Safety, Tolerability, Pharmacodynamic, Efficacy, and Pharmacokinetic Study of DYNE-251 in Participants With Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety, tolerability, and dystrophin protein levels in muscle tissue following multiple intravenous (IV) doses of DYNE-251 in participants with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. The study consists of 3 periods: a multiple-ascending dose (MAD) / placebo-controlled period (24 weeks), an open-label period (24 weeks) and a long-term extension period (96 weeks).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study Assessing Safety, Tolerability, Pharmacodynamics, Efficacy, and Pharmacokinetics of DYNE-251 Administered to Participants With Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping

Conditions
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Duchenne Muscular Dystrophy (DMD)

Intervention / Treatment
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* Drug: DYNE-251
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 4 to 16 years inclusive, at the time of informed consent/assent. Male with a confirmed DMD mutation in the dystrophin gene characterized by exon deletion amenable to exon 51 skipping. Upper extremity muscle group that is amenable to muscle biopsy. Brooke Upper Extremity Scale score of 1 or 2. Ambulatory or non-ambulatory. A non-ambulatory participant must have been non-ambulatory for <2 years before enrolment. Receiving a stable dosage of glucocorticoids for at least 12 weeks prior to the start of study drug administration, with the expectation of maintaining a stable dose during the Placebo-controlled and Open-label Period of the study (unless dose adjustment is required by weight change). Left ventricular ejection fraction of ≥50% by echocardiogram or ≥55% by cardiac magnetic resonance imaging (MRI). Exclusion Criteria: Uncontrolled clinical symptoms and signs of congestive heart failure (CHF). Any change in prophylaxis/treatment for CHF within 3 months prior to the start of study treatment. History of major surgical procedure within 12 weeks prior to the start of study drug administration or an expectation of a major surgical procedure during the study. Requirement of daytime ventilator assistance. Percent predicted FVC <40 % (applies only for participants who are age ≥7 years). Receipt of eteplirsen, or alternative exon-skipping/dystrophin-modifying therapy, within 12 weeks of randomization. Receipt of non-exon skipping investigational drug within 4 months before the start of study drug administration. Receipt of gene therapy at any time. Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo-Controlled MAD Period - DYNE-251<br>DYNE-251 will be administered 6 times over 24 weeks. | Drug: DYNE-251<br>* Administered by IV infusion, every 4 weeks<br>|
| Experimental: Placebo-Controlled MAD Period - Placebo<br>Placebo will be administered 6 times over 24 weeks. | Drug: Placebo<br>* Administered by IV infusion, every 4 weeks<br>|
| Experimental: Open-Label and Long-Term Extension Period - DYNE-251<br>DYNE-251 will be administered up to 30 times (over 120 weeks) after participants complete the Placebo-Controlled MAD Period of the study. | Drug: DYNE-251<br>* Administered by IV infusion, every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Through study completion, up to Week 145 | 
| Change From Baseline in Dystrophin Protein Levels in Muscle Tissue at Week 25 |  | Baseline, Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Muscle Tissue Exon 51 Skipping Levels at Week 25 |  | Baseline, Week 25 | 
| Change From Baseline in Muscle Tissue Percent Dystrophin-Positive Fiber (PDPF) at Week 25 |  | Baseline, Week 25 | 
| Change From Baseline in Blood Creatine Kinase (CK) Levels up to Week 145 |  | Baseline, up to Week 145 | 
| Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 145 | The NSAA is a 17-item functional scale used to measure functional motor abilities in ambulant participants with DMD and monitor progression of the disease and treatment effects in each of the items. The items are graded on a 3-point scale: 0=unable to achieve independently, 1=modified method but achieves goal with no physical assistance, and 2=normal, no obvious modification of activity. Total score range is 0 to 34. | Baseline, up to Week 145 | 
| Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 145 |  | Baseline, up to Week 145 | 
| Change From Baseline in 10-Meter Run/Walk (10MRW) Time in Ambulatory Participants up to Week 145 |  | Baseline, up to Week 145 | 
| Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 145 | The PUL scale is a validated tool specifically designed for assessing upper limb function in ambulant and non-ambulant individuals with DMD. It includes an entry item to define the broad starting functional level and 22 items subdivided into 3 areas indicative of upper limb strength as, shoulder level, midlevel, and distal level. The global score is a combination of the 3 areas and ranges from 0 to 42. Lower scores indicate higher disability. | Baseline, up to Week 145 | 
| Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 145 |  | Baseline, up to Week 145 | 
| Change From Baseline in Stride Velocity 95th Centile (SV95C) up to Week 145 |  | Baseline, up to Week 145 | 
| Maximum Observed Drug Concentration of DYNE-251 in Plasma (Cmax) |  | Through study completion, up to Week 145 | 
| Time to Maximum Concentration of DYNE-251 in Plasma (tmax) |  | Through study completion, up to Week 145 | 
| Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration of DYNE-251 in Plasma (AUC0-tlast) |  | Through study completion, up to Week 145 | 
| AUC Extrapolated to Infinity of DYNE-251 in Plasma (AUC∞) |  | Through study completion, up to Week 145 | 
| Apparent Terminal Elimination Rate Constant of DYNE-251 in Plasma (λz) |  | Through study completion, up to Week 145 | 
| Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½) |  | Through study completion, up to Week 145 | 
| Clearance (CL) of DYNE-251 in Plasma |  | Through study completion, up to Week 145 | 
| Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz) |  | Through study completion, up to Week 145 | 
| Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss) |  | Through study completion, up to Week 145 | 
| Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue |  | Through study completion, up to Week 145 | 
| Percentage of Participants With Antidrug Antibodies (ADAs) |  | Through study completion, up to Week 145 |