PBGENE-DMD Phase 1/2a Safety and Preliminary Efficacy Study in Duchenne Muscular Dystrophy (FUNCTION-DMD)

A Phase 1/2a, Multi-center, Open-label Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of PBGENE-DMD in Participants With Duchenne Muscular Dystrophy (FUNCTION-DMD)

The purpose of this Phase 1/2a trial is to evaluate the safety, tolerability, and preliminary efficacy of PBGENE-DMD in patients with DMD harboring mutations amenable to excision of exons 45-55. Given the limitations of existing therapeutic strategies, PBGENE-DMD represents a novel, innovative approach with the potential for a one-time, durable correction of the underlying genetic defect in the largest molecular subset of patients with DMD.

This is a Phase 1/2a, open-label, multicenter trial designed to evaluate the safety, tolerability, and primary efficacy of a single IV dose of PBGENE-DMD in male participants with DMD presenting with mutations that may be amenable to treatment with PBGENE-DMD. A structured, multimodal, short-term immunomodulatory regimen will be administered around the time of dosing to mitigate the risk of potential immune-mediated responses.

The trial consists of two parts: Part 1 is to confirm a safe and well-tolerated single dose of PBGENE-DMD that may be further evaluated in Part 2 (expansion).

A total of up to 18 participants may be enrolled in this trial. Total duration of trial participation for each participant: approximately 130 weeks.

Inclusion Criteria:

1. Males, 2 to 7 years of age, inclusive, at the time of informed consent/assent

2. Molecular confirmed DMD diagnosis (DMD mutation fully contained between exons 45 to 55 [inclusive])

3. Clinical phenotype consistent with DMD in the opinion of the Investigator

4. Ability to complete age-appropriate motor testing assessments requirements.

   Participants aged 2 to < 4 years at the time of screening must:

   1. Be able to walk at least 10 meters independently (without assistive devices).

   2. Be able to rise from the floor without physical assistance (use of a Gowers' maneuver is acceptable).

      Participants aged 4 to 7 years at the time of screening must:

   3. Be able to walk at least 100 meters independently (without assistive devices).

   4. Have an NSAA total score between 16 and 29, inclusive.

5. Participant has received age-appropriate routine childhood immunizations per the local country's national immunization schedule.

6. The participant's parent(s)/LAR(s) are willing and able to provide written informed consent prior to the initiation of any trial-specific procedures; where applicable, the participant must provide written or verbal assent in accordance with local regulations.

7. The participant and their parent(s)/LAR(s) are willing to participate in a LTFU study after the completion of this trial.

Exclusion Criteria:

1. Prior treatment with any gene therapy, gene editing therapy, or cell-based therapy at any time.
2. Receipt of any investigational medication or experimental therapy within 6 months prior to Day 1.
3. Prior or ongoing use of any product designed to increase dystrophin expression, investigational, or otherwise, including exon-skipping therapies, within 6 months of the scheduled Day 1 dose or inability or unwillingness to refrain from initiating or resuming these therapies for at least 5 years following gene therapy administration.
4. Prior ongoing use of any product designed to increase dystrophin expression, investigational, or otherwise, including exon-skipping therapies, within 6 months of the scheduled Day 1 dose.
5. Concurrent enrollment in another clinical trial, unless it is observational (non-interventional).
6. A positive test for antibodies to AAV9
7. A participant has any condition that would contraindicate treatment with immunosuppression.
8. Participants with pathogenic mutations in exons 1-44 and/or exons 56-79.
9. Evidence of cardiomyopathy or clinically significant left ventricular dysfunction, defined as LVEF <50% on screening echocardiogram.