Sarepta Therapeutics' gene therapy Elevidys (delandistrogene moxeparvovec) failed to meet its primary endpoint in the Phase 3 EMBARK trial, a study evaluating its efficacy in treating Duchenne muscular dystrophy (DMD). The results, published in Nature Medicine, revealed that the gene therapy did not significantly improve motor function after 52 weeks compared to placebo, despite prior FDA approval for the treatment.
The EMBARK trial, a randomized, double-blind, placebo-controlled study, involved 125 patients with DMD. Sixty-three patients received delandistrogene moxeparvovec, while 62 received a placebo. After 52 weeks, patients treated with the gene therapy showed a 2.6-point improvement on the North Star Ambulatory Assessment (NSAA) compared to a 1.9-point improvement in the placebo group. However, this difference of 0.65 points (95% CI, –0.45 to 1.74; P = .2441) was not statistically significant.
According to the researchers, the heterogeneity of disease progression in DMD poses a significant challenge in clinical trial design, particularly for short-duration studies. They noted that motor function in patients aged 4-7 years can be variable, with some still improving, others maintaining, and some beginning to decline. The daily use of corticosteroids by patients in the study may have also masked the treatment's potential benefits, as corticosteroids can improve short-term muscle strength and function.
Secondary Endpoint Analysis
While the primary endpoint was not met, key secondary endpoints, including time to rise and the 10-meter walk test, showed improvements favoring delandistrogene moxeparvovec, although these did not reach statistical significance. At week 52, the least squares mean change from baseline in time to rise was -0.27 seconds (-0.56 to -0.02) for the gene therapy group compared to 0.37 seconds (0.08-0.67) for the placebo group, a difference of -0.64 seconds (95% CI; -1.06 to -0.23).
For the 10-meter walk test, the least squares mean change from baseline to 52 weeks was -0.34 seconds (-0.55 to -0.14) for patients receiving the gene therapy compared to 0.08 seconds (-0.13 to 0.29) for those receiving placebo, a difference of -0.24 seconds (95% CI; -0.71 to -0.13).
Safety Profile
Safety data from the EMBARK trial indicated that the safety profile of delandistrogene moxeparvovec was consistent with previous findings. There were 675 adverse events (AEs) reported after treatment with the gene therapy, compared to 514 with placebo. Treatment-related treatment-emergent AEs (TR-TEAEs) occurred in 76.2% of patients receiving the gene therapy, with the majority (83.3%) being mild to moderate in severity and most (98.3%) resolving. Most TR-TEAEs occurred within 90 days of treatment.
"Results from EMBARK Part 1 confirmed that, at week 52, the safety profile of delandistrogene moxeparvovec is consistent with prior experience, and AEs were medically manageable with appropriate monitoring and treatment," the researchers stated. They added that immune reactions stimulated by the AAV vector are thought to be the primary cause of AEs in systemic AAV gene therapy, and each vector serotype may have a distinctive safety profile.
