FDA expert lashes out at 'worrisome' Sarepta approval in JAMA

External FDA expert Aaron Kesselheim, who advised against the regulator approving Sarepta’s ($SRPT) new and highly controversial Duchenne med Exondys 51 (eteplirsen), has used a JAMA article to hit out at the regulator’s processes and the biotech that led to its green light last month.

In the article, Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy, co-authored with Lewis Avorn, a professor of medicine at Harvard Medical School, the two questioned the trial design and the mining of the data, which included excluding two eteplirsen-treated patients who deteriorated quickly while receiving therapy.

“These analyses suggested a statistically significant advantage for the remaining treated patients,” the authors said.

Kesselheim, who was at the April FDA advisory meeting discussing whether the med should be approved (he voted against), said that meeting also brought into view the controversy around this drug.

“That hearing included more than a thousand public attendees and more than 4 hours of comments from patients, families, advocates, scientists, and legislators,” he writes. “The public presentations were frequently emotional, and nearly all of the presenters (51 of 52) favored drug approval. The advisory committee was generally unimpressed with the efficacy data.”

The article sympathizes with these presentations, saying that the voices of patient advocates “should be made known,” but argues that many such groups “are financially supported by drug manufacturers to help advance their goals. Even in the absence of such support, popular opinion can be shaped by uncritical enthusiasm by patients and their families, or by unbalanced reports from the manufacturer.”

He noted the delays that came after this meeting, and the further controversy when CDER head Janet Woodcock “overruled” concerns about the drug’s approval. “The internal FDA review staff took the unusual step of appealing to Commissioner Robert Califf, MD, who upheld Woodcock’s decision,” he says.

Kesselheim said that even after the approval, the appeasement that Sarepta would have to do another trial to prove efficacy was still problematic. The deadline for these data is not for another 5 years, and crucially, a placebo group was not required, “although it would be difficult to recruit patients to a placebo-controlled trial of an approved drug,” the authors note.

“Accordingly, without a true control, it is not clear how the results regarding drug efficacy will be assessed. Barring a major unexpected safety problem, it is unlikely that the new study could provide sufficient evidence leading to removing eteplirsen from the market.”

The authors do not believe this is the best way forward, as it means that more rigorous data from follow-up trials “may be years away, or may never become available. This will further increase the nation’s growing expenditures for medications, even in the absence of clear patient benefit.”

The article concludes that “Patients with DMD need better treatments, and drugs like eteplirsen might one day fill that role. For now, though, the drug has provided a worrisome model for the next generation of molecularly targeted therapies: demonstrate a slight difference in a laboratory test, activate the patient community, win approval, and charge high prices, while relying on limited regulatory follow-up.”

This is the second FDA expert in as many weeks to come out against the drug’s approval. John Jenkins, who runs the FDA’s office for new meds, spelled out his problems with the approval in a presentation earlier this month, saying that the “path taken by Sarepta NOT a good model for other development programs.”