Phase 2 Multiple-Ascending-Dose Study of SRP-5051 PPMO in Patients with DMD Amenable to Exon 51 Skipping: Part A Results


Clinical Trials

Poster Number: 45


Craig Campbell, MD, Schulich School of Medicine, University of Western Ontario, Katherine Mathews, MD, University of Iowa, Marc van de Rijn, Sarepta Therapeutics, Inc, Emanuel Palatinsky, Sarepta Therapeutics, Inc, Xiao Ni, Sarepta Therapeutics, Inc, Nanshi Sha, Sarepta Therapeutics, Inc, Ihor Sehinovych, Sarepta Therapeutics, Inc, Jon Tinsley, Sarepta Therapeutics, Inc, Jyoti Malhotra, PhD, Sarepta Therapeutics, Inc., Han Phan, MD, Rare Disease Research, LLC / UAB

Background: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are a next-generation chemistry platform in which a cell-penetrating peptide is conjugated to the PMO backbone, with the goal of increasing tissue penetration, exon skipping, and dystrophin production with less frequent dosing. SRP-5051 is an investigational PPMO designed to skip DMD exon 51. Objective: Here we report results from the Part A dose-finding phase of MOMENTUM (NCT04004065), an ongoing phase 2 study of SRP-5051. Methods: Patients amenable to exon 51 skipping (aged 7?21 years) received ascending doses of SRP-5051 (4, 10, 20, or 30 mg/kg) intravenously every 4 weeks. Primary endpoint was safety; other endpoints included exon skipping, dystrophin protein, and pharmacokinetics of each dose. Results: Eighteen patients were enrolled. At week 12, exon skipping for the 20- and 30-mg/kg cohorts was 2.57% and 10.79%, respectively (versus 0.26% and 1.62% at baseline), and mean dystrophin protein was 3.06% and 6.55% of normal (versus 0.17% and 0.92% at baseline); all patients in these cohorts experienced an increase in exon skipping and dystrophin production. Immunofluorescence results from the 30-mg/kg cohort showed correct localization of dystrophin to the sarcolemma. Overall, 17/18 (94.4%) patients experienced a treatment-emergent adverse event (TEAE); the majority were mild to moderate in severity. Ten (55.6%) patients experienced treatment-related TEAEs of hypomagnesemia (including 2 serious cases) prior to the implementation of magnesium monitoring and supplementation; most cases were mild to moderate, asymptomatic, and resolved with supplementation. No other safety concerns were identified. Conclusions: MOMENTUM Part A results show SRP-5051 increases exon skipping and dystrophin production and that the majority of TEAEs were mild to moderate in severity. All participants from Part A have been invited to enrol in Part B of MOMENTUM.