Thursday, October 4, 2012

Sarepta Fails to Report Meaningful Dystrophin Expression Data, Falls Behind Prosensa

Restoring truncated, yet largely functional dystrophin in Duchenne Muscular Dystrophy (DMD) by exon skipping is a promising approach to this devastating disease.  For this, however, to have any meaningful therapeutic impact, it has been estimated that one would have to achieve about 20% of wild-type (probably somewhat higher for truncated versions) dystrophin levels in all muscle fibers.

Releasing 48-week data from one of the most manipulated clinical trials that I have seen, Sarepta Therapeutics just reported that treatment with their exon-skipping antisense morpholino eteplirsen resulted in 34-52% dystrophin-positive muscle fibers.  Impressive? I can’t tell, but what is more worrisome is that I don’t know why the company does not tell either.

Percent muscle fibers expressing dystrophin does not mean equal amount of dystrophin restored.

In a New England Journal of Medicine paper last year, Sarepta’s competitor Prosensa (with partner GSK) reported in a similar-sized study that in 10 out of 12 patients, the percent of fibers expressing dystrophin following treatment with their exon skipper PRO051 was between 60 and 100%.  Yes, 60-100% and nost just 34-52% as in Sarepta's case.

What is more, the immunofluorescence intensity and Western blot data in the Prosensa study showed that those fibers expressing dystrophin did so at much reduced levels compared to healthy muscle, on the order of 5-20% (overall bulk levels).  In other words, it is quite likely that the ~50% of fibers that express dystrophin in the Sarepta study together express at most 3-10% of normal dystrophin, well short of what is expected to be therapeutic.  It is also possible, however, that Sarepta’s assay is very sensitive such that even fibers with just 1% or so of wild-type signals were counted in. 

Given that stating the percent fibers expressing any dystrophin is almost meaningless, you have to wonder why Sarepta has not presented the data.

But then you ask, then why did the lame start to walk in the study (à 6 minute-walk-test data)?  Actually, I don’t believe that this was shown in the study either.  Just because this is a devastating disease in children does not mean that rigorous trial design and execution can be entirely done away with.  Yet, in this already tiny 12-patient, single-center (!), and open-label (!) study, the company wisely discarded the worst responders early on allowing the 6 MWT numbers to be 'statistically significant'.   There seemed to be more subgroup analyses presented than patients in the study.  If I were a regulatory agency, I would strongly consider refusing to even just look at the 6 MWT data.

Why am I writing this?  First of all, I am obviously trying to find any shares to short.  And second of all,  what really irks me is that as orphan drugs become more and more popular in drug development, a number of companies are doing away with rigorous science, drive aggressive patient recruiting and disease awareness campaigns (best if a pediatric indication is involved), and expect the rest of us to subsidize the enormous costs of these drugs.  Fine, if the drugs worked, but not for placebos.  Wait another 5-10 years and there will be an enormous backlash and those that need access to these drugs will suffer the most.


Anonymous said...

With the amount of research going into AAV delivered shRNA for DMD, and other MD's for that matter, surely it's only a matter of time before Sarepta's antisense approach is going be left behind??

James said...


Appreciate the commentary on the dystrophin side of things. But I'm not sure your characterizations about the trial and 6WMT data are correct.

1- The trial is most certainly NOT open-label. It was double blinded up to about week 32 to 36.

2- With respect to the 2 boys dropped from the 6WMT analysis, the company's explanation appears rational. Those boys become non-ambulant within weeks of starting the trial. So how do you expect them to take the test?

You might want to consider that all of ProSensa's data is ENTIRELY open-label. Much harder to take their 6MWT data seriously. Also toxicity issues.

Anonymous said...

Dirk, you have seriously lost all credibility with this one, as it's clear that you have never even glanced at Prosensa's study or how poorly designed it was compared to Sarepta's.

1) Prosensa patients "had no pretreatment muscle biopsy in patients in whom a dystrophin response was reported, making establishment of a proper baseline to distinguish minimally positive from negative fibres difficult." Why is this important? "In Duchenne muscular dystrophy, sections of muscle often have discernible trace levels after immunostaining with the antibodies to dystrophin used,9,13 and these pretreatment levels need to be taken into account to provide an accurate measurement of both number of positive fibres and dystrophin intensity." Did SRPT make that same mistake? No. Only Prosensa neglected to take measurements before commencing the trial.

2. Are the two studies reporting the same thing when they report "dystrophin positive fiber" percentages? NO. SRPT has a much more stringent measure of dystrophin positive fibers: "In our study, we first established the level of dystrophin in the pretreatment muscle biopsy sample, and regarded those levels as the baseline for that individual—ie, judged fibres as positive only if they exceeded the intensity levels of the pretreatment biopsy."

3. Prosensa cheated by using patients so young that they typically are continuing to walk further even WITHOUT ANY TREATMENT based on normal growth: "several of these children were younger than 7 years and, according to longitudinal observation,19 boys younger than 7 years with Duchenne muscular dystrophy gain motor function."

4. Prosensa's improvement came earlier, whereas SRPT's treatment takes time. Why? Because Prosensa's flawed study was entirely OPEN LABEL, producing an immediate PLACEBO EFFECT: "Additional confounding factors are the variability in the walking test (SD 36 m19) and the powerful placebo effect of open-label studies".

Freefdawatchlist said... I think SRPT is less then $10 worth but since shorts are out there is potential it will go higher before dropping.

Anonymous said...

I think before you make such hasty and sweeping comment, check your facts first. Read through this Lancet article in Results section which discusses the differences between how dystrophin levels were measured and also the efficacy results seen in ph1/2 studies for eteplirsen and PRO. Here's the link:


Dirk Haussecker said...

Thanks for the comments/criticisms.

On the comparability of dystrophin expression with the Prosensa study: If you look at Figure 2 and Table 2 of the NEJM Goemans et al paper, baseline expressions are presented.

On the open-label issue. I admit that I was not aware that it's been a double-blind study until week 24 (not week 32/36 as was suggested by one commenter). I then revisited the conference call slides, and curiously the lame started to walk after week 24. What a coincidence. Now you could argue that it is prolonged dystrophin expression that was responsible for the delay in clinical response, but in this case (esp. if they expected that before the study), why did they compromise this potentially important finding by prematurely unblinding the study?

And by the way, do the 6 MWT data correlate with dystrophin restoration levels? I have missed the discussion on this important issue.

Anonymous said...


James said...


Re Blinding

That's not correct, see the recent article on TheStreet. CEO said study wasn't unblinded to patients until well after 24 weeks.

Re Prosensa

Look at the table. They only test 3 patients at baseline for dystrophin.

Dirk Haussecker said...

Here's the entry stating that blinding for 24 weeks:

The entry for the open-label extension study is here:

I agree, the baseline in the Prosensa study is very spotty and, what is even more concerning, there is no real increase in dystrophin expression from week 2 to 7, not to speak of dose-dependency. So in a competitive sense, it's a Plus for Sarepta, but from a mechanistic point-of-view the poor quality of the data seem to make exon skipping in muscles even more questionable/challenging (also for Sarepta).

Anonymous said...

The comparison of the two studies is really a non-issue. However, Prosensa is deep into their Phase III and have in fact been enrolling the open label extension since Sept 2011. The risk to Sarepta here is if GSK will be able to file in the near term. If that drug is approvable, then the likelhood of accelerated approval for SRPT - and the market conditions upon - will both be severely limited. Also one could argue that the drugs are sufficiently similar that an award of Orphan Drug exclusivity to one could prevent the other from obtaining approval. I've not looked thoroughly into this last issue so correct me if I'm wrong.
As for the Eteplirsen trial, any study (and there are many) analyzing the natural history of DMD would tell you that the likelhood of this magnitude of improvement over 48 weeks in 6/12 patients is extremely unlikely. Kids simply don't improve at this age over that time frame.

Dirk Haussecker said...

Maybe knowing that you are on drug gives you that extra bit of energy in the 6 MWT? And why was there no dose response?

Anonymous said...

Orphan Drug designation is designed to prevent generic competition. For example, Teva cannot launch a competing generic version of eteplirsen. Since the two compounds (PRO & SRPT's) are different, both can get Orphan drug designation.

Anonymous said...

Orphan drug designation gives exclusivity against SIMILAR products (and I think that the Sarepta and Prosensa products are sufficiently similar). Exclusivity is lost however if the later filing competiting products shows significant clinical benefit (either efficacy or tolerance) over the product holding exclusivity.

Anonymous said...

Don't agree with you. Look at levoleucovorin Orphan Drug designation when generic leucovorin is already approved in SIMILAR indication.

Anonymous said...

And the two drugs are essentially the same ( L vs R isomers) and clinically cannot be differentiated at all except for dose.

Anonymous said...

I have a 12 year old son Jake with Duchenne MD. His best friend Austin also has DMD.Austin has a brother Max that also has it. Max was one of the boys in the clinical trial for Sarepta's eteplirsen. Austin and Max both have the same exon deletion. Austin was not eligible for the trial due to the 6 minute walk test.Both my son and Austin are non ambulatory. On of the next trials will be for my son Jakes deletion.If the status que stays the same he will not be eligible. Max was not able to walk more then 30 to 50 yrds without having to go into a manuel wheelchair. He just did a three mile walk for Halloween ! That's for the Naysayers ! I'm sure most of you that are reading this are well aware of Dystrophin half life. It's about 29 days. Sarepta could have dosed at a higher level for the trial like Prosensa did but that wasen't the case. I would like to give you a bit of insite into the MD community.I have not met One, not One parent that is not as frustrated as I am.This frustration spawns several grass roots orginizations. Example,Parent Project MD born out of frustration with MDA progress. MDA feels that that takes money away from their cause. Cure Duchenne, born out of frustration with Parent Project MD.This frustration also spawns something else,competition for the money thats out there for research.It also spawns something else,animosity and bigotry.The top three MDA, Parent Project and Cure Duchenne, The Three Musketeers "All For One" "One For All"! This is not the case! The same thing exists in the breast cancer,autisim,diabetic and other communities.I can say that when you hear the expression "walk a mile in someone elses shoes" It doesn't stop there ! after you walk that mile you change your shoes and get ready to walk the next ten! I will also take the time to state that the same competition exists in the Pharmaceutical industry along with the animosity ! Take a look at what GSK did to Sarepta in europe with the trial.GSK is the big boy on the block with the power and money and Sarepta is the 90lb weakling on the beach. That's crap ! I do appreciate reading all of your comments' and the fact that you take the time to post them,but if you really wan't to engross yourself in Duchenne MD you should do some field work and go out and talk to some of the families affected by this ! If you would like to see the news story on Max ans Austin done by WCAX TV 3 in Vermont go to their web site WWW.WCAX.Com. You should really watch this and maybe it would broaden your horizons !Sometimes you have to take the blinders off ! Alot of us don't take the time to think outside the box. We see things in black and white but there is a gray area !

Anonymous said...

some additional comments from other analyst on this topic

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