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FDA Approves Sarepta Gene Therapy, But Only After Top FDA Official Bucks Agency Staff

FDA Approves Sarepta Gene Therapy, But Only After Top FDA Official Bucks Agency Staff


A Sarepta Therapeutics gene therapy that failed its confirmatory test has now converted its accelerated FDA approval into a traditional one, expanding use of the treatment to a wider group of Duchenne muscular dystrophy patients. In approving the therapy, the FDA’s top biologics official cited a wider range of supporting evidence, overruling agency staff who were unconvinced that the data show the therapy works to treat the muscle-wasting disease.

The FDA decision announced late Thursday permits use of the therapy, Elevidys, in all Duchenne patients age 4 and older. For patients who can still walk, the decision is a standard FDA approval. But in those 4 and older whose disease has progressed to the point of requiring a wheelchair, the FDA ruling is an accelerated approval that requires an additional confirmatory clinical trial to confirm that Elevidys benefits these patients.

Duchenne muscular dystrophy stems from genetic mutations that lead to a deficiency of dystrophin, a protein key to muscle function. The gene that codes for dystrophin is found on the X chromosome so Duchenne almost exclusively affects boys. Lacking dystrophin, patients develop progressively worsening muscle weakness that eventually becomes fatal as the disease affects the lungs and the heart. The corticosteroids approved for Duchenne can slow the disease’s progression. Cambridge, Massachusetts-based Sarepta already has three approved Duchenne drugs that work by get a cell’s protein-making machinery to produce a truncated version of dystrophin. But each of these Sarepta antisense oligonucleotide therapies addresses a only a specific genetically defined patient group. All three are also chronic treatments, once-weekly infusions that must be taken for life.

Gene therapy aims to restore some level of dystrophin production with a one-time treatment. The gene that codes for this protein is a large one — too big to fit on the engineered viruses used to deliver a genetic medicine to cells. Elevidys employs a mini-version of the gene, which in turn codes for a smaller version of dystrophin. Elevidys won accelerated approval last June based on Phase 2 data showing the therapy led to production of micro-dystrophin. That goal is a surrogate endpoint — an indication the therapy might be working. To confirm patient benefit, and to convert the accelerated approval into a traditional one, Elevidys needed to meet additional goals in a confirmatory study intended to show that micro-dystrophin is helping muscles. This change was scored according to widely used rating scale for assessing motor function in Duchenne patients.

A Main Goal Miss, But Success on Secondary Endpoints

Last October, Sarepta reported results showing that the score improvement in the Elevidys arm was not enough to achieve statistical significance compared to the placebo group. Nevertheless, the company pointed to statistically significant score changes on secondary goals that encompassed other measures of muscle function, such as how fast patients can walk 10 meters and how quickly they can rise from the floor.

A memo explaining the FDA reviewers’ conclusions is posted to the agency’s website. While reviewers acknowledged the results for the secondary endpoints, they note that the study design does not enable them to distinguish whether the benefit comes from Elevidys or if it’s just chance. Reviewers also acknowledged video evidence and testimony of patient benefit presented during an FDA advisory committee meeting last year. They said the placebo effect is unlikely to produce such sustained benefit, but the failure for two randomized, placebo-controlled studies to show a similar effect suggests that only a subset of Duchenne patients may benefit. Who these responders are is unclear. Furthermore, the randomized studies did not include patients unable to walk, so there is no evidence of effectiveness in these patients. Reviewers said the smaller size of the micro-dystrophin may account in part for the trial results.

“Taken together, the totality of the data does not provide substantial evidence of effectiveness of Elevidys for treatment of ambulatory DMD (Duchenne muscular dystrophy) patients of any age,” the FDA clinical and pharmacology memo states. “The results argue against traditional approval for Elevidys for ambulatory DMD patients aged 4- to 5-years old, or for broadening of the indication of Elevidys to include DMD patients regardless of age or ambulatory status.”

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, reviewed the same data and reached different conclusions. While acknowledging Elevidys’s failure to meet the main goal of its Phase 3 test, Marks said in a separate memo that he found the observations on the secondary and exploratory endpoints led to results that were clinically meaningful for patients. Addressing the question of micro-dystrophin’s efficacy, Marks said it is not surprising that only a percentage of a 4-year-old’s total muscle mass might be affected by the therapy, resulting in only a partial correction of the muscle problems caused by Duchenne.

“Far from being insignificant, such partial correction may make the difference in critical functional parameters, such as continuation of the ability to climb stairs or walk independently,” Marks wrote.

A Rare But Not Unprecedented Move

It’s rare for a therapy to win regulatory approval after failing a confirmatory study, but it’s happened before. Biopharma information services firm Citeline points to Roche cancer drug Avastin as one example. The antibody drug won accelerated approval in 2009 as a treatment for glioblastoma multiforme, an aggressive brain cancer. While the drug failed to achieve the overall survival goal of its confirmatory study, it did show statistically significant and clinically meaningful results on the measure of progression-free survival. The FDA concluded that these results were sufficient to support traditional approval of the drug in this indication.

As for instances where a top FDA official has overruled the agency’s staff to approve a drug, Sarepta’s first Duchenne drug might be the most famous example, according to Amanda Micklus, principal analyst at Citeline. Exondys 51 received accelerated approval in 2016. That regulatory decision overcame the objections of FDA reviewers and a negative vote from an FDA advisory committee. Janet Woodcock, head of the agency’s Center for Drug Evaluation and Research at the time, signed off on accelerated approval of the therapy based on clinical data indicating an increase in dystrophin production. Sarepta has yet to complete the confirmatory study assessing Exondys 51’s effect on muscles.

The Elevidys approval comes one week after Pfizer’s experimental gene therapy for Duchenne failed to achieve the main goal of its Phase 3 clinical trial. Pfizer said it is still reviewing next steps for the therapy, but analysts are doubtful about its future. Unlike the Sarepta therapy, Pfizer’s treatment failed to achieve both the primary and secondary endpoints of its trial. Meanwhile, micro-dystrophin gene therapies from contenders Solid Biosciences, Genethon, and Regenxbio are all in earlier stages of development.

Elevidys carries a $3.2 million wholesale price for the one-time treatment. Sarepta reported $200.3 million in sales for the product in 2023. In a note sent to investors Friday, William Blair analyst Tim Lugo wrote that the Elevidys approval is the “best-case scenario” for Sarepta. Most Duchenne patients younger than 4 are not yet diagnosed with the disease, and thus will age into the age range covered by expanded Elevidys label, opening up the market for the product. William Blair projects the therapy will achieve about $3.2 billion in sales in 2025. Looking more broadly, Lugo wrote that the effects of the Elevidys approval could ripple across the gene therapy sector.

“The lasting impact of the approval will likely shape the FDA and gene therapy space for some time, and we believe a more patient-focused and less adversarial FDA review process is likely to continue across several areas in the agency, especially for heterogenous and deadly diseases with few good treatment options,” he said.

Additional clinical tests of Elevidys are underway. An ongoing Phase 2 test could support expanding the treatment to younger patients. Sarepta is also conducting a Phase 3 study enrolling patients who no longer have the ability to walk as well as older Duchenne patients who are still ambulatory. This global clinical trial will serve as the confirmatory study required of the therapy’s accelerated approval in non-ambulatory Duchenne patients. Roche holds the rights to market Elevidys outside of the U.S. under a deal struck in 2019. The Swiss pharmaceutical giant is responsible for regulatory submissions and commercialization of the therapy in the rest of the world.

Photo by Sarepta Therapeutics



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