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

Autor: Mendell JR; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA., Sahenk Z; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.; Departments of Pathology and Neurology, The Ohio State University, Columbus, Ohio, USA., Lehman KJ; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Lowes LP; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA., Reash NF; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Iammarino MA; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Alfano LN; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Lewis S; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA., Church K; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Shell R; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Potter RA; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA., Griffin DA; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA., Hogan M; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA., Wang S; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA., Mason S; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA., Darton E; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA., Rodino-Klapac LR; Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Muscle & nerve [Muscle Nerve] 2024 Jan; Vol. 69 (1), pp. 93-98. Date of Electronic Publication: 2023 Aug 14.
DOI: 10.1002/mus.27955
Abstrakt: Introduction/aims: Delandistrogene 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.
Methods: An 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 × 10 14 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.
Results: Four 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).
Discussion: Gene 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.
(© 2023 Sarepta Therapeutics Inc and The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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