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

• ClinicalTrials.gov Identifier: NCT05524883
• Recruitment Status: Recruiting
• First Posted: September 1, 2022
• Last Update Posted: May 7, 2024
• Sponsor: Dyne Therapeutics
• Information provided by (Responsible Party): Dyne Therapeutics

Tracking Information

• First Submitted Date: August 30, 2022
• First Posted Date: September 1, 2022
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: August 12, 2022
• Estimated Primary Completion Date: November 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 30, 2022)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 6, 2024)

• 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 145 For Participants Dosed at Q4W or Q8W Interval With a Second Biopsy Performed at Week 25 [ Time Frame: Baseline, up to Week 145 ]
• 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 145 For Participants Dosed at Q8W Interval With a Second Biopsy Performed at Week 49 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, 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.
• Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in 10-Meter Run/Walk (10MRW) Time in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 145 [ Time Frame: Baseline, 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.
• Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in Stride Velocity 95th Centile (SV95C) in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Maximum Observed Plasma Drug Concentration of DYNE-251 (Cmax) [ Time Frame: Through study completion, up to Week 145 ]
• Time to Maximum Observed Plasma Drug Concentration of DYNE-251 (tmax) [ Time Frame: Through study completion, up to Week 145 ]
• 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 145 ]
• 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 145 ]
• Apparent Terminal Phase Elimination Rate Constant of DYNE-251 in Plasma (λz) [ Time Frame: Through study completion, up to Week 145 ]
• Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½) [ Time Frame: Through study completion, up to Week 145 ]
• Total Body Clearance (CL) of DYNE-251 [ Time Frame: Through study completion, up to Week 145 ]
• Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz) [ Time Frame: Through study completion, up to Week 145 ]
• Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss) [ Time Frame: Through study completion, up to Week 145 ]
• Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue [ Time Frame: Through study completion, up to Week 145 ]
• Percentage of Participants With Antidrug Antibodies (ADAs) [ Time Frame: Through study completion, up to Week 145 ]

Original Secondary Outcome Measures (submitted: August 30, 2022)

• Change From Baseline in Muscle Tissue Exon 51 Skipping Levels at Week 25 [ Time Frame: Baseline, Week 25 ]
• Change From Baseline in Muscle Tissue Percent Dystrophin-Positive Fiber (PDPF) at Week 25 [ Time Frame: Baseline, Week 25 ]
• Change From Baseline in Blood Creatine Kinase (CK) Levels up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, 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.
• Change From Baseline in Time to Rise From Floor in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in 10-Meter Run/Walk (10-MRW) Time in Ambulatory Participants up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Change From Baseline in Performance Upper Limb (PUL) Scale Version 2.0 Score up to Week 145 [ Time Frame: Baseline, 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.
• Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) up to Week 145 [ Time Frame: Baseline, up to Week 145 ]
• Maximum Observed Drug Concentration of DYNE-251 in Plasma (Cmax) [ Time Frame: Through study completion, up to Week 145 ]
• Time to Maximum Concentration of DYNE-251 in Plasma (tmax) [ Time Frame: 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) [ Time Frame: Through study completion, up to Week 145 ]
• AUC Extrapolated to Infinity of DYNE-251 in Plasma (AUC∞) [ Time Frame: Through study completion, up to Week 145 ]
• Apparent Terminal Elimination Rate Constant of DYNE-251 in Plasma (λz) [ Time Frame: Through study completion, up to Week 145 ]
• Apparent Terminal Elimination Half-Life of DYNE-251 in Plasma (t½) [ Time Frame: Through study completion, up to Week 145 ]
• Clearance (CL) of DYNE-251 in Plasma [ Time Frame: Through study completion, up to Week 145 ]
• Volume of Distribution at the Terminal Phase of DYNE-251 in Plasma (Vz) [ Time Frame: Through study completion, up to Week 145 ]
• Volume of Distribution at Steady State of DYNE-251 in Plasma (Vss) [ Time Frame: Through study completion, up to Week 145 ]
• Tissue Phosphorodiamidate Morpholino Oligomer (PMO) Concentration of DYNE-251 in Muscle Tissue [ Time Frame: Through study completion, up to Week 145 ]
• Percentage of Participants With Antidrug Antibodies (ADAs) [ Time Frame: Through study completion, up to Week 145 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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 period (96 weeks).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy (DMD)

Intervention

• Drug: DYNE-251
  Administered by IV infusion
• Drug: Placebo
  Administered by IV infusion

Study Arms

• Experimental: Placebo-Controlled MAD Period - DYNE-251
  DYNE-251 will be administered once every 4 weeks (Q4W) or once every 8 weeks (Q8W) over 24 weeks.
  Intervention: Drug: DYNE-251
• Experimental: Placebo-Controlled MAD Period - Placebo
  Placebo will be administered Q4W or Q8W over 24 weeks.
  Intervention: Drug: Placebo
• Experimental: Open-Label and Long-Term Extension Period - DYNE-251
  DYNE-251 will be administered Q4W or Q8W for up to 96 weeks after participants complete the Placebo-Controlled MAD Period of the study.
  Intervention: Drug: DYNE-251

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 6, 2024): 88
• Original Estimated Enrollment (submitted: August 30, 2022): 46
• Estimated Study Completion Date: November 2026
• Estimated Primary Completion Date: November 2026 (Final data collection date for primary outcome measure)

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 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 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.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes

• Ages: 4 Years to 16 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Dyne Clinical Trials; +1-781-317-1919; clinicaltrials@dyne-tx.com

• Listed Location Countries: Australia, Belgium, Canada, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT05524883
• Other Study ID Numbers: DYNE251-DMD-201; 2021-005478-24 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Dyne Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Dyne Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Dyne Therapeutics
• Verification Date: May 2024