FDA expands approval of Sarepta gene therapy

Duchenne muscular dystrophy is a condition that causes progressive muscle weakness and can lead to patients being unable to walk by the time they become teenagers. Currently, there's no cure for the condition, and treatments, which typically consist of steroid medications and physical therapy, are limited.

Last year, FDA gave accelerated approval to Sarepta's gene therapy, Elevidys, to treat Duchenne muscular dystrophy in children ages four and five who have a confirmed mutation in a gene called DMD. The treatment is given as an intravenous infusion and costs roughly $3.2 million per patient.

Last week, FDA announced that it gave traditional approval to Elevidys for ambulatory patients ages four and older with a confirmed mutation in the DMD gene. The agency also gave the drug accelerated approval for non-ambulatory patients ages four and older with the mutation.

In a news release, Peter Marks, director of FDA's Center for Biologics Evaluation and Research, said the approval addressed "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."

"The (expansion) is a defining moment for the Duchenne community," said Sarepta CEO Doug Ingram. "Today also stands as a watershed occasion for the promise of gene therapy and a win for science."

Controversy over the approval

According to STAT+, there's been some controversy over Elevidys' expanded approval, with Marks overruling recommendations from FDA review teams and some of his staff.

Last October, Sarepta released the results of a confirmatory trial showing that the treatment missed its primary goal, which was a measure of how well patients could move. However, company executives said that the trial was able to meet secondary and exploratory endpoints, which they argued showed that the treatment's mechanism of action worked and could slow the progression of the disease.

FDA's clinical and clinical pharmacology review team disagreed with Sarepta's assessment, STAT+ reports. According to the review team, the trial didn't confirm the treatment's benefit for four- and five-year old patients, and the company "provided no satisfactory data to support effectiveness claims for all ages and for non-ambulatory patients."

Despite the review team's conclusion, Marks said that "the available data are compelling, including the positive benefit shown on the secondary endpoints and the exploratory evidence" from clinical trials. He also noted that there is a lack of alternative treatments for Duchenne muscular dystrophy.

Two of Marks' top lieutenants also objected to Marks' decision. In a letter to Marks, Lola Fashoyin-Aje, director of the Office of Clinical Evaluation, and Nicole Verdun, super office director of the Office of Therapeutic Products, said that Elevidys failed two consecutive, placebo-controlled trials in four- to seven-year-olds.

Fashoyin-Aje and Verdun also noted there wasn't data that showed patients' muscle function improved after receiving more microdystrophin and that Sarepta only included data from a handful of patients using wheelchairs.

Although Fashoyin-Aje and Verdun said that Elevidys "may be efficacious" for some patients, it was difficult to determine which patients would benefit. Both Fashoyin-Aje and Verdun said they would have recommended Sarepta run another clinical trial, but that was now "infeasible" because of Marks' decision to approve the drug.

According to STAT+, this is not the first time Marks has overruled his staff in a decision regarding Elevidys. Last year, Marks overruled his staff to give Elevidys its initial accelerated approval for four- and five-year-olds. Other top FDA officials have also overruled their staff on other drug decisions, including for Biogen's Alzheimer's drug Aduhelm in 2021.

These decisions underscore concerns that executives and patient advocates, who may have ties to the industry, have become too influential over top decision-makers, which have allowed treatments that may not be effective or safe to enter the market, STAT+ writes.

"I don't know what to say. Peter Marks makes a mockery of scientific reasoning and approval standards that have served patients well over decades," said former FDA chief scientist Luciana Borio. "This type of action also promotes the growing mistrust in scientific institutions like the FDA."

However, the Muscular Dystrophy Association said that it trusts FDA's decision, which weighs the risks and benefits of the drug. "Ultimately, what we want is what's best for our patient community – and that's balancing that risk-benefit ratio appropriately," said Sharon Hesterlee, the association's chief researcher.

Parents of patients with the condition have also praised FDA's decision. "Marks has demonstrated he is capable of the kind of regulatory flexibility that is needed to appropriately analyze treatments in a condition like Duchenne," said Jennifer Handt, whose 6-year-old son Charlie received Elevidys in a clinical trial. "This new day for medicine in rare disease requires new thinking and at times, bold action — including overruling division staff." (Howard, CNN, 6/21; Dunleavy, Fierce Pharma, 6/21; Mast/Herper, STAT+ [subscription required], 6/20)

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