The US Food and Drug Administration (FDA) on Monday approved Sarepta Therapeutics’ first drug to treat patients with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness in young children.
The approval is highly controversial after a FDA advisory committee voted against approval in April as the outside experts said there was not substantial evidence that the drug is effective in providing clinical benefit, which is the standard for traditional approval. Before that vote and afterwards, the DMD patient community protested vigorously.
DMD, occurring in about one out of every 3,600 male infants worldwide, is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between the ages of three and five, and worsen over time.
The agency said that following the hearing, Sarepta submitted additional data “showing substantial evidence of dystrophin production, although the amount of dystrophin produced was only a small fraction of the normal level.”
The injection, known as Exondys 51 (eteplirsen), is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, who constitute approximately 13% of the population with DMD. Sarepta said late Monday that the average cost per patient will be $300,000.
Ultimately, the new injection, known as Exondys 51, was approved under FDA’s accelerated approval program, reserved for drugs to treat serious or life-threatening diseases, and where there is a lack of available therapy.
“Based on the data submitted by the applicant, the Agency has concluded that there is a statistically significant increase in dystrophin production in indicated patients who are exposed to the drug that meets this requirement,” FDA said Monday.
That approval followed a contentious scientific disagreement inside of FDA pitting Janet Woodcock, director of the Center for Drug Evaluation and Research (who was in favor of approval) against Ellis Unger, director of the Office of Drug Evaluation.
The fight boiled down to what should be considered a "statistically significant increase in dystrophin, the surrogate endpoint," and, according to Unger, whether "an exceptionally small magnitude" implies clinical benefit, according to the 126-page approval letter.
"This decision could be precedent setting with respect to accelerated approval, i.e.,
where the bar should be set for changes in a pharmacodynamic biomarker that are
deemed 'reasonably likely to predict clinical benefit.' Moreover, to my
knowledge, this could be the first time a Center Director has overruled a review
team (and an advisory committee) on a question of whether effectiveness has been
demonstrated," Unger wrote in an email to Woodcock.
In his appeal of Woodcock's decision to override the advisory committee's vote and other reviewers' qualms with the the application, Unger noted that the position of the
review team in the Division of Neurology Products, the Office of Biometrics, the Office of
Clinical Pharmacology, the Office of Drug Evaluation-I, and the Office of New Drugs "(verbal
acknowledgement from Dr. John Jenkins) is that the applicant has not provided evidence
that this drug is effective at the dose studied."
However, FDA Commissioner Robert Califf noted in his letter on the dispute that he deferred to Woodcock on the approval decision.
Moving forward, FDA said it is requiring Sarepta (company's stock increased in value by more than 80% as of Monday morning and the company also won a rare pediatric priority review voucher as a result of the approval, which it says it will sell) to conduct a clinical trial to show that the drug preserves motor function, with eteplirsen being compared to placebo.
The required study is designed to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, FDA said it “may initiate proceedings to withdraw approval of the drug.
“In this case, flexibility is warranted because of the life-threatening nature of the disease; the lack of available therapy; the fact that the intended population is a small subset of an already rare disease; and the fact that this is a life-limiting disease of children. These factors, combined with the dystrophin production data – and the drug’s low risk profile – led the Agency to approve the drug under the accelerated approval pathway,” FDA said.