Changing the Paradigm: The Eteplirsen Ad Comm

There is no way around it, today was hard. Hundreds of us – the largest gathering of Duchenne families in history – came together to tell the FDA that eteplirsen is safe, effective, and should be approved using the tools that have been given to the FDA, tools that our community worked with Congress to put in place. And while being a part of this gathering was one of the highlights of the over 30 years I have been in this community, it also broke my heart – over and over and over again. 52+ times. As family after family reminded us of the devastation of this disease and the tiny deaths we witness our loved ones live through.

The raw emotion and passion of this community is unlike anything I have ever witnessed before. You opened your hearts, your stories for the world to hear. Your testimonies were incredibly compelling, beautifully expressed, and poised. Once again, our community I think, will be held up as a model to other rare diseases, representing the way you convene a group of people to share their experiences with a product as effectively as possible.

It felt like a trial. It felt like we were defending our children and their right to a treatment we believe in. Like you, I am dumbfounded by the closing votes and discussion (see our recap below). But this is part of the process. A decision has not been made – these were recommendations. And I believe that the number of questions with mixed votes represent opportunities for us to change minds and continue to influence the agency. Every member who abstained from voting seemed visibly torn, weighing I believe the benefit/risk equation our families presented. It was our responsibility to educate the FDA today with data and first-hand accounts of the effectiveness of this treatment. I believe we did this.

As I told in my testimony today, 20 years ago I lost my second son to Duchenne. When my sons were alive, they had no options. Today we are talking about a drug with significantly greater impact, one that is focused on the fundamental defect in Duchenne, restoring dystrophin. Eteplirsen is safe. Four years of safety data with no adverse effects. We can argue small numbers. We can argue about quantification of dystrophin.   

But what is critical is to discuss the impact of an incremental effect. A positive incremental effect has a ripple effect across a lifetime. Extending ambulation, preventing scoliosis, decreased financial impact in terms of accommodation (school, home, employment), and perhaps most important, preserving quality of life.

Taking Action

Our community doesn't know the meaning of the word quit. We have been and will continue to be an incredibly driven group because we are fighting for the most important thing in the world...our children. PPMD has connected with Sarepta to find out how we can help them between now and the PDUFA date of May 26. We will look at policy opportunities and we will reach out to our champions in Washington. And we will make every effort to speak to the FDA directly.  

Voting Results

Today’s final discussion and vote are similar to scenarios we discussed in a previous webinarThe questions were included in briefing documents the FDA published last ThursdaySeven questions were presented with a discussion followed by a vote on that discussion. 

The questions, as well as the votes, were designed to facilitate discussion around the findings and complexities of each of the studies that had been presented throughout the day. 

1) Discussion: Discuss the evidence presented about dystrophin production, including the following:

  • A.The strength of evidence that eteplirsen increased the amount of dystrophin in muscles of treated 
patients, relative to their baseline. 

  • B. Clinical meaning of the amount of dystrophin observed in the muscles of eteplirsen-treated patients, taking into consideration the range of amounts of dystrophin known to be typically present in patients with DMD and in patients with Becker muscular dystrophy. 


  • Moderate evidence for dystrophin production – but how much is clinically significant? Is this dystrophin that’s manufactured through exon skipping better that naturally produced dystrophin?
  • It’s possible that dystrophin couples in some way that is relative to function.
  • Is that universal – or applicable to only a subset of patients.
  • I agree it’s ambiguous.
  • Might not be a Threshold effect? If there is – it may very well take very little.
  • Whether or not the biospsies taken the correct ones? Can we make comparisons?
  • Hoffman – plenty of evidence that mechanism of action is working
  • (Is this the question, however)
  • JW – re-explaining the question after AC members seemed to all be very supportive of a positive vote
  • Question of dose-effect in 30md/kg vs 50 mg/kg – AC member responded that dose escalation study has not yet been conducted.
  • Paul Romitti – Felt more confident with the 3 blinded review; sees evidence of efficacy here with re-analysis and re-reads – both immunoflourecence and WB

2) Vote: Has the Applicant provided substantial evidence from adequate and well controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit? 

  • This is the standard for AA.
  • Is Eteplirsen likely to meet the standard for approvability.
  • Must factor in clinical data. What weight does it give to the decision?
  • Whether or not dystrophin is increased?
  • Reasonably likely – no standard established.
  • Threshold – not established for DMD.
  • Does the clinical experience in these pts: Is it reasonably likely to predict clinical benefit?

Yes – 6

Hoffman, Dupree, Foley, Green, Gunvalson, Romitti


  • compelled by OPH testimony

No – 7

Alexander, Gonzalez*, Kesselheim, Kryscio, Nuckolls, Onyike, Ovbiagele


  • studies not well-controlled,
  • thinks WB comparison is most important and doesn’t think this fits the definition of an adequate and well-controlled study
  • lack of association between dystrophin findings and clinical findings
  • technique concerns
  • Gonzalez believes that it is more likely than not that drug produces dystrophin – but doesn’t feel that trial was adequately well-controlled to demonstrate reasonably likely clinical benefit
  • Concerned about dystrophin production data presented
  • Question about correlation between levels and outcomes

Abstain - 0

Paul Romitti ‘hit the wrong button’ and changed his vote during discussion.

3) Discussion: Discuss the strengths and weaknesses of the clinical evidence of efficacy provided by Study 201/202, with particular consideration of the design of the study, sample size, statistical methods, general concerns regarding a comparison to a historical control group, specific concerns with respect to the comparability of these two groups (in particular, how motivational factors and differences in assessment of physical performance outcomes may have affected the 6-minute walk endpoint and other endpoints), and any other issues that you think may be important. 


  • Placebo controls are flawed, but historical controls are worse.
  • Noted contrast between conclusions reached between analyses that followed patients by age vs length of treatment – plots of primary outcome, versus study enrollment alone
  • Gonzalez: Reviewing data from sponsor, every 2nd endpoint was so positive – placebo group may have elicited striking changes and caused study to end sooner. Why no placebo group?
    • Ed Kaye – Not enough drug manufactured to do such a large trial at study initiation. Did external control (next best thing)… to move trial forward.
    • Onyekie – Drug isn’t having effect across the board – all other outcomes should line up in the same direction. Impact should converge across the board. In this case, they don’t. (FDA slides 87, 92-94)
      • Referenced Austin LeClaire’s testimony and the fact that he could stack cans – why not have a secondary outcome about PUL or grip strength? Testimony from families captured benefit that trial didn’t.
      • Ed – we did look at grip strength (did not go down in 4 years) and pulmonary function; we appreciate the small size of the study but when you look at the totality of the data, it is already in favor of eteplirsen
      • Were patients assisted when they were timed to rise from the floor?
        • Ed explaining Rise Time: “unaided”
        • Discussion became very confusing

4) Vote: Were decisions to administer the 6-minute walk test (vs. conclusions that the patient could no longer walk) sufficiently objective and free of bias and subjective decision-making by patients, their caregivers, and/or health care professionals to allow for a valid comparison between patients in Study 201/202 and an external control group? 

Yes – (Sufficiently Objective) – 5

Dupree, Gunvalson, Hoffman, Onyike, Romitti

  • Magnitude of error wouldn’t be enough to distort the small sample size
  • Plenty of potential for bias but no real evidence – so anything is just speculation

No –  (Biased) – 7

Alexander, Foley, Gonzalez, Green, Krysico, Nuckolls, Obbiagele

  • Open label
  • Control patients deemed unable to perform 6 MWT
  • Difficulties with using a historical control
  • Concerns about the ways the controls may not have been comparable with the treated patients
  • There were pts with 10 meter w/r, but not 6MWT
  • Predetermined selection criteria for historical control group were not sufficient to control for biases

Abstain – 1

Kesselheim – not a very good question, convinced through the course of the day that 6MWT was a valid clinical endpoint, didn’t agree with part of the question

Non-Voting - 0


5) Vote: What is the impact of the North Star Ambulatory Assessment results on the persuasiveness of the findings in Study 201/202?

a. Strengthen 
- 1

b. Weaken 
- 5 
Alexander, Kryscio, Nuckolls, Onyike, Ovbiagele

  • NSAA is closer to a functional rating scale
  • NSAA measures many of the same things as the 6MWT, this weakens the strength of the 6MWD
  • Moved by the slides of the really big error bars (likely due to the small numbers of patients in this comparison
  • Trend lines are virtually indistinguishable, and confidence lines overlap

c. No effect 
- 7
Green, Dupree, Foley, Gonzelz, Romitti, Hoffman, Kesselheim

No-Voting: 0

Clarifying questions:
Do we use totality of evidence presented by both sponsor and FDA? Yes

6) Vote: What is the impact of the other tests of physical performance (e.g., rise time, 10-meter run/walk) on the persuasiveness of findings in Study 201/202?

- 1


  • Liked Craig’s presentation

b. Weaken 
- 2

Alexander, Onyike

  • Would have liked to have seen more effect of the study drug on these outcomes

c. No effect 
- 10

Dupree, Hoffman, Ovbiagele, Foley, Kesselheim, Romitti, Gonzalez, Kryscio, Green, Nuckolls

  • Disagreement between FDA and sponsor wasn’t resolved
  • No correlation between these and 6MWT
  • 10M walk/run doesn’t add much to the assessment
  • rise time is just one component of the NSAA
  • absence of control group makes interpretation of any secondary outcome measures difficult to interpret


7) Vote: Do the clinical results of the single historically-controlled study (Study 201/202) provide substantial evidence (i.e., evidence from adequate and well-controlled studies or evidence from a single highly persuasive adequate and well-controlled study that is accompanied by independent findings that substantiate efficacy) that eteplirsen is effective for the treatment of DMD? 

Clarifying question: To what extent are we to take into consideration to testimony of the views of the community?

  • Janet Woodcock – As the community stated, we are instructed to have flexibility when considering the ‘totality of the data’.
  • John Jenkins – We have a rare opportunity to have all of the patients gathered here. One of the things you can do is try and reconcile what you are hearing from the patients who are here with the data that you have seen today.
  • Janet Woodcock - This is the full approval question, based on the persuasiveness of the trial that was conducted in the clinic.

Yes – 3

Dupree, Foley, Gunvalson

  • Evidence of amelioration of the clinical phenotype of Duchenne

No – 7

Alexander, Gonzales, Kesselheim, Kryscio, Nuckolls, Onyike, Ovbiagele

  • Confused by patients in follow on studies?
  • Not a well-controlled study
  • Analyses didn’t meet the thresholds necessary for approval
  • Findings do not support approval based on statistical grounds – what I considered meaningful are not properly measured in this study (Onyike) – “I hope you will consider in the future participating in placebo controlled studies” – created an outburst in the room

Abstain – 3

Green, Hoffman, Romitti

  • Still room to grow here

Ben Dupree cried as he gave his reasoning for supporting the vote.

Enough said.

PPMD's Submissions

Open Public Hearing Testimony:

Written Testimony:

Click here to download the written testimony submitted by PPMD to the Peripheral and Central Nervous System Drug Advisory Committee.

What's next?

And now we wait. Once again. We wait until the agency makes a decision, wait until we are told if we are allowed to treat our sons with a therapy we believe to be safe and effective. Some days it feels like waiting is our full time job.  

Tonight, be proud of yourself. 

If you participate in the eteplirsen trial or any trial for any potential therapy in the Duchenne pipeline, you are our hero! You have forever changed the progression of Duchenne with your bravery and selflessness. "Thank you" will never be enough.

If you spoke at the Open Public Hearing, be confident that your heartfelt testimony made an impact. Opening your heart, your home, your family's story today was not in vain. You moved people around the world - thousands watching online.

If you attended the Ad Comm today as a spectator, watching from one of the satellite rooms via the live stream, your presence and your energy motivated and inspired all of the OPH participants. Your belief in us helped us believe in the job we had to do. 

And if you followed the meeting from home or work, via social media or live streaming, I hope you felt represented and that you felt like your story or a version of your story was told. You might not have physically been there, but your spirit was felt and appreciated.

We were so proud too, of the #MakeDuchenneHistory coalition that came together and organized a monumental, logistical feat. Each group put their talents and skill set to use so that the community could come together easily and effectively. We are stronger when we speak in one voice.

There have been many historic moments in Duchenne over the last few years as we continue to lead the rare disease community with unprecedented strides in Congress and with federal agencies. For a disease with no approved treatment (as of yet!), this community has done more to change the landscape in the clinical trial process since the AIDS community years ago.

Today, was arguably our most important day as a community. We set new records with the greatest number of participants in the OPH, in attendance, and streaming an Ad Comm that had to be extended to accommodate this incredible participation. We came together as one extended, powerful family. Today was for every single person with Duchenne.   

I go to sleep tonight proud and more hopeful than I have been in a long time. As always, I will pray that we end Duchenne. And tonight, I pray that today will go down in our collective as the day we made Duchenne history with the approval of the first Duchenne therapy.

Photos provided by David Stalling.

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Comment by Alpa Khushalani on May 2, 2016 at 3:44pm

We are ever so grateful to you Pat for continuing to motivate our community and giving us hope even in the face of continuous disappointments. Thank you so so very much ! 

Comment by Steven on April 27, 2016 at 2:21am

The turn out was amazing, I just can't help but worry about the broader implications of the bazaar (truly, bazaar) hard line it seems the FDA has taken on this particular disease and drug approvals.  Investors and biotechs vested in further research into DMD therapies are (rightfully so) getting more and more gun shy about even dipping their toes into the muddied waters.  If it gets much worse, it seems there could be a significant impedance on the community, and stagnate research while pharmaceutical companies try and pick up the pieces.  I think it's far more important to approve this drug to prevent the aforementioned from happening, regardless of it's perceived ineffectiveness.  I just hope the FDA understands that this is a very real, and terrifying implication that could affect more than just this generation.

Comment by David Stalling on April 26, 2016 at 5:12pm

An excellent recap and powerful testimony, Pat. Thank you for all that you, your staff and volunteers of PPMD have done and continue to do to fight for and help improve the lives of our amazing boys and all of us affected by DMD. Keep up the good fight!   

Comment by Rahul Deshpande on April 26, 2016 at 9:05am

Pat many thanks for your efforts. Your speech was moving and touched the heart. I saw the entire Ad Comm via live streaming. The DMD community made an excellent case for approval of Eteplirsen. The way children and their parents spoke was highly commendable. It is unfortunate that the majority in the advisory committee did not give positive views about Eteplirsen. But I felt the voting questions written by FDA were confusing and questioned more on the way the trials were conducted. For the last question the committee was confused whether they should take the opinion of the community or not and FDA did not tell them clearly to consider the opinion of the community. Looks like its going to be a tough road for the community to get approval for DMD drugs from FDA.

Comment by Shelly on April 25, 2016 at 11:28pm
Thanks Pat for everything. Fingers crossed!

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