A Sarepta Therapeutics gene remedy that failed its confirmatory check has now transformed its accelerated FDA approval into a standard one, increasing use of the therapy to a wider group of Duchenne muscular dystrophy sufferers. In approving the remedy, the FDA’s high biologics official cited a wider vary of supporting proof, overruling company employees who have been unconvinced that the info present the remedy works to deal with the muscle-wasting illness.
The FDA choice introduced late Thursday permits use of the remedy, Elevidys, in all Duchenne sufferers age 4 and older. For sufferers who can nonetheless stroll, the choice is a normal FDA approval. However in these 4 and older whose illness has progressed to the purpose of requiring a wheelchair, the FDA ruling is an accelerated approval that requires a further confirmatory scientific trial to verify that Elevidys advantages these sufferers.
Duchenne muscular dystrophy stems from genetic mutations that result in a deficiency of dystrophin, a protein key to muscle perform. The gene that codes for dystrophin is discovered on the X chromosome so Duchenne virtually solely impacts boys. Missing dystrophin, sufferers develop progressively worsening muscle weak spot that ultimately turns into deadly because the illness impacts the lungs and the guts. The corticosteroids permitted for Duchenne can sluggish the illness’s development. Cambridge, Massachusetts-based Sarepta already has three permitted Duchenne medicine that work by get a cell’s protein-making equipment to provide a truncated model of dystrophin. However every of those Sarepta antisense oligonucleotide therapies addresses a solely a particular genetically outlined affected person group. All three are additionally persistent remedies, once-weekly infusions that should be taken for all times.
Gene remedy goals to revive some stage of dystrophin manufacturing with a one-time therapy. The gene that codes for this protein is a big one — too large to suit on the engineered viruses used to ship a genetic drugs to cells. Elevidys employs a mini-version of the gene, which in flip codes for a smaller model of dystrophin. Elevidys received accelerated approval final June primarily based on Part 2 information exhibiting the remedy led to manufacturing of micro-dystrophin. That objective is a surrogate endpoint — a sign the remedy could be working. To verify affected person profit, and to transform the accelerated approval into a standard one, Elevidys wanted to satisfy extra targets in a confirmatory research meant to indicate that micro-dystrophin helps muscular tissues. This variation was scored in line with extensively used ranking scale for assessing motor perform in Duchenne sufferers.
A Primary Aim Miss, However Success on Secondary Endpoints
Final October, Sarepta reported outcomes exhibiting that the rating enchancment within the Elevidys arm was not sufficient to attain statistical significance in comparison with the placebo group. However, the corporate pointed to statistically important rating modifications on secondary targets that encompassed different measures of muscle perform, comparable to how briskly sufferers can stroll 10 meters and the way shortly they will rise from the ground.
A memo explaining the FDA reviewers’ conclusions is posted to the company’s web site. Whereas reviewers acknowledged the outcomes for the secondary endpoints, they notice that the research design doesn’t allow them to tell apart whether or not the profit comes from Elevidys or if it’s simply likelihood. Reviewers additionally acknowledged video proof and testimony of affected person profit offered throughout an FDA advisory committee assembly final yr. They mentioned the placebo impact is unlikely to provide such sustained profit, however the failure for 2 randomized, placebo-controlled research to indicate an identical impact means that solely a subset of Duchenne sufferers might profit. Who these responders are is unclear. Moreover, the randomized research didn’t embrace sufferers unable to stroll, so there is no such thing as a proof of effectiveness in these sufferers. Reviewers mentioned the smaller dimension of the micro-dystrophin might account partly for the trial outcomes.
“Taken collectively, the totality of the info doesn’t present substantial proof of effectiveness of Elevidys for therapy of ambulatory DMD (Duchenne muscular dystrophy) sufferers of any age,” the FDA scientific and pharmacology memo states. “The outcomes argue in opposition to conventional approval for Elevidys for ambulatory DMD sufferers aged 4- to 5-years outdated, or for broadening of the indication of Elevidys to incorporate DMD sufferers no matter age or ambulatory standing.”
Peter Marks, director of the FDA’s Middle for Biologics Analysis and Analysis, reviewed the identical information and reached totally different conclusions. Whereas acknowledging Elevidys’s failure to satisfy the primary objective of its Part 3 check, Marks mentioned in a separate memo that he discovered the observations on the secondary and exploratory endpoints led to outcomes that have been clinically significant for sufferers. Addressing the query of micro-dystrophin’s efficacy, Marks mentioned it’s not shocking that solely a proportion of a 4-year-old’s whole muscle mass could be affected by the remedy, leading to solely a partial correction of the muscle issues attributable to Duchenne.
“Removed from being insignificant, such partial correction might make the distinction in essential purposeful parameters, comparable to continuation of the power to climb stairs or stroll independently,” Marks wrote.
A Uncommon However Not Unprecedented Transfer
It’s uncommon for a remedy to win regulatory approval after failing a confirmatory research, nevertheless it’s occurred earlier than. Biopharma data companies agency Citeline factors to Roche most cancers drug Avastin as one instance. The antibody drug received accelerated approval in 2009 as a therapy for glioblastoma multiforme, an aggressive mind most cancers. Whereas the drug failed to attain the general survival objective of its confirmatory research, it did present statistically important and clinically significant outcomes on the measure of progression-free survival. The FDA concluded that these outcomes have been ample to help conventional approval of the drug on this indication.
As for situations the place a high FDA official has overruled the company’s employees to approve a drug, Sarepta’s first Duchenne drug could be essentially the most well-known instance, in line with Amanda Micklus, principal analyst at Citeline. Exondys 51 acquired accelerated approval in 2016. That regulatory choice overcame the objections of FDA reviewers and a unfavorable vote from an FDA advisory committee. Janet Woodcock, head of the company’s Middle for Drug Analysis and Analysis on the time, signed off on accelerated approval of the remedy primarily based on scientific information indicating a rise in dystrophin manufacturing. Sarepta has but to finish the confirmatory research assessing Exondys 51’s impact on muscular tissues.
The Elevidys approval comes one week after Pfizer’s experimental gene remedy for Duchenne failed to attain the primary objective of its Part 3 scientific trial. Pfizer mentioned it’s nonetheless reviewing subsequent steps for the remedy, however analysts are uncertain about its future. In contrast to the Sarepta remedy, Pfizer’s therapy failed to attain each the first and secondary endpoints of its trial. In the meantime, micro-dystrophin gene therapies from contenders Strong Biosciences, Genethon, and Regenxbio are all in earlier phases of improvement.
Elevidys carries a $3.2 million wholesale worth for the one-time therapy. Sarepta reported $200.3 million in gross sales for the product in 2023. In a notice despatched to traders Friday, William Blair analyst Tim Lugo wrote that the Elevidys approval is the “best-case state of affairs” for Sarepta. Most Duchenne sufferers youthful than 4 usually are not but recognized with the illness, and thus will age into the age vary coated by expanded Elevidys label, opening up the marketplace for the product. William Blair initiatives the remedy will obtain about $3.2 billion in gross sales in 2025. Trying extra broadly, Lugo wrote that the consequences of the Elevidys approval may ripple throughout the gene remedy sector.
“The lasting influence of the approval will possible form the FDA and gene remedy area for a while, and we consider a extra patient-focused and fewer adversarial FDA evaluation course of is prone to proceed throughout a number of areas within the company, particularly for heterogenous and lethal illnesses with few good therapy choices,” he mentioned.
Extra scientific exams of Elevidys are underway. An ongoing Part 2 check may help increasing the therapy to youthful sufferers. Sarepta can be conducting a Part 3 research enrolling sufferers who not have the power to stroll in addition to older Duchenne sufferers who’re nonetheless ambulatory. This international scientific trial will function the confirmatory research required of the remedy’s accelerated approval in non-ambulatory Duchenne sufferers. Roche holds the rights to market Elevidys outdoors of the U.S. below a deal struck in 2019. The Swiss pharmaceutical big is chargeable for regulatory submissions and commercialization of the remedy in the remainder of the world.
Photograph by Sarepta Therapeutics
