Long‐term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial

Abstract

Introduction/AimsDelandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long‐term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild‐type protein) expression may positively alter disease progression in patients with DMD. We evaluated long‐term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD.MethodsAn open‐label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 1014 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests.ResultsFour patients (mean age, 5.1 years) were enrolled. There were 18 treatment‐related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9‐point difference in NSAA score, relative to a propensity‐score–weighted external control cohort (least‐squares mean [standard error] = 9.4 [3.4]; P = .0125).DiscussionGene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.

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.…”

Sustained clinical benefit following systemic gene replacement therapy in Duchenne muscular dystrophy

“…The patients, who showed minimal side effects at the time of initial dosing, 6 continue to show significant and sustained improvements in their North Star Ambulatory Assessment (NSAA) scores compared with baseline values 4 years earlier. 5 The stability of their NSAA scores is particularly striking in contrast to those from well-matched, natural-history controls.…”

“…In this edition of Muscle and Nerve , Mendell et al 5 report four‐year follow‐up data for their cohort of DMD patients treated with intravenous (IV) delandistrogene moxeparvovec. The patients, who showed minimal side effects at the time of initial dosing, 6 continue to show significant and sustained improvements in their North Star Ambulatory Assessment (NSAA) scores compared with baseline values 4 years earlier 5 . The stability of their NSAA scores is particularly striking in contrast to those from well‐matched, natural‐history controls.…”

“…Long‐term follow‐up studies such as that provided by Mendell et al 5 are critical to reassuring physicians as to the longer‐term safety and sustained clinical efficacy of gene therapy in DMD patients. The sustained benefit of this DMD cohort parallels similar reassuring longer‐term efficacy data that have been reported for children with SMA 13 …”

“…2,3 Further engineering of the AAV capsid shows promise for enhancing muscle and reducing liver-targeting in preclinical models of DMD. 4 Skeletal muscle, a post-mitotic tissue whose regeneration and repair is mediated by satellite cells 3 In this edition of Muscle and Nerve, Mendell et al 5 report fouryear follow-up data for their cohort of DMD patients treated with intravenous (IV) delandistrogene moxeparvovec. The patients, who showed minimal side effects at the time of initial dosing, 6 continue to show significant and sustained improvements in their North Star Ambulatory Assessment (NSAA) scores compared with baseline values 4 years earlier.…”