EMBARK Study Evaluates DMD Gene Therapy

This content originally appeared on our sister site, NeurologyLive.

Sarepta Therapeutics has launched the phase 3 EMBARK study (NCT05096221) to evaluate their gene therapy delandistrogene moxeparvovec (SRP-9001), for the potential treatment of Duchenne muscular dystrophy (DMD).¹

The trial design was presented by Francesco Muntoni, MD, chair, pediatric neurology, University College London Institute of Child Health and Great Ormond Street Hospital for Children, at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, March 13-16, Nashville, Tennessee.

Doug Ingram, president and chief executive officer, Sarepta, said in a statement that "The launch of the pivotal trial “represents the culmination of enormous effort and success from a research, development, and manufacturing perspective and is an extraordinarily important moment for the patient community and a leap forward in our effort to change the course of Duchenne."²

SRP-9001 uses the adeno-associated virus serotype rh74 (rAAVrh74) vector to deliver the micro-dystrophin-encoding gene to skeletal and cardiac muscle tissue.

The EMBARK study will enroll up to 120 patients, boys with a DMD mutation within exons 18-44 or 46-79. Participants must be ambulatory and between 4 to 8 years of age. Participants will be dosed with a single, intravenous dose of 1.33x10¹⁴ vs/kg.

The study was initiated in Novermber 2021 and will consist of 2, 52-week phases. Participants randomized to placebo will receive SRP-9001 in the second phase.

EMBARK is primarily assessing change in North Star Ambulatory Assessment (NSAA) total score from baseline to week 52. Secondary end points include micro-dystrophin protein expression at week 12 as measured by western blot and number of skills gained or improved at week 52 as measured by NSAA.

Investigators will also assess timed function tests such as Time to Rise, 100-Meter and 10-Meter Walk/Run, and 4-Stair Climb, as well as stride velocity as measured by a wearable device and Patient-Reported Outcomes.

Sarepta presented additional information from Study 101 (NCT03375164) that evaluated SRP-9001 at MDA 2022. This open-label trial evaluated a dose of 2x10¹⁴ vg/kg via peripheral arm vein in 4 ambulatory patients with DMD between the ages of 4 and 7 without preexisting AAVrh74 antibodies and a stable corticosteroid dose of ≥12 weeks.Participants were also given daily prednisolone, 1 mg/kg, at day 1 prior to gene delivery and also underwent a 30-day taper after infusion.³

SRP-9001 was well tolerated in this study with minimal adverse events (AEs). There were no serious AEs or discontinuations from the study after 3 years on SRP-9001. Treatment-emergent AEs, mild or moderate in severity, mostly occurred during the first 90 days post-infusion and were all resolved by the end of the study period.

Safety was the primary outcome, but investigators observed biomarker efficacy via secondary outcomes that included micro-dystrophin expression by Western blot and immunohistochemistry. Robust transgene expression in all patients was observed after 12 weeks, with a mean of 81.2% of muscle fiber micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment.

Notably, all patients had confirmed vector transduction and showed functional improvement of NSAA at posttreatment compared with baseline that was maintained for 1 year. All 4 patients demonstrated general improvements in functional measures compared with baseline that appeared to me maintained 3 years after infusion.

Led by Jerry Mendell, MD, neurologist, Nationwide’s Children Hospital, the study authors concluded that these new findings provide proof-of-concept support for the continuation of trials looking at SRP-9001 in patients with DMD.⁴

REFERENCES
1. Muntoni F, Mercuri E, Schara-Schmidt U, et al. EMBARK study design: phase 3 trial evaluating the safety and efficacy of delandistrogene moxeparvovec (SRP-9001) in Duchenne muscular dystrophy. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 28
2. Sarepta Therapeutics announces initiation of EMBARK, a global pivotal study of SRP-9001, a gene therapy for the treatment of Duchenne muscular dystrophy. News release. Sarepta Therapeutics. November 4, 2021. Accessed March 14, 2022. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-initiation-embark-global-pivotal
3. Sarepta Therapeutics announces positive safety and efficacy data from the SRP-9001 micro-dystrophin gene therapy trial published in JAMA neurology. News release. Sarepta Therapeutics. June 15, 2020. Accessed March 14, 2022. globenewswire.com/news-release/2020/06/15/2048220/0/en/Sarepta-Therapeutics-Announces-Positive-Safety-and-Efficacy-Data-from-the-SRP-9001-Micro-Dystrophin-Gene-Therapy-Trial-Published-in-JAMA-Neurology.html
4. Mendell JR, Sahenk Z, Lehman KJ, et al. Phase 1/2a trial of delantistrogene moxeparvovec (SRP-9001) in patients with Duchenne muscular dystrophy: 3-year safety and functional outcomes. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 47