The Eteplirsen Precedent: No Denying It – So Let’s Define It
Executive Summary
US FDA allowing Sarepta to seek accelerated approval for follow-on DMD agent – following 'precedent' set by eteplirsen. Now the new challenge is to define exactly what that precedent is.
It took almost 18 months to become clear, but it is now safe to say that the US FDA’s September 2016 approval of Sarepta Therapeutics Inc.’s eteplirsen for Duchenne Muscular Dystrophy is precedent-setting after all.
The circumstances surrounding that approval were obviously unprecedented from the first. The drug was approved because Center for Drug Evaluation & Research Director Janet Woodcock overruled FDA’s Division of Neurology Drug Products and the Office of Drug Evaluation I leadership team of Ellis Unger and Bob Temple. The approval decision came only after a further review by then-Commissioner Robert Califf, who deferred to Woodcock’s decision after considering an internal appeal lodged by Unger. (Also see "Sarepta's Eteplirsen Approved After Contentious Internal FDA Debate" - Pink Sheet, 19 Sep, 2016.)
Rather than reject the application, FDA granted an accelerated approval based on small increases in dystrophin levels, with clinical evidence of functional improvement to be determined in future studies (including placebo-controlled trials of related compounds in other genetic variants of DMD).
At the time, Califf declared that the approval decision is “not a precedent.”
It always seemed hard to imagine how that declaration could be enforced – and sponsors, at least, never felt obliged to follow Califf’s decree. (Also see "FDA's Fears Realized: Sponsors Pitching Investors 'Sarepta Model'" - Pink Sheet, 25 Oct, 2016.)
FDA Throws In The Towel
As of February 2018, it seems, FDA has decided to throw in the towel as well. The eteplirsen approval is a precedent after all.
The first public indication of the change of heart came February 20, when PTC Therapeutics Inc. announced that its appeal of FDA’s decision to reject ataluren for nonsense-mutation DMD had been denied. While approval was not granted, FDA did says, according to the company, that it would consider accelerated approval based on data showing increased dystrophin production (assuming PTC could produce such data using appropriate testing).
Nothing about the communication explicitly cited eteplirsen as a precedent, but it sure felt familiar –including the hands-on role taken by Woodcock in over-ruling Unger. As acting director of the Office of New Drugs, Woodcock heard the appeal – and the advice on accelerated approval as an option directly contradicts Unger’s views expressed during an advisory committee review of ataluren. (Also see "PTC’s Ataluren and Accelerated Approval: Is Eteplirsen A Precedent After All?" - Pink Sheet, 28 Feb, 2018.)
At about the same time, Sarepta was discussing potential approval pathways for its next DMD agent – golodirsen, which targets the exon-53 mutation, rather than exon-51 like eteplirsen. After receiving the formal minutes of the meeting, Sarepta shared the feedback – it can file for AA based on dystrophin data.
And, at least in Sarepta’s telling, FDA itself cited the “precedent” of eteplirsen in its response. Here is the key quote from Sarepta’s press release:
It is worth noting one very big difference in the two announcements: Sarepta’s feedback came not from Woodcock in the context of a dispute or appeal, but directly from Unger in his role as office director discussing the issue up front.
That is remarkable, considering the extraordinary steps Unger took to stop the eteplirsen approval in the first place – and his comments last summer suggesting that he continues to view the decision as a mistake. (Also see "FDA’s Unger On Exondys Approval As Precedent: 'We Hope Not'" - Pink Sheet, 4 Jul, 2017.)
How to explain Unger’s apparent willingness to invoke the “precedent” he fought so hard not to set?
It would be nice to know the order of events. Did Unger already know that he was being overruled on PTC when he met with Sarepta on golodirsen? If so, he may simply have been bowing to the inevitable and skipping the likely appeal by Sarepta if the division said it would not consider accelerated approval.
Two Possible Precedents
More likely, though, the issue hinges on what exactly the “precedent” of eteplirsen means.
For Unger, in particular, the issue with eteplirsen wasn’t so much the use of the Accelerated Approval pathway. Instead, it was two other issues – and those two issues are probably far more important in considering how the eteplirsen precedent applies in the future.
First, there was the magnitude of the dystrophin increase detected, which Unger believed fell far short of an amount that would likely to translate into a clinically meaningful effect even if the underlying dystrophin hypothesis is correct.
More seriously, Unger (and most of the review team) objected to the entire approach to developing eteplirsen – an approach that seemed to rely on patient advocacy to substitute for rigorous, methodical evidence generation. On that point, at least, FDA appears to have made sure that the eteplirsen approach is not the model.
Getting Sponsors To Do The Right Thing
FDA’s neurology group went out of its way to praise PTC for the size and rigor of its clinical development program for ataluren, even as they offered a negative assessment of the efficacy data it generated. The sponsor may not be perfect, but it did conduct large placebo-controlled trials over a period of years.
Similarly, Sarepta – now that it is a commercial enterprise under new management – has taken a very different approach with golodirsen than it did with eteplirsen. This is not a case of retrofitting accelerated approval to fit a study that failed to meet its original endpoints; this is a program that makes sense if you assume dystrophin production is reasonably likely to predict clinical benefit.
For that instance, at least, there is ample precedent for FDA showing regulatory flexibility for sponsors who do things the right way.
From the editors of the RPM Report