Update on Regulatory Review of Gene Therapy for Duchenne Muscular Dystrophy

Patients and families with Duchenne Muscular Dystrophy (DMD) await regulatory action.
· 10 min read

For months, patients and families with Duchenne Muscular Dystrophy (DMD) awaited new regulatory action on the Biologics License Application (BLA) for SRP-9001 (delandistrogene moxeparvovec). Plagued with setbacks and delays, on June 22, the US Food and Drug Administration (FDA) granted accelerated approval for the first Duchenne gene therapy for ambulatory pediatric patients 4 through 5 years of age with a confirmed mutation in the DMD gene. Developed by biotechnology company, Sarepta Therapeutics, the continued approval of Elevidys hinges upon confirming its clinical benefit in further testing (EMBARK clinical study described below), with initial results expected to be available later this year.

While this approval is narrower than Sarepta originally pursued, based upon limitations in the data the company submitted to regulators, the FDA based its decision on the therapy’s ability to help patients make a tiny protein, called microdystrophin, that the FDA deems “reasonably likely” to result in a health benefit. However, while Elevidys did not demonstrate a significant treatment effect on functional outcomes, a subgroup analysis showed a numerical advantage in a rating scale that measures functional motor abilities (NSAA) for Elevidys as compared to placebo.

A major concern noted in the review process was the observation of safety issues in the three studies (Studies 101, 102 and 103),which included acute serious liver injury, immune-mediated myositis and myocarditis. The final approved labeling states that Elevidys is contraindicated in patients with any deletion in exon 8 and/or 9 in the DMD gene due to the increased risk for immune-mediated myositis.

Cost of Therapy

At $3.2 million just for the cost of the therapy, excluding infusion and pre-treatment therapies, this falls into one of the most expensive treatments available. Without a true demonstrated clinical benefit and proven sustained durability of the treatment, coverage will likely be limited and other currently available non-gene therapy treatments will likely be therapeutic options, including corticosteroids, Emflaza, Exondys 51, Vyondys 53, Amondys 45, Viltepso.


Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a leader in precision genetic medicine for rare diseases, is responsible for global development and manufacturing for SRP-9001 and plans to commercialize SRP-9001 in the United States. In December 2019, Roche partnered with Sarepta to combine Roche’s global reach, commercial presence and regulatory expertise with Sarepta’s gene therapy candidate for Duchenne to accelerate access to SRP-9001 for patients outside the United States.


Here's the Background

Following discussions with FDA, the Agency had indicated that, subject to the completion of the BLA review, it would work toward potentially granting an accelerated approval for SRP-9001, initially for use in Duchenne patients ages 4-5 years old.

Certain members of the FDA Review Committee recommended approval of the Biologics License Application (BLA) via the Accelerated Approval pathway, based on the data relevant to their areas of expertise. However, the Clinical Pharmacology and Statistics review teams and supervisors concluded that the data submitted in the BLA in support of Accelerated Approval of Elevidys was not adequate to meet the threshold for approval.

Despite the Review Committee decision not to recommend approval of the BLA, this decision was overridden by Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“This approval addresses an urgent unmet medical need and is an important advancement in the treatment of Duchenne Muscular Dystrophy, a devastating condition with limited treatment options, that leads to a progressive deterioration of an individual’s health over time,” said Dr. Marks. “The FDA remains committed to facilitating the development of innovative new therapies to reduce the impact of debilitating diseases and to improve outcomes and quality of life for those affected.”

EMBARK, the global, randomized, double-blind, placebo-controlled Phase 3 trial of SRP-9001, is the proposed confirmatory study. The Agency has informed Sarepta that, in addition to confirming the results of the initial BLA approval, if the trial meets its objectives, the Agency intends to entertain a non-age-restricted expansion of the SRP-9001 label based upon the review of the EMBARK data. EMBARK is fully enrolled, with top-line results expected in the fourth quarter of 2023.

What Led to the Pushback

In a June 15, 2023 letter to Dr. Peter Marks and Robert M. Califf, M.D., Commissioner Food and Drug Administration, U.S. Department of Health and Human Services, the non-profit Public Citizen consumer advocacy organization with over 500,000 members and supporters, urged the FDA to reject the accelerated approval for SRP-9001. Click here to read the entire letter.

“We have no financial conflicts of interest regarding the development of treatments for DMD or any other gene therapies.” wrote the authors. “As stated in our testimony, we are deeply concerned about the efficacy and safety of SRP-9001 as a treatment for early-stage (ambulatory) DMD.”

Public Citizen leaders expressed their view that the advisory committee reached a distinctively mixed, but mostly negative, conclusion on SRP-9001, with more than half of the members concerned about the efficacy data and other members endorsing a potential treatment despite the concerns about efficacy, safety, and the regulatory history of very similar treatments for DMD.

Instead, they recommended that the FDA should defer further regulatory consideration until after the ongoing confirmatory trial is completed.

“Although we are fully aware of the clinical situations of patients with ambulatory DMD, granting accelerated approval of SRP-9001 based on weak and unconvincing evidence is not a path forward,” they concluded.

Since conditional approval was granted for SRP-9001, the stakes for an ongoing validating study are critical. If the therapy does not show efficacy upon FDA review of the emerging data, the agency would either work towards withdrawing SRP-9001 or see if the sponsor was willing to withdraw it. The agency says this “has sometimes happened.” 

Additional Drug Development for DMD Underway

Coincidentally, on the same day that the letter from Public Citizen was made public, Cure Duchenne, Muscular Dystrophy Association and Parent Project Muscular Dystrophy announced a Collaborative Research Grant for DMD.

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The clinical trial grant will test repurposing of the FDA-approved drug Vyvgart (efgartigimod alfa-fcab developed by argenx), for its potential ability to reduce antibodies to adeno-associated virus (AAV) in DMD patients.

The three organizations provided $100,000 each to sponsor a one-year clinical study to assess the safety and efficacy of Vyvgart to lower AAV antibodies precluding DMD patients from gene therapy. Vyvgart is an approved drug currently used to treat autoimmune diseases by reducing overall levels of circulating IgG antibodies.

The study will investigate whether Vyvgart has the ability to reduce AAV antibodies to levels compatible with safe and effective delivery of gene therapies in DMD patients. Positive results from the study may be applicable to the translation of AAV gene therapies for other neuromuscular diseases.

"We are just beginning to realize the impact of gene therapies that can treat the underlying root cause of genetic diseases,” said Barry Byrne, MD, Ph.D., MDA Chief Medical Advisor, and Associate Chair of Pediatrics and director of the Powell Gene Therapy Center at the University of Florida. “Disease-modifying therapies are no longer a thing of the future. Our goal now is to figure out how to best maximize and achieve the biggest impact with the technology in our hands.”

This co-funded clinical trial aims to suppress anti-AAV antibodies in a subset of DMD patients who are currently not eligible for gene therapy due to pre-existing AAV antibodies from natural infections. The trial will also explore the potential for reducing in DMD patients anti-AAV antibodies acquired from previous participation in gene therapy trials in order to enable future redosing efforts.

Sharon Hesterlee, Ph.D., Chief Research Officer, MDA, shares, “Should an approved drug be able to reduce AAV antibodies to acceptable levels, it would serve as an efficient way to open doors for patients who are currently ineligible for gene therapy. This approach could also possibly provide re-treatment options for patients who are starting to see a reduction in drug effect, although the hurdle would be higher there.”

Additionally, another DMD gene therapy product from Pfizer, fordadistrogene movaparvovec, is also in Phase 3 trials and is anticipated to be reviewed by the FDA in mid-2024. The study will evaluate the safety and dystrophin expression following gene therapy in boys with DMD. It is a single-arm, non-randomized, open-label study.

Unveiling a World of Possibilities: September - AscellaHealth Gene Therapy and Specialty Pharmacy Awareness Month

As we look forward to September's annual AscellaHealth Gene Therapy and Specialty Pharmacy Awareness Month, we are reminded of the incredible progress being made in the field of rare and orphan diseases. The advancements in recent groundbreaking treatments and the potential of new gene therapies show promise for those with complex, chronic conditions. These cutting-edge therapies offer expanded therapeutic options and the hope of a potential cure for individuals living with challenging medical conditions.

At AscellaHealth, we are committed to providing accurate information and education to all stakeholders. With more than 900 ongoing gene therapy developments and specialty drugs accounting for nearly 60% of pharmacy benefits costs, staying informed is crucial to making informed decisions and improving patient outcomes.

Together, as we celebrate Gene Therapy and Specialty Pharmacy Awareness Month, we can pave the way for better access to life-changing treatments and continue our mission to enhance health outcomes and quality of life for communities nationwide.

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