Sarepta to Expedite Timeline for Muscular Dystrophy Gene Therapy

Courtesy of Sarepta Therapeutics

In its second-quarter conference call, Sarepta Therapeutics indicated plans to accelerate its timeline for SRP-9001 (delandistrogene moxeparvovec), a gene therapy for Duchenne muscular dystrophy (DMD).

Sarepta currently has three antisense therapeutics for DMD on the market. The company's original plan was to not apply to regulators until 2023, but now, it plans to submit the drug to the U.S. Food and Drug Administration in the next few months, with plans to launch the drug in mid-2023.

In July, Sarepta and its partner on the drug, Roche, presented promising functional data at the 17th International Congress on Neuromuscular Diseases (ICNMD 2022) in Brussels. DMD is a rare genetic disease that results in progressive muscle degeneration and weakness. Caused by mutations in the dystrophin gene, which codes for muscle, the disease primarily occurs in boys and typically causes impaired pulmonary function, acute respiratory failure and death.

SRP-9001 is a gene transfer technology that delivers the therapy to muscle tissue for the targeted production of essential dystrophin. Sarepta’s other DMD therapies utilize gene skipping technology. In that, the therapy skips over the deleted part of the gene, resulting in a truncated but mostly functional dystrophin protein.

The data from Cohort 1 of Study SRP-9001-103, ENDEAVOR, demonstrated a 3.8-point improvement (unadjusted means) and 3.2-point improvement (least squared means) on the North Star Ambulatory Assessment (NSAA) 52 weeks after treatment compared to external control.

Doug Ingram, Sarepta’s CEO, launched right into the conference call by discussing the accelerated regulatory plans for SRP-9001, noting, “we previously disclosed that we were engaging with the U.S. FDA about the possibility of submitting a Biologics License Application, or BLA, for the Accelerated Approval of SRP-9001 to treat Duchenne muscular dystrophy. We also cautioned numerous times that we would not change our base case assumption on the timing of approval unless we have strong conviction on the receptivity to an Accelerated Approval BLA by the FDA. As we announced last week, our discussions are now complete, and our base case assumption has indeed changed.”

They expect to submit the BLA this fall. It’s not clear yet if an advisory committee meeting will be called, but they think it would likely be in the spring of 2023, and, “Assuming a successful review, we anticipate approval and launch in mid-2023,” Ingram said.

Further, they are ramping up commercial preparations for what Ingram said “will be the largest gene therapy launch in the United States.. He added, "That will include augmenting our commercial and medical affairs organizations, site readiness, and importantly, building sufficient inventory to serve the community at large without delay.”

The company is also planning to launch its Pivotal EMBARK trial in 120 patients for the gene therapy. Ingram said that “the demand has been intense for EMBARK and site initiation and enrollment ramped up enormously in the second quarter. Based on our current screen rates, we should be fully screened and enrolled in the next few weeks.”

Because Accelerated Approvals, typically based on biomarker results rather than clinical benefit, require confirmatory trials, Ingram noted that the FDA and Congress have been encouraging companies to already have confirmatory in motion at the time of Accelerated Approval. Sarepta expects EMBARK to be its confirmatory trial, which is expected to be fully enrolled by the time the BLA is filed. 

Companies focusing on DMD gene therapies have proceeded cautiously after a fatal case of myocarditis was observed in Pfizer’s gene therapy candidate. In May 2022, four companies, Pfizer, Sarepta, Genethon and Solid Biosciences, were all observing serious side effects in their gene therapy clinical trials for DMD. In an unprecedented move, they partnered to analyze the data along with independent experts and then presented it at the American Society of Gene and Cell Therapy Meeting.

Serious adverse events (SAEs) were seen in five patients across three trials, and appeared about three to seven weeks after the initial gene infusion. Muscle weakness and variable cardiac involvement were observed.

Researchers now believe the SAEs were related to a “specific transgene/genotype-related ‘class effect.’” They believe that the mechanism of the SAEs was a T-cell-mediated immune response to the transgene protein expressed by all of the therapies in a cross-reactive immune response, but it was determined by the patient’s genotype. The SAEs occur only in patients with specific genome deletions, including N-terminal epitopes, which are present in the transgene protein.

It's a good bet that due to the issues, the FDA will call for an advisory committee meeting.

Previous DMD therapies were designed for patients with specific mutations in the dystrophin gene. These are Exondys 51, Vyondys 53 and Amondys 45. This new therapy is expected to target the ambulatory patient population, which Sarepta indicates is about 50% of the market. The company also plans to launch the ENVISION Study 303 in the non-ambulatory patient population later this year.