A Sarepta Therapeutics gene remedy that failed its confirmatory take a look at 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 prime biologics official cited a wider vary of supporting proof, overruling company workers who have been unconvinced that the information present the remedy works to deal with the muscle-wasting illness.
The FDA resolution 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 typical 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 substantiate that Elevidys advantages these sufferers.
Duchenne muscular dystrophy stems from genetic mutations that result in a deficiency of dystrophin, a protein key to muscle operate. The gene that codes for dystrophin is discovered on the X chromosome so Duchenne nearly completely impacts boys. Missing dystrophin, sufferers develop progressively worsening muscle weak point that finally turns into deadly because the illness impacts the lungs and the center. The corticosteroids authorised for Duchenne can sluggish the illness’s development. Cambridge, Massachusetts-based Sarepta already has three authorised Duchenne medication that work by get a cell’s protein-making equipment to supply a truncated model of dystrophin. However every of those Sarepta antisense oligonucleotide therapies addresses a solely a selected genetically outlined affected person group. All three are additionally continual therapies, 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 huge to suit on the engineered viruses used to ship a genetic medication 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 based mostly on Part 2 knowledge 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 fulfill extra targets in a confirmatory examine supposed to point out that micro-dystrophin helps muscular tissues. This transformation was scored in keeping with broadly used score scale for assessing motor operate in Duchenne sufferers.
A Fundamental 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. Nonetheless, the corporate pointed to statistically vital rating adjustments on secondary targets that encompassed different measures of muscle operate, similar to how briskly sufferers can stroll 10 meters and the way rapidly 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 observe that the examine design doesn’t allow them to differentiate whether or not the profit comes from Elevidys or if it’s simply probability. Reviewers additionally acknowledged video proof and testimony of affected person profit offered throughout an FDA advisory committee assembly final yr. They stated the placebo impact is unlikely to supply such sustained profit, however the failure for 2 randomized, placebo-controlled research to point out the same impact means that solely a subset of Duchenne sufferers could profit. Who these responders are is unclear. Moreover, the randomized research didn’t embody sufferers unable to stroll, so there isn’t any proof of effectiveness in these sufferers. Reviewers stated the smaller dimension of the micro-dystrophin could account partly for the trial outcomes.
“Taken collectively, the totality of the information 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 towards conventional approval for Elevidys for ambulatory DMD sufferers aged 4- to 5-years previous, 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 knowledge and reached completely different conclusions. Whereas acknowledging Elevidys’s failure to fulfill the principle objective of its Part 3 take a look at, Marks stated 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 stated it’s not stunning 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 could make the distinction in vital practical parameters, similar 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 examine, however it’s occurred earlier than. Biopharma info 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 examine, it did present statistically vital 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 prime FDA official has overruled the company’s workers to approve a drug, Sarepta’s first Duchenne drug could be essentially the most well-known instance, in keeping with Amanda Micklus, principal analyst at Citeline. Exondys 51 acquired accelerated approval in 2016. That regulatory resolution overcame the objections of FDA reviewers and a unfavourable 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 based mostly on scientific knowledge indicating a rise in dystrophin manufacturing. Sarepta has but to finish the confirmatory examine 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 principle objective of its Part 3 scientific trial. Pfizer stated 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 Stable Biosciences, Genethon, and Regenxbio are all in earlier levels of growth.
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 observe despatched to traders Friday, William Blair analyst Tim Lugo wrote that the Elevidys approval is the “best-case situation” for Sarepta. Most Duchenne sufferers youthful than 4 usually are not but identified 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 tasks the remedy will obtain about $3.2 billion in gross sales in 2025. Wanting extra broadly, Lugo wrote that the results of the Elevidys approval might ripple throughout the gene remedy sector.
“The lasting impression of the approval will possible form the FDA and gene remedy house for a while, and we imagine a extra patient-focused and fewer adversarial FDA evaluate course of is prone to proceed throughout a number of areas within the company, particularly for heterogenous and lethal ailments with few good therapy choices,” he stated.
Further scientific exams of Elevidys are underway. An ongoing Part 2 take a look at might help increasing the therapy to youthful sufferers. Sarepta can be conducting a Part 3 examine enrolling sufferers who now not have the power to stroll in addition to older Duchenne sufferers who’re nonetheless ambulatory. This world scientific trial will function the confirmatory examine required of the remedy’s accelerated approval in non-ambulatory Duchenne sufferers. Roche holds the rights to market Elevidys outdoors of the U.S. underneath a deal struck in 2019. The Swiss pharmaceutical big is liable for regulatory submissions and commercialization of the remedy in the remainder of the world.
Picture by Sarepta Therapeutics
