Rare Disease Report

Duchenne Mom Comments on AdComm and Eteplirsen's Chances

MAY 04, 2016
James Radke, PhD
Last week, we reported on the historic meeting in which the FDA Advisory Committee (AdComm) reviewed the data for Sarepta’s eteplirsen to treat patients with Duchenne muscular dystrophy amenable to exon 51 skipping therapy.  It was historical because of the 52 people who spoke during the public forum of the meeting. Their participation made it clear that the patient community is strongly in favor of approving the orphan drug. That public consensus is in sharp contrast to the FDA staff’s negative review they gave the drug in their report presented to the AdComm group.  
And as we wrote last week, if Sarepta gains approval of eteplirsen, it will be not because of what Sarepta presented. It will be because of what the patient community presented. The patient community were extremely well organized and presented compelling information to the AdComm that was not fully covered in eteplirsen's NDA or the FDA's  briefing document.
Among the 52 public forum speakers was Christine McSherry, mother of a boy with Duchenne and fexecutive director of the Jett Foundation
Christine also made the AdComm meeting historic by presenting the first-of-its-kind Patient Centered Outcomes Report during the meeting.
In this exclusive interview with Rare Disease Report, Christine talks about the AdComm meeting and the plans for the Duchenne community moving forward. 

The FDA is expected to make a decision on eteplirsen on or before May 26, 2016.

Rare Disease Report: How much effort/coordination was involved in getting everyone to the AdComm meeting and for providing such  good questions with minimal overlap?

Christine McSherry: We started planning in September for AdComm, believing that AdComm would take place in November and then January. So by the time April 25th came around, we had been working for 7 months. It was a difficult to transport over 900 people from all over the world to Hyattsville, Maryland, but Jett Foundation's team has an unwavering amount dedication to the Duchenne and rare disease community.

The Jett team included staff and our community volunteers who set out to anticipate every detail - from ground transportation to medical equipment to food, lodging, and airfare. We brought in community members from 38 different states and 8 different languages. We crossed many language and cultural barriers. Our extensive and amazing Camp Promise program provided services for over 130 campers during the event and the Sunday leading up to it.

In the end, regardless of whether or not FDA grants eteplirsen approval, we have a more educated patient community that understands regulatory science and policy and who all played an important part of changing history for the ways in which regulators view applications for drug approval in rare disease, small populations and unmet medical need.

Can you describe the mood of the people at the AdComm meeting during and immediately after the meeting?

Our community came in with the expectation that if we brought our A-game, brought all of the top researchers and clinicians in Duchenne to FDA-even if they only got to speak for 3 minutes, the FDA and the AdComm panel would listen to those who had real experience working with Duchenne.

The day got emotional for patients and families at the end, because even though the panel listened to the world renowned Duchenne experts and the patients- the panel was still divided. Patients and families were sad, people who had no connection to the patient community were sad. Scientists and clinicians were angry, they believe this drug deserves accelerated approval yet they had no formal way, other than a 3 minute testimony, to express their expertise and opinions.

In my opinion the day was a success, the panel and FDA ended the day with much more knowledge about Duchenne than they had when the day started. As a patient community, we did everything we could in the confines of the system to bring expertise and patient perspective to the FDA and the panel, we did our job, now it is time for FDA to do theirs. 

Do you think the questions presented to the Advisory Board were appropriate? Are there any other question you think should have been asked?

You should need three legs of a stool to get a drug to market; efficacy, safety, and mechanism of action. It seems strange, that the voting questions were crafted so that panelists couldn't vote based on the efficacy and safety of the drug, but on the design of the Sarepta's clinical trials. I think it would have been more appropriate if the questions were on safety and efficacy-because at the end of all this, those two things are what matters to FDA and to the patients. Does the drug work? Is it safe?
But what was encouraging to me was question #2, the accelerated approval question. This question led to a closely split vote. That question and the voting results are encouraging to me, because it opens the door again for dystrophin as a surrogate endpoint-which could accelerate the development of other follow on exons. 

What is the Duchenne community (or the Jett Foundation) doing in the next few weeks to ensure that the public’s particpation at the AdComm meeting is including the the FDA’s final decision?

We are working to spread the message that the science is on our side, and that what happened at AdComm is representative of a process problem within FDA. The patient perspective as described in Section 1137 of FDASIA was presented during the development and review of eteplirsen, through quantified patient reported outcomes and patient testimony. 
We are also trying to spread the message that not granting accelerated approval to eteplirsen by it's May 26th PDUFA date, and requiring Sarepta to do either a placebo controlled trial or a withdrawal trial is not a viable option for the Duchenne Community.  
In the tiny mutation specific population that is amenable to eteplirsen, where nearly all patients in this country who are eligible or who may be eligible, are currently enrolled in the still open confirmatory trial or the younger patient trial, a large placebo controlled study would be impossible. And going to Europe to try to enroll European patients wouldn’t work either, BioMarin has a patent block pending in the European courts preventing Sarepta from running any trials in Europe. 
A withdrawal study also would not be possible or ethical in this pediatric population. A withdrawal study would most likely consist of Sarepta taking 1/3 of the patients in the confirmatory trial off drug, and observing them as they decline for somewhere between 48 and 92 weeks, or until there is a statistically significant separation between the treated arm and the new placebo arm. That means some of our kids, who only recently began receiving eteplirsen as part of the confirmatory, are at risk of being pulled off drug and allowed to decline, so FDA can see what happens.
These are the messages we are trying to get out there in the media, in Congress, and at FDA right now. The scientific experts believe in this drug, you must take patient perspective and patient reported outcomes into consideration, and that the only way forward is accelerated approval; a large placebo controlled study or a withdrawal study are not options for eteplirsen.  

Do you think eteplirsen will get approved?

I think, given Jett Foundation's Patient Reported Outcome Report, the Duchenne patient and expert community involvement, and the data-both safety and efficacy, there is a high possibility of approval. FDA has an opportunity to show how they can use the flexibility in Title 21 and in FDASIA to approve drugs based off of data sets that aren't perfect, and to show that they are using the patient perspective in their review of specific products. I would hate to see them squander such an opportunity, and I would hate to see what happens to innovation and investment in all of rare disease if eteplirsen isn't approved.
Ultimately - yes I believe eteplirsen will be approved.

The agency brought up some interesting points in their questions. There was a clear disconnect between the questions that asked about a well controlled trial and the efficacy/safety that the panel was hearing from the OPH testimonies.

And because the disconnect was in fact so wide - this tells me that efficacy and safety do not necessarily fall into the divisions definition of well controlled. Either the agency needs to apply flexibility to "well controlled" or redefine it in legislation through a new statute. Otherwise, FDA and rare disease communities will continue to be far apart on the very issue that is suppose to be in the forefront of their missions - getting safe and efficacious drugs to patients as quickly as possible. 


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