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

Phase 1

Recruiting

• Conditions: Duchenne Muscular Dystrophy (DMD)
• Interventions: Drug: DYNE-251; Drug: Placebo

• Registration Number: NCT05524883
• Lead Sponsor: Dyne Therapeutics

Brief Summary

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 (192 weeks).

Detailed Description

Not available

Study Timeline

• Study Start: 2022-08-12
• Study First Submitted: 2022-08-30
• Study First Submitted QC: 2022-08-30
• Study First Posted: 2022-09-01
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-22
• Last Update Posted: 2024-10-24
• Primary Completion: 2029-11
• Study Completion: 2029-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 88

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Placebo-Controlled MAD Period - DYNE-251	DYNE-251	DYNE-251 will be administered once every 4 weeks (Q4W) or once every 8 weeks (Q8W) over 24 weeks.
Placebo-Controlled MAD Period - Placebo	Placebo	Placebo will be administered Q4W or Q8W over 24 weeks.
Open-Label and Long-Term Extension Period - DYNE-251	DYNE-251	DYNE-251 will be administered Q4W or Q8W for up to 192 weeks after participants complete the Placebo-Controlled MAD Period of the study.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Through study completion, up to Week 241
Change From Baseline in Dystrophin Protein Levels in Muscle Tissue at Week 25	Baseline, Week 25

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 241	Baseline, up to Week 241
Change From Baseline in 10-Meter Run/Walk (10MRW) Time in Ambulatory Participants up to Week 241	Baseline, up to Week 241
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	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	Baseline, Week 25
Change From Baseline in Blood Creatine Kinase (CK) Levels up to Week 241 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25	Baseline, up to Week 241
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	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	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	Baseline, Week 49
Change From Baseline in Blood CK Levels up to Week 241 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49	Baseline, up to Week 241
Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 241	Baseline, up to Week 241	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.
Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 241	Baseline, up to Week 241	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.
Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 241	Baseline, up to Week 241
Change From Baseline in Stride Velocity 95th Centile (SV95C) in Ambulatory Participants up to Week 241	Baseline, up to Week 241
Maximum Observed Plasma Drug Concentration of DYNE-251 (Cmax)	Through study completion, up to Week 241
Time to Maximum Observed Plasma Drug Concentration of DYNE-251 (tmax)	Through study completion, up to Week 241
Area Under the Plasma Drug Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration of DYNE-251 in Plasma (AUC0-tlast)	Through study completion, up to Week 241
Area Under the Plasma Drug Concentration Versus Time Curve From Time 0 (Dosing) Extrapolated to Time Infinity of DYNE-251 (AUC∞)	Through study completion, up to Week 241
Apparent Terminal Phase Elimination Rate Constant of DYNE-251 in Plasma (λz)	Through study completion, up to Week 241
Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½)	Through study completion, up to Week 241
Total Body Clearance (CL) of DYNE-251	Through study completion, up to Week 241
Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz)	Through study completion, up to Week 241
Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss)	Through study completion, up to Week 241
Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue	Through study completion, up to Week 241
Percentage of Participants With Antidrug Antibodies (ADAs)	Through study completion, up to Week 241

Trial Locations

Locations (30)

UPMC Children's Hospital of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of California San Diego; 🇺🇸 La Jolla, California, United States

UCLA; 🇺🇸 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

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Shriners Hospitals for Children Portland; 🇺🇸 Portland, Oregon, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

University of Utah - PPDS; 🇺🇸 Salt Lake City, Utah, United States

Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States

Children's Hospital at Westmead; 🇦🇺 Westmead, New South Wales, Australia

Murdoch Children's Research Institute; 🇦🇺 Parkville, Victoria, Australia

UZ Gent; 🇧🇪 Gent, Belgium

UZ Leuven; 🇧🇪 Leuven, Belgium

CHR Citadelle; 🇧🇪 Liège, Belgium

Children's and Women's Health Centre of British Columbia; 🇨🇦 Vancouver, British Columbia, Canada

London Health Sciences Centre; 🇨🇦 London, Ontario, Canada

Children's Hospital of Eastern Ontario; 🇨🇦 Ottawa, Ontario, Canada

CHI [Children's Health Ireland] at Temple Street Children's University Hospital; 🇮🇪 Dublin, Ireland

Fondazione Policlinico Universitario A Gemelli; 🇮🇹 Rome, Lazio, Italy

Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN; 🇮🇹 Genova, Liguria, Italy

Fondazione Serena Onlus - Centro Clinico NeMO; 🇮🇹 Milan, Lombardia, Italy

Ospedale San Raffaele S.r.l. - PPDS; 🇮🇹 Milan, Lombardia, Italy

Hospital Universitario Vall d'Hebron - PPDS; 🇪🇸 Barcelona, Spain

Hospital Sant Joan de Déu Universidad de Barcelona; 🇪🇸 Barcelona, Spain

Alder Hey Children's Hospital; 🇬🇧 Liverpool, Merseyside, United Kingdom

Royal Victoria Infirmary; 🇬🇧 Newcastle Upon Tyne, Northumberland, United Kingdom

Leeds Teaching Hospitals NHS Trust; 🇬🇧 Leeds, West Yorkshire, United Kingdom

Great Ormond Street Hospital; 🇬🇧 London, United Kingdom