IV WVE-N531 treatment to raise dystrophin in Duchenne patients amenable to exon 53 skipping

An Open-label Phase 1b/2 Study of WVE-N531 in Patients With Duchenne Muscular Dystrophy

We will try IV WVE-N531 in people with Duchenne who have DMD mutations that can be treated by exon 53 skipping to see if it raises dystrophin and is safe and tolerable.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 26 (estimated)
• Ages: 4 Years to 18 Years
• Sex: Male
• Sponsor: Wave Life Sciences Ltd. (Industry-sponsored)
• Locations: 5 sites (Little Rock, Arkansas and 4 other locations)
• Trial ID: NCT04906460 on ClinicalTrials.gov

What this trial studies

This is an open-label Phase 1b/2 program giving intravenous WVE-N531 to males with Duchenne muscular dystrophy whose DMD mutations are amenable to exon 53 skipping. The trial has sequential parts (A and B completed, optional B extension, and a newly added Part C) with dosing initially every other week then switched to every four weeks; muscle biopsies are taken at baseline and after specified treatment intervals to measure dystrophin. Primary endpoints in Parts B and C are dystrophin protein levels, with ongoing safety, tolerability, digital and functional outcome monitoring and safety follow-up for up to 10 months after the last dose. Part C will enroll up to 15 new patients and includes open muscle biopsy at baseline and after 24 weeks of treatment.

Who should consider this trial

Good fit: Male patients with clinical DMD and a documented DMD gene mutation amenable to exon 53 skipping who have adequate cardiac and pulmonary function and can undergo open muscle biopsies are ideal candidates.

Not a fit: Patients without an exon 53–amenable DMD mutation, those with severe cardiopulmonary compromise, or those unable/unwilling to undergo muscle biopsies are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, WVE-N531 could increase dystrophin levels and potentially improve or slow muscle decline in patients with exon 53 amenable DMD mutations.

How similar studies have performed: Other exon-skipping antisense oligonucleotide approaches, including agents targeting exon 53, have produced modest increases in dystrophin but limited definitive functional benefit, and WVE-N531 applies a novel chemistry to this established strategy.

Eligibility criteria

Inclusion Criteria:

Part A and Part B:

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 ).
5. Ambulatory or non-ambulatory male
6. Stable pulmonary and cardiac function, as measured by the following: (Part B):

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) and/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 ).

Part C

1. New patients to be screened for Part C.
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) .
5. Ambulatory male
6. Stable pulmonary and cardiac function, as measured by the following:

1\. Reproducible percent predicted forced vital capacity (FVC) ≥50%; 2. Left ventricular ejection fraction (LVEF) \>55% in patients as measured (and documented) by echocardiogram (ECHO) and/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 .

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 and Part C: Major surgery within 3 months prior to Day 1 or planned major surgery for any time during the study.
3. Part B: Diagnosis of active alcohol, cannabinoid, or other substance use disorder (except nicotine) within 6 months prior to the Screening visit
4. Part C: Any recreational substance use (including prescribed cannabinoids), with the exception of nicotine, irrespective of legality, within 2 months prior to Screening and/or unwilling to refrain from such use for the duration of the study.

Where this trial is running

Little Rock, Arkansas and 4 other locations

• Arkansas Children's Hospital — Little Rock, Arkansas, United States (Recruiting)
• Rare Disease Research LLC — Atlanta, Georgia, United States (Recruiting)
• Istiklal Hospital/ Clinical Research Unit — Amman, Jordan (Recruiting)
• The Specialty Hospital (TSH)/ Advanced Clinical Center — Amman, Jordan (Recruiting)
• Oxford Children's Hospital, Oxford University Hospitals NHS Foundation Trust — Headington, Oxford, United Kingdom (Recruiting)

Study contacts

• Study coordinator: Clinical Operations

Conditions Duchenne Muscular Dystrophy