May 17, 2023

Sarepta's Muscular Dystrophy Drug Gets Nod From FDA Advisors. Controversy Ensues.

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Updated 5/19/2023

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.

Factors to consider

The FDA's decision will be influenced by several factors:

  1. Uncertainty: An FDA official, Peter Marks, acknowledged that there is still uncertainty regarding the therapy. The split vote indicates differing opinions among the committee members, reflecting the ongoing debate over the sufficiency of the evidence supporting the therapy's efficacy and safety.
  2. High cost: Although the official price has not been set, media reports suggest that SRP-9001 may cost around $2 million per patient treatment, which is double the cost of the current standard-of-care therapies for Duchenne muscular dystrophy. The high price raises concerns about accessibility and affordability, particularly considering potential competition from other DMD treatments under development.
  3. Competition: SRP-9001 faces competition from other emerging DMD treatments. Pfizer, through its acquisition of Bamboo Therapeutics, has developed a Phase 3 gene therapy candidate fordadistrogene movaparvovec, which also aims to address the underlying genetic cause of DMD. Other companies, such as the National Children's Hospital, REGENXBIO, and Solid Biosciences, are also advancing dystrophin gene therapies for DMD. The market competition, coupled with the high cost, adds complexity to the evaluation of SRP-9001's overall value and potential impact.

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."
~ Agency reviewers

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."
~ University of California, Davis, physician Craig McDonald, presenting on behalf of Sarepta, said during the meeting, STAT reported

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.

$3B in value created overnight

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:

  1. FDA advisory committee support: The positive vote by the FDA's Cellular, Tissue and Gene Therapies Advisory Committee in favor of accelerated approval of SRP-9001 is a strong endorsement for the potential of the gene therapy in treating DMD. This outcome reflects a level of confidence in the therapy's effectiveness and safety.
  2. Addressing an unmet medical need: Duchenne muscular dystrophy is a devastating genetic disorder caused by the absence of the dystrophin protein. SRP-9001 is specifically designed to correct the underlying genetic mutation and facilitate the production of dystrophin in muscle tissue. If approved, it has the potential to provide a significant therapeutic advancement in addressing the unmet medical needs of DMD patients.
  3. Market potential: Duchenne muscular dystrophy affects a significant number of patients worldwide, and there is a high demand for effective treatments. The market is estimated to grow to $4B within the next few years. If SRP-9001 receives accelerated approval, Sarepta could capture a considerable market share, potentially leading to significant revenue growth.
  4. Competitive advantage: Sarepta's gene therapy, SRP-9001, is positioned to address the underlying cause of DMD by providing a functional form of the dystrophin protein. This novel approach sets it apart from other available therapies and positions Sarepta as a frontrunner in the race to develop effective treatments for DMD.
  5. Pipeline expansion: In addition to SRP-9001, Sarepta has been actively expanding its pipeline of therapies for DMD and other neuromuscular diseases. The company is also developing exon-skipping therapies targeting different genetic mutations, such as casimersen (SRP-4045) and golodirsen (SRP-4053). These therapies aim to expand treatment options for a broader spectrum of DMD patients. Its approved drug, Exondys 51 (eteplirsen), targets a specific subset of DMD patients who have genetic mutations amenable to exon 51 skipping. This therapy helps restore the production of the dystrophin protein by skipping specific exons in the dystrophin gene that contribute to its malfunction. Exondys 51 was the first FDA-approved treatment for DMD targeting the underlying genetic cause.

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, but may choose to buy and sell shares in the future.


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