Thursday, July 25, 2013

FDA Questions around Dystrophin Quantitation by Sarepta Delay DMD Drug

As most of you know, yesterday was the day that morpholino antisense company Sarepta would provide guidance on whether they would be seeking accelerated approval for the Duchenne Muscular Dystrophy (DMD) exon skipping drug eteplirsen based on their interactions with the FDA.  This was a widely watched event not just for eteplirsen and boys with DMD, but also because regulators highly supportive of Sarepta’s meager data package would indicate a new lowered standard for the approval of rare, severe diseases.

Dystrophin as surrogate biomarker

Accelerated approval may be granted by the FDA in the absence of full clinical evidence of drug efficacy if the results from surrogate biomarkers that are thought to reasonably predict clinical outcome pointed in the right direction.  For dystrophin exon skipping this is an important potential avenue given that for most genetic lesions causing the disease it would be difficult to conduct full-fledged placebo-controlled clinical trials.

Although this is not really the case for exon 51 candidates, the most frequently affected exon in DMD and that eteplirsen is addressing, Sarepta ran one of the worst designed and conducted clinical trials for this indication involving just 12 boys (in case you are asking again why I hold this view: minute size of study when larger patient numbers were clearly feasible as the Prosensa/GSK competition shows; single-center; key supportive data miraculously collected with unblinding of the trial; key secondary endpoint- 6MWT- added with unblinding of trial; exclusion of patients in results analysis as company saw fit etc).  As a result, obtaining approval by simply showing dystrophin production has been Sarepta’s best hope with the data at hand.

Hardly anyone would argue that dystrophin was an inadequate surrogate marker.  The loss/absence of dystrophin is what causes the muscle wasting, and there is strong evidence that restoring dystrophin or even a somewhat less functional Becker’s type truncated version would be beneficial.  It would also be no surprise to see some increase in dystrophin with a gain-of-function approach such as this exon skipping one. 

No, the key questions are how much of Becker’s type dystrophin production was needed to be clinically meaningful to patients and how you actually quantitatively measure the increase in such dystrophin.

Questionable science

I don’t want to argue here about the amount of Becker’s type dystrophin needed to be clinically meaningful.  The reason is that if you do not have reliable numbers, such a question is moot.  As I had explained in a post a few months ago, the data presentation by Sarepta on the amount dystrophin produced reminded me of some of the worse cases of ‘data management’ and misinterpretation that you sometimes come across in the literature: there was apparently unequal loadings between drug-treated and control samples which suggested a high amount of skipped dystrophin by Western blot, a molecular technique looking at protein content; the RT-PCR that was supposed to support meaningful skipped dystrophin production by looking at the RNA (not protein) level actually suggested the opposite as the PCR cycle number seemed inappropriately high. 

Moreover, choosing percent dystrophin positive fibers instead of the absolute amount of dystrophin produced as the primary endpoint in the clinical trial always seemed wrong to me as for this gain-of-function approach you could imagine a very low amount of dystrophin that can be detected by the particular assay could yield very high percent positive fiber numbers, but of which the clinical relevance would still be highly uncertain (e.g. if sensitivity of assay could pick up 1% of normal, and the restored dystrophin was homogeneously distributed between the fibers).

And these are only the obvious questions.  What I would also like to know (and the FDA may or may not know) following the piecemeal data release by the company and the surprising finding that after 12 weeks no dystrophin restoration could be observed, yet after 24 weeks the company apparently could, would be the comparability of the data (e.g. the immunohistochemistry/IHC) across the different time-points, who performed the analysis, the appropriateness of the antibody used in the IHC and the Western blots, the collection method of the biopsies etc etc

FDA also doubtful

It is becoming clearer with each report on the company’s interaction with the agency that this methods issue is a real sticking point before a proper evaluation can be conducted.  This can also be seen from today’s press release: ‘The Agency, however, requested additional information related to the methodology and verification of dystrophin quantification.’

Alas, this should come as no surprise.  It is still good to see confirmation that the FDA is taking a scientifically sound approach, but as the discussion around eteplirsen had become quite politicized, one could have been excused for falling for the belief (as I’m sure countless retail shareholders did) that politicians and not scientists have taken over the eteplirsen approval process.  I had even considered whether we were about to witness a landmark event lowering the evidence bar for the approval of orphan drugs to unprecedentedly low levels.  Apparently not.

PS: The fact that Sarepta would decide to file for accelerated approval sometimes in the first half of 2014 should not come as a surprising.  Even if they themselves had considerable doubts about the success of accelerated approval or even about acceptance for review following their FDA interactions, there was nothing to be gained from not stating such intent: the stock price would have plummeted much more than the roughly 20% it did yesterday.  The interim now can be used to exercise their ATM (=issuing new shares on the actively trading markets) at still much elevated levels.

Disclaimer: The above was written based to the best of my knowledge and belief. Nevertheless, no guarantees can be given as to the factual accuracy of the content. I should also add that I am not 'against' eteplirsen.  I just don't think that there is sufficient evidence yet to decide either way. And for parents eager to get their kids on eteplirsen now, I believe, given the apparent safety of the drug, that a way could be found in which Sarepta were to reciprocate the support by the patient community and provide the drug at cost until a possible full approval.


Anonymous said...

The FDA cannot approve a surrogate marker prior to an application having been made, so there is nothing newsworthy in the quoted statement from the PR. The PR merely sets us up for the possibility that SRPT will receive full approval (requiring no Phase III) rather than accelerated approval. The timeline would be the same either way. There is no delay from the FDA. Any slowness emanates from the company itself. Everyone who is aware of what is going on has seen that the FDA (contrary to your hopeless mischaracterization) is doing everything in its power to speed up the approval process for eteplirsen. The delays have come from the company itself, which is simply understaffed and unable to ramp up manufacturing quickly enough to meet the needs of an FDA filing. Janet Woodcock would have put eteplirsen on the market months ago. That she hasn't is no reflection on her or the FDA. This process is going as fast as possible, and the limiting factor is Sarepta's manufacturing capabilities. This is an open secret, and even someone such as yourself could have known this after a little digging around (which you seem loathe to do). The drug will be approved in 2014.

Anonymous said...

Excellent analysis! I too am thankful the FDA is a scientific organization that makes decisions based on facts and data, and not hype and wishful thinking.

Thank you for having the balls to publicly stand up to an angry mob of SRPT investors so rabid they are not seen since the days of Provenge.

You are also crossing the great Adam Fokstein, which according to Ryan Flinn at WCG, should not be crossed.

I don't have a position in SRPT, but AA filing is the best outcome for both longs and shorts, IMHO . The reasons for longs are obvious. For shorts, instead of waiting for 2-3 years for a real randomized studies, they can now focus on the FDA panel expected some time in 2H14, potentially a doubleheader with GSK/RNA NDA.

Anonymous said...

Good research Dirk. Thanks. What's your view on having a biomarkers to measure Dystrophin. Would that ease some concerns?

BiotechDudeDiligence said...

good write-up Dirk. But it is not clear yet that this outcome has caused any delay to the filing timeline, as implied by your title.

Dirk Haussecker said...

Based on the order that the issues were presented in the press release, it does seem like the methods issue has become the rate-limiting factor. If CMC/scale-up were the rate-limiting factor, did company also guide towards potentially filing towards the end of H1 2014 based on CMC? If so, they've been toying around with AA for a while now and for resolving CMC taking that long would be outrageous. Actually, it is incredible that Sarepta, aka AVI, after more than 30 years of morpholino drug development, still has not gotten passed small-scale manufacturing.

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.