Clinical trial NCT05524883: Safety, Tolerability, Pharmacodynamic, Efficacy, and Pharmacokinetic Study of DYNE-251 in Participants With Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Duchenne Muscular Dystrophy (DMD)
Lead sponsor: Dyne Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-09-01
Enrollment: 86
Sex: MALE
Minimum age (years): 4
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Through study completion, up to Week 241
measure: Change From Baseline in Dystrophin Protein Levels in Muscle Tissue at Week 25
timeFrame: Baseline, Week 25
Secondary outcomes:
measure: 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
timeFrame: Baseline, Week 25
measure: 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
timeFrame: Baseline, Week 25
measure: 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
timeFrame: Baseline, up to Week 241
measure: 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
timeFrame: Baseline, Week 49
measure: 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
timeFrame: Baseline, Week 49
measure: Change From Baseline in Muscle Tissue PDPF at Week 49 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49
timeFrame: Baseline, Week 49
measure: 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
timeFrame: Baseline, up to Week 241
measure: Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 241
timeFrame: Baseline, up to Week 241
measure: Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 241
timeFrame: Baseline, up to Week 241
measure: Change From Baseline in 10-Meter Run/Walk (10MRW) Time in Ambulatory Participants up to Week 241
timeFrame: Baseline, up to Week 241
measure: Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 241
timeFrame: Baseline, up to Week 241
measure: Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 241
timeFrame: Baseline, up to Week 241
measure: Change From Baseline in Stride Velocity 95th Centile (SV95C) in Ambulatory Participants up to Week 241
timeFrame: Baseline, up to Week 241
measure: Maximum Observed Plasma Drug Concentration of DYNE-251 (Cmax)
timeFrame: Through study completion, up to Week 241
measure: Time to Maximum Observed Plasma Drug Concentration of DYNE-251 (tmax)
timeFrame: Through study completion, up to Week 241
measure: Area Under the Plasma Drug Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration of DYNE-251 in Plasma (AUC0-tlast)
timeFrame: Through study completion, up to Week 241
measure: Area Under the Plasma Drug Concentration Versus Time Curve From Time 0 (Dosing) Extrapolated to Time Infinity of DYNE-251 (AUC∞)
timeFrame: Through study completion, up to Week 241
measure: Apparent Terminal Phase Elimination Rate Constant of DYNE-251 in Plasma (λz)
timeFrame: Through study completion, up to Week 241
measure: Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½)
timeFrame: Through study completion, up to Week 241
measure: Total Body Clearance (CL) of DYNE-251
timeFrame: Through study completion, up to Week 241
measure: Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz)
timeFrame: Through study completion, up to Week 241
measure: Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss)
timeFrame: Through study completion, up to Week 241
measure: Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue
timeFrame: Through study completion, up to Week 241
measure: Percentage of Participants With Antidrug Antibodies (ADAs)
timeFrame: Through study completion, up to Week 241
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: UCLA University California of Los Angeles
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Rare Disease Research, LLC
state: Georgia
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Shriners Hospitals for Children Portland
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah - PPDS
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Parkville
country: Australia
facility: Murdoch Children's Research Institute
state: Victoria
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: CHR Citadelle
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Dublin
country: Ireland
facility: CHI [Children's Health Ireland] at Temple Street Children's University Hospital
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario A Gemelli
state: Lazio
city: Milan
country: Italy
facility: Fondazione Serena Onlus - Centro Clinico NeMO
state: Lombardia
city: Milan
country: Italy
facility: Ospedale San Raffaele S.r.l. - PPDS
state: Lombardia
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Teugbyeolsi
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu Universidad de Barcelona
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital
state: Merseyside
city: Newcastle Upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
state: Northumberland
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
state: West Yorkshire
city: Bristol
country: United Kingdom
facility: Bristol Childrens Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
References: