Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy

Abstract

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein.Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2.Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (−0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved.Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1‐Year Interim Results from Study SRP‐9001‐103 (ENDEAVOR)

“…The commercial process material was designed to enable large‐scale production under good manufacturing practice conditions for concentration, purity, biosafety, and potency within pre‐defined windows for a drug lot to be released, thus ensuring quality and consistency. The safety and efficacy profile of the commercial process material in ENDEAVOR cohort 1 was consistent with what has been observed with the clinical process material, used in SRP‐9001‐101 10,40 and SRP‐9001‐102 41 . Most TR‐TEAEs were mild to moderate in severity.…”

“…ENDEAVOR cohort 1 data, collected as early as 12 weeks post-treatment, demonstrated robust transduction of target muscle, and corresponding expression and sarcolemmal localization of delandistrogene moxeparvovec micro-dystrophin that is likely to continue beyond 12 weeks at equivalent levels, as observed in SRP-9001-102. 41 In accordance with this micro-dystrophin expression, functional assessments following treatment with delandistrogene moxeparvovec showed rapid and sustained improvement over 1 year. The increases in NSAA total score observed in cohort 1 of ENDEAVOR were similar to those reported for SRP-9001-101 at year 1.…”

“…Notably, the improvement on NSAA observed in patients treated with delandistrogene moxeparvovec in SRP‐9001‐101 has been maintained for >4 years, with a mean patient age of >9 years 40 . Furthermore, in SRP‐9001‐102, delandistrogene moxeparvovec stabilized motor function for up to 2 years post‐treatment 41 . Collectively, the delandistrogene moxeparvovec micro‐dystrophin expression and functional outcomes data show that this micro‐dystrophin may stabilize the sarcolemma, thereby preserving muscle function and consequently improving the disease course in patients with DMD.…”

“…The safety and efficacy profile of the commercial process material in ENDEAVOR cohort 1 was consistent with what has been observed with the clinical process material, used in SRP-9001-101 10,40 and SRP-9001-102. 41 Most TR-TEAEs were mild to moderate in severity. A total of 84% of TR-TEAEs resolved; there were no new safety signals identified in cohort 1 and none associated with clinically relevant complement activation.…”

“…40 Furthermore, in SRP-9001-102, delandistrogene moxeparvovec stabilized motor function for up to 2 years post-treatment. 41 Collectively, the delandistrogene moxeparvovec micro-dystrophin expression and functional outcomes data show that this micro-dystrophin may stabilize the sarcolemma, thereby preserving muscle function and consequently improving the disease course in patients with DMD.…”