Open-label Study of WVE-N531 in Patients with Duchenne Muscular Dystrophy (FORWARD-53)

This is a Phase 1b/2 open-label study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical effects of intravenous (IV) WVE-N531 in patients with Duchenne muscular dystrophy (DMD). To participate in the study, patients must have a documented mutation of the DMD gene that is amenable to exon 53 skipping intervention. This study has 2 parts, Part A and Part B. Part A is completed. Part B is completed. Following completion of Part B, all patients have elected to continue to receive study drug in an optional open-label extension arm.

Following completion of Part A, eligible patients rolled over into Part B to continue to receive treatment. In addition, new patients were enrolled up to a total of 11 patients in Part B. All patients received WVE-N531 at 10 mg/kg every other week (Q2W) until competent authority approval of a protocol update, when all patients were switched to Q4W dosing. Muscle biopsies were performed following 24 weeks and for new Part B patients (those that did not take part in Part A) following 48 weeks of treatment. Following completion of Part B, all patients elected to continue to receive study drug at Q4W for up to 1 year in an optional open-label extension arm.

The primary endpoint is dystrophin protein levels and participants will also be evaluated for safety, tolerability, digital and functional endpoints. Safety monitoring will occur through 10 months after the last dose.

Eligibility Criteria:
Inclusion Criteria:

1. Part A patients may be screened for Part B upon completion of a washout period of ≥18 weeks from last dose in Part A. New patients may also be screened for Part B
2. Diagnosis of DMD based on clinical phenotype .
3. Documented mutation in the DMD gene associated with DMD that is amenable to exon 53 intervention
4. Score of ≥1 on item 1 or 2 of the shoulder component of the Performance of the Upper Limb (PUL) (Part B only)
5. Ambulatory or non-ambulatory male
6. Stable pulmonary and cardiac function, as measured by the following: (Part B only)

   1. Reproducible percent predicted forced vital capacity (FVC) ≥50%;
   2. Left ventricular ejection fraction (LVEF) \>55% in patients \<10 years of age and \>45% in patients ≥10 years of age, as measured (and documented) by echocardiogram (ECHO) or cardiac magnetic resonance imaging (MRI), within 6 months prior to enrollment into the study.
7. Adequate muscle at Screening to perform open muscle biopsies, preferably deltoid.
8. Currently on a stable corticosteroid therapy regimen, defined as initiation of systemic corticosteroid therapy that occurred ≥6 months prior to Screening and no changes in dose ≤3 months prior to Screening visit (Part B only).

Exclusion Criteria:

1. Clinically significant medical finding on the physical examination other than DMD that, in the judgment of the Investigator, will make the patient unsuitable for participation in, and/or completion of the study procedures.
2. Part B Specific: Major surgery within 3 months prior to Day 1 or planned major surgery for any time during the study.
3. Part B Specific: Diagnosis of active alcohol, cannabinoid, or other substance use disorder (except nicotine) within 6 months prior to the Screening visit.