Recapping the FDA-NIH Dystrophin Methodology Workshop

I always felt a strong connection to the Duchenne community while working at the NIH. As you know, that connection and the incredible work of organizations like PPMD inspired me to jump full-time into the fight to end Duchenne.

Yesterday’s FDA and NIH dystrophin methodology workshop really cemented that decision for me. Never have I been more proud to be part of a rare disease community and part of a team of intelligent, passionate people gathered together to educate regulatory agencies. PPMD was honored to be asked to join the conversation as a voice for the community, and I was honored to be a part of PPMD. I spent many years on the ‘other side of the table’ at meetings similar to this one. I must say, yesterday’s speakers were compelling and focused, and I think successful in providing the FDA and NIH with thorough explanations of a complex and complicated subject – how dystrophin is measured.

As Francesco Muntoni and I explained in the webinar PPMD hosted earlier this month, and as was concluded in the community drafted guidance submitted to the FDA last year, we believe that there is a strong likelihood that therapeutic-driven increases in dystrophin will lead to clinical benefit in the appropriate medically addressable population. I believe the representatives from FDA and NIH heard this message. And, while we were instructed by the organizers of this meeting that there would be no discussion about a specific drug, I am hopeful that this meeting will benefit all therapies in the pipeline, in particular the handful of companies expected to file NDAs this year.

Next Steps

After a day’s worth of robust discussions, we left with a few takeaways/next steps outlined by panelists and the FDA and NIH.

There has been substantial progress by academic and company researchers in how dystrophin is measured. Speaker after speaker demonstrated that the approaches used to measure and localize dystrophin in clinical studies and clinical trials have evolved to be considerably more robust and reproducible. Importantly, no tectonic shift was made in the methods recommended for measurement of dystrophin. Instead, the value of the currently used methods (Western blots to quantify dystrophin levels and immunocytochemistry to confirm dystrophin localization and its functional interaction with other components of the dystrophin-glycoprotein complex) was confirmed. The emerging technology of mass spectroscopy, while having promise for future studies, was recommended as a complement to be included along with the other two technologies.

Continuing reliance on immunoblots to assess changes in dystrophin levels and histological verification of dystrophin localization at the sarcolemma does mean that open biopsies will continue to be required in many clinical trials. Everyone connected with drug development recognizes the impact biopsies have on clinical trial participants and speakers strongly emphasized that the number of biopsies be held to a minimum and that handling of those biopsies be improved.  Many of you know that, since biopsies provide only a very small sample, the muscle, fat, and fibrotic tissue content of any one biopsy can be variable and this can confound dystrophin measurement. Guidance of biopsy sites with imaging techniques was discussed, but the panel recommended that more needs to be learned about how MRI, ultrasound, or other technologies before they become a standard for clinical trials to guide optimal selection of biopsy site.

The workshop was comprehensive in addressing the precise operating procedures used in Western blots and immunocytochemistry technologies for assessing dystrophin. Particularly important in these discussions were approaches under development by many of the researchers at the workshop to utilize standard curves and some level of automation to reduce or eliminate any subjectivity in approach. In particular, development of advances to mitigate or eliminate any unintended biases in assessment of dystrophin localization and levels emerged as an important recommendation of the workshop.

Increased cooperation among the stakeholders working to improve dystrophin quantification was one of the most encouraging observations that I made yesterday. A key action item from the last panel discussion was that such collaborations be fostered—with a working group formed to address, in particular, sample handling and unintended biases in analytic techniques.

We were pleased to see so many Duchenne families in attendance at the meeting. For our families this conversation is personal, as it is the absence of dystrophin that connects us as a community. Parent and researcher Carrie Miceli was able to comment from both perspectives and highlighted what our community truly feels and what was reflected in the imperatives letter of the guidance—that current quantification methods are sufficient and the perfect should not be the enemy of the good.

Finally, I know that Pat Furlong and I very much appreciated the opportunity from the FDA and the NIH to participate in this workshop. Each of us emphasized that the advances in dystrophin methodology are to the great benefit of future clinical trials, in allowing them to be done quicker and to more easily assess key parameters such as finding the optimal dose of the drug.  But, both of us also stressed that this worthwhile endeavor embodied in the FDA and NIH workshop not distract us from the immediate need of approval of therapies for people living with Duchenne.


The archived webcast of Friday’s FDA-NIH dystrophin methodology meeting is now available online.

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Comment by David on March 29, 2015 at 5:25pm
Here here Richard! We all want rigor in our methods but this is beyond absurd. Let's go already!!!
Comment by Shelly on March 28, 2015 at 9:11pm
All the beseeching eyes of all the parents globally are on FDA'S APPROVAL OF ETEPLIRSEN . The only hope for dmd community is approval of one such drug which is gonna affect the processing of.other potential drugs amenable to other deletions like deletion of exon 45. I think meetings like " therapeatic driven dysyrophin" should not wave FDA'S DECISION ON THE APPROVAL OF ETEPLIRSEN. We should not keep lives of young lads on stake.
Comment by Richard Darienzo on March 28, 2015 at 5:28pm
While this recent meeting between the NIH and the FDA certainly increases Duchenne's visibility within the main stream medical community,  it represents some disturbing issues.      
     Lack of dystrophin is the one and only cause of Duchenne, That is a scientific fact.  The one and only solution is to increase dystrophin levels.  The fact that the Duchenne experts had to specificly state that  "therapeutic-driven increases in dystrophin will lead to clinical benefit" is unbelievable.  The FDA and the NIH know this and yet have questioned dystrophin levels as a measure of Eteplirsen's effectiveness.  Why does it need to be explained?  The level of scrutiny is extremely discouraging. They are creating false obstacles to Eteplirsen's approval.
     Futhermore why are the current methods for measuring dystrophin being questioned? These are standard medical science practices to measure protein levels. I can't imagine the doctors and researchers at the FDA and NIH are not fully aware of this. Why are we receiving this outward mistrust or perhaps even predjudice that Duchenne researchers are not up to par? Why is the Duchenne research community being asked these rudimentary questions to justify 30 years of peer reviewed research.   Peer review is the standard for all medical research. Why is this somehow not good enough for the NIH and the FDA for Duchenne.
      There have been clinical trials for Duchenne for the last 20 years. It is very strange that this meeting is taking place only months from when the FDA says they would except a drug application from Sarepta. I am left feeling that Eteplirsen drug application will again be delayed and delayed.   I fear we are being played while children die.
Comment by Shelly on March 27, 2015 at 10:37pm
I believe that PPMD'S efforts will definitely end duchenne one day!!!!!!! The therapeutic-driven dystrophin increase in dysyrophin is gonna benefit combine the therapies and find a cure for dmd....
Comment by carrie on March 24, 2015 at 7:57pm

"we believe that there is a strong likelihood that therapeutic-driven increases in dystrophin will lead to clinical benefit in the appropriate medically addressable population"

Comment by Deb Robins on March 21, 2015 at 7:43pm

That "the perfect should not be the enemy of the good"...very apt applied to invasive measures and so much more. A metaphor I shall now borrow often! PPMD continue to make such a difference to the "Duchenne Nation". Peace. Love and End Duchenne.   

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