Gene Therapy Details Revealed in Duchenne Trial

SAVANNAH, Ga. — Delandistrogene moxeparvovec (Elevidys), a gene therapy approved to treat Duchenne muscular dystrophy, missed its primary endpoint but differences emerged in other functional outcomes, the phase III EMBARK trial showed.

The primary outcome was the change from baseline in North Star Ambulatory Assessment (NSAA) scores at 1 year. The NSAA measures 17 motor tasks; scores can range from 0 to 34, with the top score representing fully independent function.

At week 52, the mean change in NSAA score was 2.57 points for delandistrogene moxeparvovec and 1.92 points for placebo — a between-group difference of 0.65 points (95% CI -0.45 to 1.74, P=0.2441), said Jerry Mendell, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and co-authors in a poster presented at the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting. The findings also were published in Nature Medicine.

Duchenne muscular dystrophy is caused by pathogenic variants in the DMD gene that lead to a lack of functional dystrophin and muscle loss. Delandistrogene moxeparvovec delivers a gene that codes for a shortened form of dystrophin — an engineered protein called micro-dystrophin — to help preserve muscle. It is administered as a single-dose recombinant adeno-associated virus rhesus isolate serotype 74 (rAAVrh74) vector-based gene transfer therapy.

After an initial accelerated approval decision in 2023, delandistrogene moxeparvovec received full FDA approval in June 2024 to treat ambulatory or non-ambulatory patients ages 4 years and older with a confirmed DMD gene mutation. As a condition of accelerated approval, the agency required drugmaker Sarepta Therapeutics to complete a study confirming the drug’s clinical benefit. In October 2023, Sarepta said the confirmatory EMBARK trial did not meet its primary endpoint.

In his decisional memo, however, Peter Marks, MD, PhD, director of the FDA Center for Biologics Evaluation and Research, said that full approval was supported “based on the totality of the evidence,” and that several secondary endpoints in EMBARK and other studies were above minimal clinical important difference thresholds.

The findings presented at AANEM represented part 1 of the EMBARK trial. Part 2 is an open-label, crossover design study conducted for 5 years.

EMBARK randomized 125 ambulatory boys with Duchenne ages 4 to 7 years old to either a single-administration of intravenous delandistrogene moxeparvovec (1.33 × 10¹⁴ vector genomes per kg) or placebo. Mean age was about 6, and mean baseline NSAA score was 22.96 points.

At week 52, between-group differences in two key secondary outcomes — time to rise (TTR; -0.64 seconds, 95% CI -1.06 to -0.23) and the 10-meter walk/run (10MWR; -0.42 seconds (95% CI -0.71 to -0.13) — favored delandistrogene moxeparvovec.

“The separation between groups was clinically relevant for both TTR and 10MWR,” Mendell and co-authors noted.

Some other secondary endpoints numerically favored the treatment group, but were not significant. However, a pre-specified global statistical test on a composite of six functional endpoints showed a difference between delandistrogene moxeparvovec and placebo (P=0.0044), which “indicated the presence of a functional treatment effect,” the researchers said.

“Although delandistrogene moxeparvovec did not show a statistically significant difference in the primary endpoint of change from baseline to week 52 in NSAA total score versus placebo, there was a clear separation between treatment groups, most evident on key secondary and other functional endpoints that consisted of well-validated measures of ambulatory function in DMD,” they reported.

In the trial, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 were recorded with placebo. In the delandistrogene moxeparvovec group, 76.2% of participants had treatment-related, treatment-emergent adverse events. Most (83.3%) were mild to moderate, and 98.3% of those resolved.

Seven boys (11.1%) who received delandistrogene moxeparvovec experienced treatment-related serious adverse events, including acute liver injury, myocarditis, nausea, vomiting, pyrexia, and rhabdomyolysis. All were resolved. There were no deaths, discontinuations, or clinically significant complement-mediated adverse events.

“No new safety signals have been identified,” said co-author Louise Rodino-Klapac, PhD, of Sarepta Therapeutics. “Furthermore, everything we’re seeing in the commercial setting reinforces that the safety profile remains consistent regardless of age, weight, or ambulatory status,” she told MedPage Today.

“In new data presented at the World Muscle Society last week, long-term 5-year outcomes demonstrated continuation of the trend detected at earlier timepoints, with dramatically widening divergence from the expected course of disease over time,” she noted.

Two new MRI analyses of EMBARK participants also showed positive results, Rodino-Klapac observed. “The first found no evidence of harmful impacts on the heart from Elevidys,” she said.

“The second looked at multiple muscles using MRI, [magnetic resonance spectroscopy], and MRI T2,” she added. “Across all measures, we saw an improvement compared to placebo. This stabilization or improvement in fibrosis or fat accumulation at 1 year correlates with functional improvement.”

Potential study limitations in EMBARK included the placebo group being limited to 1 year due to ethical concerns about withholding disease-modifying treatment from Duchenne patients. The trial was blinded, but because vomiting and nausea were common adverse events soon after infusion, patients and caregivers may have become aware of treatment assignments.

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