Sarepta Therapeutics (NASDAQ: SRPT) received a positive outcome last Friday as the US Food and Drug Administration's (FDA) advisory committee voted 8 to 6 in favor of accelerated approval for the company's SRP-9001 (delandistrogene moxeparvovec) gene therapy for Duchenne muscular dystrophy (DMD). Duchenne is first diagnosed in children ages 3-5 (mostly male, 1-in-3,500 births), resulting in loss of muscle strength, a weakened heart, and difficulty breathing. It is confirmed by a mutation in the DMD gene which is responsible for the production of dystrophin, a protein expressed in muscles that plays a structural role in muscle cells. Patients are non-ambulatory by age 12 and confined to wheelchair for the rest of their short lives (life expectancy 20-30 year). Treatment options are limited to corticosteroids and exon-skipping drugs, three that were developed by Sarepta and granted accelerated approval, but their clinical benefit has not been confirmed in large placebo-controlled trials (even though the last hit the market in 2021...) and only a small portion of the Duchenne community has benefited from these drugs. The DMD community rejoiced when Sarepta first announced its first-in-human trial for SRP-9001. But that jubilance was quickly extinguished by harsh reality.
Sarepta's first study failed to meet its primary endpoints of functional improvement, yet some patients experienced remarkable results. It did, however, meet its desired endpoint of elevated dystrophin levels, encouraging Sarepta to apply for accelerated approval (an approval pathway that relies on surrogate biomarker data, such as protein levels, and an indication of efficacy to gain conditional approval, which must be further supported by clinically meaningful evidence in a follow-on, Phase 3 confirmatory trial). Although the Agency is not obligated to follow the advisory committee's advice, they have a history of doing so. The narrow margin by which SRP-9001 landed the committee's recommendation clearly indicates dissent amongst the experts as to whether the benefits of SRP-9001 outweigh the potential risks, and the decision is further complicated by the lack of clinically meaningful data.
For the ~250,000 DMD patients thirsting for a treatment, any potential benefit that restores some of their quality of life may justify unknown (and potentially life-threatening) adverse effects. And while the pleas of patient advocacy groups cannot be ignored, the FDA's duty is to make an objective call given the available data and current treatment options. A difficult decision indeed.
The FDA's decision will be influenced by several factors:
Conclusions about the true efficacy of the drug hinges on the similarities between Sarepta's micro-dystrophin protein encoded by their gene therapy and the full-length, endogenous dystrophin gene. However, subgroup analyses from Sarepta's previous study suggests a possible benefit for ambulatory patients that are ages 4 to 5 years. Whether Sarepta's truncated protein confers clinically meaningful benefit by successfully imitating the full-length dystrophin protein will be determined by their ongoing EMBARK trial, but FDA advisors are not convinced:
"The protein differs in important ways from both the endogenous shortened forms of dystrophin in patients with BMD, and the internally truncated dystrophins expressed through exon-skipping drugs."
"Measurement of levels of Sarepta's micro-dystrophin in muscle tissue only provides information about expression of the transgene product in cells transduced by SRP-9001, rather than insight into a pharmacologic effect on a biomarker in the pathway of the disease."
The lack of confirmatory trials for Sarepta's three (conditionally) approved exon-skipping drugs also drew criticism from patient advocates.
However, independent clinicians who witnessed the new drug's remarkable efficacy in their patients advocated on Sarepta's behalf:
“You cannot detect appreciable differences in this child from another kid on the playground. The patient’s activities are “something I have never observed in my more than three decades following patients with DMD."
Despite the controversy, Sarepta and its CEO, Doug Ingram, consider the advisory committee's positive vote as crucial for patients in urgent need of new therapies. Sarepta plans to work closely with the FDA to complete the review of its Biologics License Application (BLA) for SRP-9001.
Shares of Sarepta Therapeutics (SRPT) experienced a significant surge, rising 24.9% as of 10:37 a.m. ET on Monday (5/15/23), following the announcement of a positive outcome from the FDA advisory committee vote on SRP-9001 in the treatment of Duchenne muscular dystrophy (DMD).
The surge in stock price can be attributed to several factors:
The FDA is expected to deliver a final decision for accelerated approval of SRP-9001 will be given by May 29, 2023.
Author does not own shares of Sarepta at the time this article was published.
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