FDA, in Reversal, Approves Vyondys 53 to Treat Duchenne Patients with Exon 53 Mutations

The U.S. Food and Drug Administration has conditionally approved Vyondys 53 (golodirsen) to treat Duchenne muscular dystrophy (DMD) patients amenable to exon 53 skipping.

This accelerated approval comes less than four months after the FDA issued a complete response letter rejecting Sarepta Therapeutics’ application for approval due to safety concerns.

Sarepta filed an appeal, and said it met with officials and resolved issues raised by the agency before resubmitting its request, which led to Thursday’s decision.

An ongoing clinical trial, called ESSENCE (NCT02500381), is now a “post-marketing confirmatory trial,” the company said, which is typically required under conditional approval.

“With the approval of Vyondys 53, up to another 8% of Duchenne families will have a therapy to treat this devastating disease,” Pat Furlong, the founding president and CEO of Parent Project Muscular Dystrophy (PPMD), said in a press release. “While we need to ensure that these approved therapies are accessible for patients, today we celebrate this approval and thank Sarepta for their continued leadership in the fight to end Duchenne.”

The therapy is the first targeted treatment for people whose Duchenne-causing mutation is amenable to exon 53 skipping, Billy Dunn, MD, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

DMD is caused by a mutation in the DMD gene, which disrupts the production of dystrophin, an essential protein for muscle integrity.

Vyondys 53 is an exon-skipping therapy given by intravenous (IV) infusion (directly into the bloodstream). It was designed to skip exon 53, in the messenger RNA produced from the DMD gene, to generate a shorter but working version of dystrophin. Approximately 8% of all DMD patients have mutations that are amenable to exon 53 skipping. (Exons are the tiny bits of DNA containing information to produce proteins)

The FDA’s decision was based on results from a Phase 1/2 clinical trial (NCT02310906). After a 12-week period where Vyondys 53 was tested against placebo, all enrolled received 30 mg/kg of Vyondys 53 once a week for 144 weeks (2.7 years).

At 48 weeks of treatment, the therapy led to a significant increase in functional dystrophin levels — likely to predict clinical benefit — in 25 boys with DMD amenable to exon 53 skipping, compared with an untreated group of DMD patients (those whose mutations were not amenable to exon 53 skipping).

The most common side effects seen in at least 20% of trial patients were headache (41%), pyrexia or fever (41%), falls (29%), abdominal pain (27%), nasopharyngitis or a cold (27%), cough (27%), vomiting (27%), and nausea (20%).

“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, Sarepta’s president and CEO. “Along with Exondys 51 (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the U.S.”

Exondys 51, designed to target exon 51, was the first disease-modifying treatment approved by the FDA for a specific group of DMD patients. About 13% of these people have defects amenable to skipping exon 51.

“In the span of four months, we commenced and completed the formal dispute resolution process … resubmitted our NDA and obtained an approval — a great benefit to DMD patients awaiting treatment,” Ingram added.

Vyondys 53’s price will be similar to that of Exondys 51, Sarepta said, which is around $1,680 for a 2 milliliter supply of the IV solution and about $8,360 for a 10 ml supply. Pricing of Exondys 51 is based on a patient’s weight, and Sarepta estimated its annual cost to be around $300,000 when it was approved in September 2016.

The Phase 3 ESSENCE study (NCT02500381) will evaluate the safety and effectiveness of Vyondys 53 and of casimersen (SRP-4045) — an investigational exon-skipping therapy also by Sarepta — in DMD patients with mutations amenable to exon 53 (Vyondys 53) or exon 45 (casimersen) skipping.

The trial, which officially opened in September 2016, is enrolling up to 222 patients at sites across the U.S., Europe, Canada and elsewhere. Roughly equal groups of 111 patients are planned for each of these mutations.

Expected to conclude by 2024, its main goal is changes in muscular strength and ability as measured by the six-minute walk test (6MWT) after 96 weeks (almost two years) of treatment. Safety will be examined throughout the trial.

“Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial,” said the FDA’s Dunn.

A patient assistance program for those using Vyondys or other company therapies, called SareptAssist, is available to help with treatment use and availability, and insurance and other financial concerns. More information is at SareptAssist.com or by calling 1-888-727-3782.