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

Phase 2Active Not RecruitingNCT05524883

Dyne Therapeutics86 enrolled

Overview

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 (LTE) period (288 weeks).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Duchenne Muscular Dystrophy (DMD)

Interventions

DYNE-251

Eligibility

Sex: MALEMin age: 4 YearsMax age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 4 to 16 years inclusive, at the time of informed consent/assent. * Male with a confirmed diagnosis of DMD and with a 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 enrollment. * 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 Periods 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.

Locations (30)

University of California San Diego

La Jolla, California, United States

UCLA University California of Los Angeles

Los Angeles, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Rare Disease Research, LLC

Atlanta, Georgia, United States

UMass Memorial Medical Center

Worcester, Massachusetts, United States

Outcomes

Primary Outcomes

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Time frame: Through study completion, up to Week 337

Change From Baseline in Dystrophin Protein Levels in Muscle Tissue at Week 25

Time frame: Baseline, Week 25

Secondary Outcomes

Change From Baseline in Muscle Tissue Exon 51 Skipping Levels at Week 25 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25

Time frame: Baseline, Week 25

Change From Baseline in Muscle Tissue Percent Dystrophin-Positive Fiber (PDPF) at Week 25 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25

Time frame: Baseline, Week 25

Change From Baseline in Blood Creatine Kinase (CK) Levels up to Week 337 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25

Time frame: Baseline, up to Week 337

Change From Baseline in Dystrophin Protein Level in Muscle Tissue as Determined by Western Blot at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49

Time frame: Baseline, Week 49

Change From Baseline in Muscle Tissue Exon 51 Skipping Levels at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49

Time frame: Baseline, Week 49

Change From Baseline in Muscle Tissue PDPF at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49

Time frame: Baseline, Week 49

Change From Baseline in Blood CK Levels up to Week 337 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49

Time frame: Baseline, up to Week 337

Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 337

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.

Time frame: Baseline, up to Week 337

Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 337

Time frame: Baseline, up to Week 337

Change From Baseline in 10-Meter Run/Walk (10MRW) Time in Ambulatory Participants up to Week 337

Time frame: Baseline, up to Week 337

Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 337

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.

Time frame: Baseline, up to Week 337

Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 337

Time frame: Baseline, up to Week 337

Change From Baseline in Stride Velocity 95th Centile (SV95C) in Ambulatory Participants up to Week 337

Time frame: Baseline, up to Week 337

Maximum Observed Plasma Drug Concentration of DYNE-251 (Cmax)

Time frame: Through study completion, up to Week 337

Time to Maximum Observed Plasma Drug Concentration of DYNE-251 (tmax)

Time frame: Through study completion, up to Week 337

Area Under the Plasma Drug Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration of DYNE-251 in Plasma (AUC0-tlast)

Time frame: Through study completion, up to Week 337

Area Under the Plasma Drug Concentration Versus Time Curve From Time 0 (Dosing) Extrapolated to Time Infinity of DYNE-251 (AUC∞)

Time frame: Through study completion, up to Week 337

Apparent Terminal Phase Elimination Rate Constant of DYNE-251 in Plasma (λz)

Time frame: Through study completion, up to Week 337

Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½)

Time frame: Through study completion, up to Week 337

Total Body Clearance (CL) of DYNE-251

Time frame: Through study completion, up to Week 337

Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz)

Time frame: Through study completion, up to Week 337

Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss)

Time frame: Through study completion, up to Week 337

Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue

Time frame: Through study completion, up to Week 337

Incidence of Antidrug Antibodies (ADAs)

Time frame: Through study completion, up to Week 337