424P Micro-dystrophin expression and safety with delandistrogene moxeparvovec gene therapy for DMD in a broad population: phase 1B trial (ENDEAVOR)

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Proud, C., Zaidman, C., McDonald, C., Day, J., Thrasher, P., Asher, D., Murphy, A., Guridi, M., Ding, K., Reid, C., Lewis, S., Magistrado-Coxen, P., Palatinsky, E., Wandel, C., Potter, R., Rodino-Klapac, L., Mendell, J.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.304

Delandistrogene moxeparvovec, an rAAVrh74-based gene transfer therapy designed to address absent functional dystrophin by delivering a transgene encoding engineered micro-dystrophin, is approved (US, UAE, Qatar, Kuwait, Bahrain, Oman; Mar 2024) for ambulatory pediatric patients (pts) aged 4 through 5 years (yrs) with Duchenne muscular dystrophy (DMD) with a confirmed DMD mutation. We report outcomes across 5 cohorts from the ENDEAVOR study (NCT04626674). Pts from Cohorts 1 (ambulatory; aged ≥4–<8 yrs), 2 (ambulatory; ≥8–<18 yrs), 3 (non-ambulatory), 4 (ambulatory; ≥3–<4 yrs) and 5 (mutations in DMD exons 1–17 [5a: ambulatory, ≥4–<9 yrs; 5b: non-ambulatory]) received single-dose intravenous delandistrogene moxeparvovec (1.33×10¹⁴ vg/kg [pts <70 kg] or 9.31×10¹⁵ vg total fixed dose [pts ≥70 kg]). Primary endpoint: change in micro-dystrophin expression from baseline to Week 12 by western blot. At time of infusion, pts were ambulatory (n=40) or non-ambulatory (n=8), aged 3.24–20.23 yrs and weighed 12.5–80.1 kg. The mean (SD) transduction at Week 12 was 2.93 (1.96) and 2.67 (0.92) vector genome copies per nucleus in ambulatory and non-ambulatory pts, respectively; mean (SD) delandistrogene moxeparvovec micro-dystrophin expression was 51.03% (46.95) and 40.06% (35.86), respectively. Overall, most common treatment-emergent adverse events (AEs) were vomiting (58.3%), nausea (47.9%), glutamate dehydrogenase increase (31.3%) and decreased appetite (31.3%); most were mild to moderate in severity. There were no deaths, study discontinuations or clinically relevant complement-mediated AEs. Mean transduction, expression and AEs experienced were comparable between ambulatory and non-ambulatory pts. The safety profile was manageable and consistent with the known population treated with delandistrogene moxeparvovec; no new safety concerns were observed in the broad ENDEAVOR population, including ambulatory and non-ambulatory pts, vs. the previously studied 4- to 7-yr pt population.