Sarepta Details Phase 3 EMBARK Study in DMD

Doug Ingram

Sarepta Therapeutics’ phase 3 EMBARK study (NCT05096221) is currently underway to evaluate delandistrogene moxeparvovec (SRP-9001), an investigational gene therapy for the treatment of Duchenne muscular dystrophy (DMD).¹

SRP-9001 is an adeno-associated virus serotype rh74 (rAAVrh74) gene transfer therapy intended to deliver the micro-dystrophin-encoding gene to skeletal and cardiac muscle tissue for the targeted production of the micro-dystrophin protein. Initiated in November 2021, EMBARK will assess the therapeutic in a targeted population of 120 ambulatory boys with a confirmed DMD mutation within exons 18-44 or 46-79, between ages 4 and 8 years old. Change in North Star Ambulatory Assessment (NSAA) total score from baseline to week 52 will serve as the primary end point.

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,” Doug Ingram, president and chief executive officer of Sarepta, said in a statement at the time.²

The study includes 2 parts, both of which are 52-weeks in length. In Part 1, patients will be randomized 1:1 to SRP-9001 or placebo, according to age at randomization (>4 to <6 years vs >6 to <8 years) and baseline NSAA (<22 points vs >22 points). As for dosing, a single, intravenous 1.33x1014 vs/kg linear standard dose of commercially representative SRP-9001 will be used.¹

Individuals randomized to placebo in Part 1 will receive the study drug in Part 2, with outcomes assessed after an additional 52 weeks of treatment. Secondary end points include micro-dystrophin protein expression at week 12 measured by western blot and the number of skills gained or improved at week 52 measured by NSAA. Additionally, other timed function tests such as Time to Rise, 100-Meter and 10-Meter Walk/Run, and 4-Stair Climb will be assessed.

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Investigators also plan to assess stride velocity 95th centile measured by a wearable device and Patient-Reported Outcomes Measurement Information Score, along with other safety outcome measures.

At MDA 2022, Sarepta presented numerous abstracts from clinical trials investigating SRP-9001 in DMD, including Study 101 (NCT03375164). This was an open-label trial that infused SRP-9001 at 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. In addition to receiving SRP-9001, patients were given daily prednisolone, 1 mg/kg, at day 1 prior to gene delivery and also underwent a 30-day taper after infusion.³

Results showed that SRP-9001 was well tolerated and there were minimal adverse events (AEs). With safety as the primary outcome, secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. After 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, 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.

New safety and functional outcome data presented at MDA 2022 showed 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. Furthermore, 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

For more coverage of MDA 2022, click here.

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