Following a contentious debate pitting young boys with the terminal illness Duchene Muscular Dystrophy (DMD) against the US Food and Drug Administration (FDA), an advisory panel of outside experts on Monday voted against the approval of Sarepta Therapeutics’ controversial investigational drug eteplirsen to treat DMD.
The agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted 7-3 against approval, with three abstaining, and 7-6 against the accelerated approval of eteplirsen.
Glen Nuckolls, PhD of the National Institutes of Health, Dr. Aaron Kesselheim of Harvard and other physicians on the panel raised concerns with the controls of the trial and the way the study was conducted though questions were raised before voting on whether patient testimony should influence the vote on the studies.
“As the data currently stand, it doesn’t appear this [data] provides substantial evidence,” Kesselheim said.
Chiadi Onyike, MD, associate professor at the Johns Hopkins University School of Medicine, added: “What I would consider meaningful testimonies from the families were not included in this study.”
The vote from FDA’s outside panel of experts came as hundreds of DMD advocates piled into the hearing in Maryland and called for the drug’s approval with, at times, loud applause (in addition to 52 speakers in the open public forum, nearly all of whom were pro-eteplirsen) that seemed to rattle some of the FDA speakers who presented data and interpretations that did not support the drug’s approval.
At the end of the day, though, the Catch-22 for FDA is clear: Does the agency approve a generally safe but possibly ineffective DMD treatment based on limited data, and then rely on post-marketing data to see if the treatment is really effective, possibly raising false hopes of families and young boys that believe the drug is working? Or does FDA reject eteplirsen, wait for more data to prove its effectiveness and possibly deny access to the treatment (for up to three years) until more concrete evidence of the treatment’s effectiveness?
If approved, eteplirsen would be the first DMD treatment in the US. In January, FDA rejected BioMarin Pharmaceutical’s DMD drug drisapersen as it said the drug is not effective. About 15,000 young US boys are afflicted with DMD, a rare and fatal genetic disorder that usually leaves them unable to walk by the time they’re 18 years old.
The vote on Monday followed the release of briefing documents (which the families of the boys in the trial and Sarepta criticized) that were highly critical of the way Sarepta conducted its 12-subject study looking to prove that eteplirsen works.
Panel of Firsts
At the meeting’s outset, FDA’s Director of the Division of Neurology Products William Dunn made clear that anecdotes and emotion do not change the data with which the agency is presented to make its decision, though FDA’s approval last year of the twice-rejected female libido drug Addyi (flibanserin) seems to suggest that FDA is beginning to take patient opinions more into account in its approval decisions.
CDER Director Janet Woodcock, who rarely attends advisory committee hearings, also made clear that FDA’s final decision will not be a straightforward one (the agency is not required to follow the opinion of its advisory committee, though it often does) as FDA and Sarepta differ widely in their analyses of whether the treatment was effective, though both sides agreed that the treatment is safe.
Woodcock also explained the difficulties faced by the agency in deciding the fate of eteplirsen, particularly as there are features of the drug’s clinical development so far that are “difficult to interpret," but she also made clear that the agency’s failure to approve a drug that might actually work in the long-term could have extremely negative consequences for patients, particularly young boys.
Ed Kaye, chief medical officer and interim CEO of Sarepta Therapeutics, presented the company’s clinical findings, noting that after four years of treatment, only two boys treated with eteplirsen lost the ability to walk, which compared to 10 of 13 untreated boys who lost ambulation, though those boys were not from the trial but from historical data.
What’s more: Eteplirsen’s safety has been well established and neither FDA nor Sarepta reported any toxicity concerns based on the data.
However, in FDA’s presentations on Sarepta’s data, agency officials made clear that they called on the company to run a placebo-controlled, randomized clinical trial, and that the trial run by Sarepta and the data presented did not clearly show the drug’s effectiveness.
Robert Temple, CDER's Deputy Center Director for Clinical Science, made clear following Woodcock’s comments that FDA does rely on historically-controlled trials in certain cases, particularly for rare and fatal diseases and when there’s a predictable course of a disease.
But what remains unclear is whether a randomized, placebo-controlled trial (the gold standard for determining a drug’s efficacy) would ever be run by Sarepta if eteplirsen is granted accelerated approval.
Eric Bastings, FDA Deputy Director of the Office of Drug Evaluation’s Division of Neurology Projects, recognized and praised the DMD community advocating for and supporting the approval of eteplirsen, but he also made clear that the data supporting that approval “must be must be sufficient to draw valid scientific conclusions.”
One of the main issues, FDA officials contend, is that eteplirsen does not seem to have a significant impact on certain protein levels, known as dystrophin, which is known to cause DMD. In addition, Ronald Farkas, clinical team leader of FDA’s Division of Neurology Products, said it does not appear that eteplirsen "unequivocally" produces dystrophin.
FDA's Ashutosh Rao also raised questions on how Sarepta measured the dystrophin levels of the patients in the trial.
“Accelerated approval cannot be used to compensate for weak or insufficient data,” Bastings added.
FDA has until 26 May to make its final decision on Sarepta’s eteplirsen.