About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Darapladib Misses Its Endpoint | Main | Kevin Trudeau Goes to Jail, At Long Last »

November 13, 2013

Sarepta's Approval Woes

Email This Entry

Posted by Derek

I briefly mentioned Sarepta and etiplirsen, their proposed therapy for Duchenne muscular dystrophy (DMD) in September. In that post, I made reference to the "delirious fun of investing in biotech". Well, the company recently got some regulatory news that illustrates that point even more clearly. The FDA told Sarepta that it would not get accelerated approval for the drug, and that sent the stock into a mineshaft (and infuriated the DMD community, as you might well think).

Matthew Herper at Forbes has some good background on the story here Etiplirsen is one of these drugs aimed at a small market (one particular DMD mutation). And the clinical data were pretty thin:

It can be hard to imagine saying no to a plea like that – but sometimes that is the FDA’s job. As one muscular dystrophy expert told me when I wrote about Sarepta’s results earlier this year, it was always possible that it might be “too much to hope for” to think that eteplirsen could be approved based on the data so far. Eteplirsen was studied in only twelve boys, half of whom received the medicine immediately, the other half of whom initially got placebo but then switched to taking the drug. Those who started on the medicine earlier have higher levels of dystrophin, at least according to muscle biopsies, and appeared to be able to walk a greater distance in six minutes, a sign that their muscles are deteriorating less quickly.

Unfortunately, great results from small trials have a history of not bearing out in larger studies. Even for rare disease drugs, this study was tiny. Worse, the Sarepta results only look good when two of the 12 patients are excluded – two boys were too sick to be helped by the drug. The FDA usually insists that clinical trials be presented in what is known as an “intent-to-treat” analysis, which means that if you even thought about treating a patient they need to be included when you do the math on the study’s results. This is intended to keep scientists from lying to themselves, convincing themselves that a drug works when it doesn’t. One biotech executive with a great deal of experience in rare diseases told me recently that this issue meant the data “would never fly” with the FDA. The recent failure of a similar, but less effective, drug from Prosensa and GlaxoSmithKline GSK -1.64% made the odds dimmer.

And Adam Feuerstein of, who thought that the company would get the accelerated designation, has a look at the decision here. He spoke with a bearish investor who made this case:

The FDA's issues with trial design are so wide-ranging that it seems like wishful thinking that Sarepta will be able to agree on a study design and start enrolling by the second quarter 2014.

Major questions with dystrophin quantitative assay. Questions with results of anything less than two years. Need for a larger study to power the six-minute walk test (6MWT) data. Possible need to expand study population both high and low and go beyond 6MWT as primary endpoint. The FDA is very deeply skeptical and Sarepta will have a difficult time coming to a study design that the company thinks they can do and that the FDA will be satisfied with.

And any trial seems likely to last 2 years. Seems to me that even if all goes well, approval would get pushed out much more than two years. They're going to spend 9 months arguing over study design and probably won't start enrolling until early 2015. Two-year trial plus filing and approval. Sounds like early 2018 approval at best.

I have to say, this is consistent with worries resulting from the Prosensa trial that the market ignored. But it's actually even more negative that I expected. I thought the FDA would just say, do a larger trial along the same lines. What they're saying is much more confused than that. What is a valid marker and what do you need to get the data to support it?

It makes you wonder whether the FDA really changed their minds lately or if Sarepta misrepresented (through wishful thinking or worse) what the FDA had been telling them all along.

The agency really did made things much trickier than most people had been expecting. They're talking about completely new endpoints, rather than just shoring up the data collected so far (which was already more than the company's boosters were willing to think about, in some cases). I don't envy the folks at the FDA, but then, I never do. They get to look like heartless bureaucrats, bleating about numbers while children are suffering. The flip side, though, is trying to keep people from raising their hopes for something that does no good. If we approve things that just look as if they might work, all sorts of charlatans will rush in, human nature being what it is.

But we're not talking about approval here, just an accelerated protocol for it. Surely they could have at least agreed to fast-track this one? I think, though, that the FDA saw itself being put into an untenable position. They did not think that there was enough solid evidence to approve the drug as it stood, and accelerated approval would ensure that no more was going to be forthcoming. All that would do would be to get everyone's hopes up even more, for what still would looked very much like a rejection based on insufficient data. And in that case, why not tell the company now and get it over with?

Comments (6) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs


1. Anonymous on November 13, 2013 10:28 AM writes...

Another Cambridge biotech down the drain!

Permalink to Comment

2. Anonymous on November 13, 2013 10:49 AM writes...

From my recollection Sarepta reported the FDA was open to an NDA filing based on the minimal PII dataset prior to the results of the GSK/Prosena drisapersen PII study. It's my understanding the mechanism of action was the same for both drisapersen and Sarepta's eteplirsen. The failed PIII for drisapersen demonstrated that increased levels of dystrophin were not predictive of clinical effect. Meanwhile the increase in dystrophin level was a central endpoint of the Sarepta trial which was to be used to support submission.

Now, with the GSK/Prosena dataset at hand, the agency and scientific community is much more informed about dystrophin reliability as a biomarker in DMD, but there is no clear surrogate by which to measure efficacy. This puts the onus on Sarepta to demonstrate efficacy and select more appropriate biomarkers, where it rightfully belongs. Hopefully they were scrambling to do this once the GSK results were released, and I applaud the FDA for not being influenced by the investor and company fanaticism supporting eteplirsen.

Permalink to Comment

3. Anonymous on November 13, 2013 10:59 AM writes...

Correction to #2 - prior to the results of the GSK/Prosena drisapersen PIII study.

Permalink to Comment

4. Reverend J on November 13, 2013 11:21 AM writes...

@1 I think reports of the companies demise are exaggerated. They didn't get fast tracked that's a lot different than say GSK's drug not making it in Phase III. That and you should not be reveling in someones failure, have some sympathy for not only the people at the company who put a lot and time into R&D but for the families who where putting their hopes into this drug.

Permalink to Comment

5. Gerry Atrickseeker on November 15, 2013 6:48 PM writes...

In this case it seems that the FDA unnecessarily erred on the side of caution. While it is important to protect patients against possible toxicities of new drugs, in the case of Eteplirsen there was no evidence of toxic effects among the boys treated. Unlike the Prosensa/GSK drug, which is a relatively toxic phosphorothioate oligo, the Sarepta drug is a morpholino oligo and is much less toxic. Thus it seems likely that little harm would be done by letting additional patients be treated while more was being learned about the drug.

Permalink to Comment

6. an objective observer on November 22, 2013 12:46 PM writes...

This isn't about reveling in failure. I have spent 20 years in biotech, as an investor and as an executive, and I have rarely seen a more egregious example of data manipulation than what Sarepta's management team pulled, at the expense not only of investors, but far more importantly, at the expense of all these mothers of boys with DMD who fell for Sarepta's hype hook, line and sinker. The heartbreak here is that a management team can so brutally and heartlessly manipulate the emotions of such an incredibly vulnerable population for its own ends.

The 6MWD results from Sarepta's 12 subject study look no different in aggregate or on an individual subject basis than the natural history of the disease, a fact that Sarepta obscured by excluding from analysis the subjects who fared poorly in the study and by pretending the crossover subjects did not actually receive drug for 3 months, during which time the mean 6MWD for those subjects was plummeting - Sarepta claimed "we don't see dystrophin during the first 12 weeks so we can pretend they weren't taking drug during that time" - but in fact Sarepta has previously shown nice dystrophin production at week 12 at lower eteplirsen doses than used in the phase 2, so they know very well eteplirsen generates dystrophin production by week 12. And the dystrophin data themselves are highly suspect - counting positive fibers is a joke, given that dystrophin is not produced along the entire length of myocytes. So while a myocyte may look dystrophin-positive in one transverse section, it will look negative in a slice taken just a few mm away. Look at the IF in Anthony et al, Hum Gene Ther Meth 2012; 23: 336-345, where you can see the variability in IF across different blocks from the same biopsy in eteplirsen-treated subjects. Does it even make sense to imagine that a myocyte containing a few dystrophin-expressing nuclei here and there will be protected from contraction-induced injury?

Thank goodness the FDA simply looked at the data in all its inadequacy and did not cave into the political and PR pressure Sarepta attempted to apply by duping and deceiving one of the most vulnerable populations out there - the moms of boys with a terminal disease.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry