
9 
44.7 
10 
47.5 
11 
49.4 
12 
50.9 
13 
52.1 
14 
53.2 
15 
54.1 
16 
55.1 
17 
55.9 
18 
56.8 
19 
57.7 
20 
58.5 
21 
59.4 
22 
60.3 
23 
61.2 
24 
62.1 
25 
63.0 
26 
63.9 
27 
64.9 
28 
65.8 
29 
66.8 
30 
67.7 
31 
68.7 
32 
69.7 
33 
70.7 
34 
71.7 
35 
72.8 
36 
73.9 
37 
75.0 
38 
76.4 
39 
78.2 
40 
81.3 
 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 47 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13.1.4 
FATIGUE 
Fatigue 
8a 
Adult v1.0 
Raw Score 
Scale Score 
8 
33.1 
9 
38.5 
10 
41.0 
11 
42.8 
12 
44.3 
13 
45.6 
14 
46.9 
15 
48.1 
16 
49.2 
17 
50.4 
18 
51.5 
19 
52.5 
20 
53.6 
21 
54.6 
22 
55.6 
23 
56.6 
24 
57.5 
25 
58.5 
26 
59.4 
27 
60.4 
28 
61.3 
29 
62.3 
30 
63.3 
31 
64.3 
32 
65.3 
33 
66.4 
34 
67.5 
35 
68.6 
36 
69.8 
37 
71.0 
38 
72.4 
39 
74.2 
40 
77.8 
 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 48 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13.1.5 
PAIN INTERFERENCE 
Pain Interference 
8a 
Adult v1.1 
Raw Score 
Scale Score 
8 
40.7 
9 
47.9 
10 
49.9 
11 
51.2 
12 
52.3 
13 
53.2 
14 
54.1 
15 
55.0 
16 
55.8 
17 
56.6 
18 
58.1 
19 
58.1 
20 
58.8 
21 
59.5 
22 
60.2 
23 
60.8 
24 
61.5 
25 
62.1 
26 
62.8 
27 
63.5 
28 
64.1 
29 
64.8 
30 
65.5 
31 
66.2 
32 
66.9 
33 
67.7 
34 
68.4 
35 
69.2 
36 
70.1 
37 
71.0 
38 
72.1 
39 
73.5 
40 
77.0 
 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 49 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13.1.6 
PHYSICAL FUNCTION 
Physical Function 
10a 
Adult v2.0 
Raw Score 
Scale Score 
10 
13.5 
11 
16.6 
12 
18.3 
13 
19.7 
14 
20.9 
15 
22.1 
16 
23.1 
17 
24.1 
18 
25.0 
19 
26.0 
20 
26.9 
21 
27.7 
22 
28.6 
23 
29.4 
24 
30.2 
25 
31.0 
26 
31.8 
27 
32.5 
28 
33.3 
29 
34.0 
30 
34.8 
31 
35.5 
32 
36.3 
33 
37.0 
34 
37.8 
35 
38.5 
36 
36.3 
37 
40.1 
38 
40.9 
39 
41.7 
40 
42.6 
41 
43.5 
42 
44.4 
43 
45.5 
44 
46.6 
45 
47.9 
46 
49.4 
47 
51.2 
48 
53.4 
49 
55.8 
50 
61.9 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
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Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 50 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
13.1.6.1 Scale used in NHS part 
Physical Function 
12a 
Adult v1.0 
Short Form Conversion Table for People 
Who Can Walk (answered 12 items) 
Short Form Conversion Table for People 
Who Cannot Walk (answered 6 items) 
Raw Score 
Scale Score 
Raw Score 
Scale Score 
12 
13.3 
6 
13.8 
13 
16.1 
7 
16.8 
14 
18.1 
8 
19.0 
15 
19.6 
9 
20.7 
16 
20.9 
10 
22.3 
17 
22.1 
11 
23.7 
18 
23.1 
12 
25.0 
19 
24.1 
13 
26.2 
20 
25.1 
14 
27.4 
21 
26.0 
15 
28.6 
22 
26.8 
16 
29.8 
23 
27.7 
17 
31.0 
24 
28.5 
18 
32.2 
25 
29.3 
19 
33.4 
26 
30.0 
20 
34.6 
27 
30.8 
21 
35.9 
28 
31.5 
22 
37.3 
29 
32.3 
23 
38.8 
30 
33.0 
24 
40.4 
31 
33.7 
25 
42.2 
32 
34.4 
26 
44.7 
33 
35.1 
27 
46.9 
34 
35.8 
28 
49.8 
35 
36.5 
29 
52.8 
36 
37.1 
30 
59.9 
37 
37.8 
 
 
38 
38.5 
 
 
39 
39.2 
 
 
40 
39.9 
 
 
41 
40.6 
 
 
42 
41.3 
 
 
43 
42.0 
 
 
44 
42.8 
 
 
45 
43.5 
 
 
46 
44.3 
 
 
47 
45.2 
 
 
48 
46.1 
 
 
49 
47.0 
 
 
50 
47.9 
 
 
51 
48.9 
 
 
52 
50.0 
 
 
53 
51.1 
 
 
54 
52.4 
 
 


 
 
Dynacure 
 
DYN101-C101 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Issue Date 29-SEP-2020 
 
Template: WCT-TP-ST-006-03 
 
Page 51 of 51 
Effective Date: 05-Sep-2017 
 
Confidential 
 
Physical Function 
12a 
Adult v1.0 
Short Form Conversion Table for People 
Who Can Walk (answered 12 items) 
Short Form Conversion Table for People 
Who Cannot Walk (answered 6 items) 
Raw Score 
Scale Score 
Raw Score 
Scale Score 
55 
53.8 
 
 
56 
55.8 
 
 
57 
57.3 
 
 
58 
59.5 
 
 
59 
61.7 
 
 
60 
66.1