FDA’s Approval of Duchenne Therapy Exondys 51 Sparks Lawsuit by NYU Professor

The U.S. Food and Drug Administration (FDA), which in September 2016 approved Serepta Therapeutics’ Duchenne muscular dystrophy (DMD) treatment Exondys 51 (eteplirsen), now finds itself the subject of a lawsuit aimed at forcing the FDA to turn over information about the approval process.

Charles Seife, a journalism professor at New York University and former writer for Science magazine, sued the FDA after it approved the drug against the recommendation of an outside expert panel, according to the Reuters report. Seife said the law requires the FDA to expedite the federal Freedom of Information Act request he filed last year because of its importance to the public.

The approval Seife questions was controversial, because much of the data Serepta used to accelerate Exondys 51’s approval was based on a small study in a dozen children with no placebo control to compare the results. Rather, that study compared eteplirsen against historical data in DMD patients.

The FDA in its 2016 accelerated approval concluded nevertheless that the data submitted “demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in some DMD patients wth a mutation amenable to exon 51 skipping. It also required a clinical trial be conducted to “confirm” the drug’s benefit.

John Jenkins, former director of the FDA’s new drugs office, wasn’t happy with the way Exondys 51 was approved either. Last October, Jenkins — who has since retired — gave a talk at the NORD Summit in Arlington, Virginia. During the presentation, “Lessons learned from eteplirsen and other recent rare disease programs,” he specifically called the path taken by Sarepta “not a good model for other development programs,” Ben Adams reported in a news story for FierceBiotech.

Exondys 51 is an exon-skipping drug that treats patients with a mutation of the dystrophin gene amenable to exon 51 skipping.

In April 2016, an FDA panel of outside experts voted 7-6 that Sarepta did not provide enough evidence that the drug produced dystrophin at a level that was reasonably likely to produce a clinical benefit. And, in a separate 7-3 vote, a majority decided that the clinical trial was poorly designed, the Boston Globe reported.

Parents of children with the disease and DMD advocate groups had strongly pressed the FDA to approve the treatment.

In his presentation, Jenkins criticized what he said are poorly planned and executed development programs that misuse patient resources and delay obtaining the knowledge necessary to understand the real benefits and risks of a particular drug to support regulatory review.

“In many cases, randomized controlled clinical trials represent the fastest way to determine if a drug is effective and that companies should randomize as early as possible in development to avoid potentially misleading and uninterpretable findings from open-label trials,” he said.

However, he added that “flexibility in FDA regulations does not mean marketing approval prior to demonstration of substantial evidence of effectiveness,” and that the FDA’s speedy review programs are not to be used as a “rescue for a failed program.”

Sarepta is now conducting the required “confirmatory” study, a 96-week and open-label clinical trial at 39 sites across the United States, with final data expected in early 2019. The Phase 3 study (NCT02255552) is currently recruiting an estimated 160 DMD patients, ages 7 to 16, both those with a mutation amenable to exon 51 skipping to be treated with eteplirsen, and those without such a mutation to serve as a control group. The trial will also assess the treatment’s safety and a number of biomarkers.

If clinical benefit is established in the trial, Exondys 51 will likely be fully approved; if not, FDA approval could be withdrawn.