ELEVIDYS Study Fails Primary End Point in DMD, Secondary End Points Show Statistically Significant Benefit


Despite the announcement, CEO Doug Ingram shared that the company is seeking a wider approval for delandistrogene moxeparvovec-rokl regardless of age or ambulatory status.

Dough Ingram, president and chief executive officer, Sarepta

Doug Ingram

Sarepta Therapeutics’ global, pivotal, phase 3 EMBARK study (Study SRP-9001-301; NCT05096221) of delandistrogene moxeparvovec-rokl gene therapy, marketed as ELEVIDYS, in children with Duchenne muscular dystrophy (DMD) has failed its primary end point according to new topline data.1

The EMBARK study’s key primary end point was change in North Star Ambulatory Assessment (NSAA) scores at week 52 compared to placebo, the difference in which was not statistically significant. Treated patients improved 2.6 points on NSAA total score compared to 1.9 points in placebo-treated patients for a 0.65-point difference (n=125; P =.24). Key secondary end points of change in time to rise (TTR) and 10-meter walk test (10MWT) compared to placebo were statistically significant across all age groups.

“First of all, every EMBARK measure favors this therapy ELEVIDYS. Every key secondary end point is strongly statistically significant, as are all of the age subgroup analyses in the key secondary end points, even though they were not in fact powered to be statistically significant. Across all of the end points that most powerfully predict loss of ambulation (TTR, 10MWT, 4-stair climb), ELEVIDYS is powerfully statistically significant,” Doug Ingram, president and chief executive officer, Sarepta, said during a conference call on the new data. "On the issue of clinical meaningfulness, literature notes arise time that slows beyond 5 seconds is the single most predictive metric for early loss of ambulation and ELEVIDYS reduces those odds by literally over 90%. While we did not hit statistical significance on NSAA, it is clear, you can look at the curves and see it, this is because NSAA was simply not as sensitive as the various time tests and indeed, too insensitive to pick up a decline in the 6-7-year-old age group in 52 weeks and every other timed metric detected in these degenerating boys.”

Key Takeaways

  1. Delandistrogene moxeparvovec-rokl (ELEVIDYS) gene therapy for Duchenne muscular dystrophy did not meet its primary end point but showed significant improvements in secondary end points like TTR and 10MWT.
  2. ELEVIDYS received FDA accelerated approval for children aged 4-5 years, and further evaluation for those aged 4-7 years is ongoing.
  3. Although NSAA scores didn't reach significance, ELEVIDYS effectively reduces functional decline, possibly allowing age and ambulation restrictions to be reconsidered.

Delandistrogene moxeparvovec-rokl, which Roche has commercial rights to, was approved under the accelerated approval pathway under the name ELEVIDYS for children aged 4-5 years with DMD in June 2023 based on data from Study 102 (NCT03769116), Study 103 (ENDEAVOR; NCT04626674), and Study 101 (NCT03375164).2 Study 102 similarly failed its primary NSAA end point although subgroup analyses revealed the strongest clinical benefit in boys aged 4-to-5 years, supporting the approval in only that narrow population. Notably, the EMBARK study is still evaluating the therapy in children aged 4-to-7 years. ELEVIDYS uses the adeno-associated virus AAVrh74 recombinant vector to deliver microdystrophin and is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.

READ MORE: Genetic Medicine in DMD: End Points, Assessment, and Approvals

At 52 weeks, investigators found that on TTR, the least squares mean (LSM) difference was -0.64 (n = 124; P = .0025) between treated patients and placebo in all ages, -0.5 (n = 59; P = .0177) between patients aged 4-to-5 years, and -0.78 (n = 65; P = .0291) in patients aged 6-to-7 years. Similarly, on 10MWT, LSM difference was -0.42 (P = .0048) in all patients, -0.33 (P = .0319) in patients aged 4-to-5 years, and -0.52 (P = .0363) in patients aged 6-to-7 years. Although more detailed data are yet to be shared, Sarepta stated that all other timed functional end points, including stride velocity 95th centile (SV95C) and time to ascend 4 steps, demonstrated a consistent trend in treatment benefit in favor of ELEVIDYS.

“The strong prognostic power of time to rise, and the particular importance of the 5-second milestone in predicting functional decline and future loss of ambulation, is clearly demonstrated in natural history. In EMBARK, the reduction in patients progressing past this milestone when treated with ELEVIDYS is highly clinically relevant,” EMBARK investigator Craig McDonald, MD, professor and chair, UC Davis Health Department of Physical Medicine and Rehabilitation, said in a statement.1 “The consistency of the positive effect across all timed function tests and age groups provides evidence of a meaningful treatment effect. In addition, it is important to note that this is the first clinical trial in the history of DMD trials to show a statistically significant and meaningful improvement on the novel measure of 95th centile stride velocity derived from an objective community wearable activity monitor.”

There were no new safety signals in the EMBARK study and the most common treatment-related adverse events (AEs) continue to be gastrointestinal events such as vomiting, nausea, and decreased appetite; and pyrexia. Seven participants (11.1%) experienced a serious AE related to treatment.

“The point of EMBARK was to prove that this mechanism of action works and there's nothing unusual about it that would make it work better in 4-to-5s than it would in 6-to-7s or 8-to-9s or 10-to-11s that or nonambulatory [patients]. So long as a person has muscle they can be protected; they can benefit from ELEVIDYS,” Ingram said during the call. “On that basis, the conversations we've had with [the FDA] is that we believe that the ambulation restrictions and the age restrictions should be removed, as they do not exist in other Duchenne therapies that have been approved.”

1. Sarepta Therapeutics announces topline results from EMBARK, a global pivotal study of ELEVIDYS gene therapy for Duchenne muscular dystrophy. News release. Sarepta Therapeutics. October 30, 2023. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-topline-results-embark-global-0
2. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. News release. Sarepta Therapeutics. June 22, 2023. Accessed October 30, 2023. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene
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