Saturday, October 13, 2012

Sarepta Discloses Dystrophin Expression Data at World Muscle Society Congress

Last week, I criticized Sarepta Therapeutics for failing to disclose critical dystrophin expression data regarding their exon-skipping drug candidate eteplirsen for the treatment of DMD.  Instead, they merely disclosed the percentage of muscle fibers staining positive for dystrophin, i.e. fibers that expressed some dystrophin, which, of course, would be a much more impressively sounding number.  Adding to what I perceived as dubious data presentation was 6-minute-walk test (6MWT) data of which the integrity seemed compromised based on cherry-picking the patients and the fact that the apparent improvement occurred in the open-label extension phase of the study.

Admittedly, the percentage positive fiber number was a previously defined primary endpoint whereas the amount of overall dystrophin relative to normal/healthy was not.  Therefore, like other biotechs frequently do, it might always have been Sarepta’s intention that only the primary endpoint data be presented initially ('top-line data'), with the balance to be disclosed at a future scientific conference or peer-reviewed presentation.

Accordingly, Sarepta today presented additional data at the World Muscle Society Confress in Perth, Australia.  I was pleased to see that at least some dystrophin expression Western blot data were revealed (slide 12)- with a direct comparison to ‘normal’ at that.

First of all, you can see on the left the ‘normal control’ (healthy) comparison.  The labeling seems to be somewhat off as I believe the outermost left lane represents the sample.  You can also see that the normalization control ‘actin’ was less abundant in the control sample compared to the patient samples (by naked eye about 3-5 fold).  This means that the 'normal' dystrophin signal is an under-estimate relative to the patient samples. What is more, because the dystrophin signal in the ‘normal control’ is over-saturated (big black blotch), the ‘real’ relative dystrophin amount should be even more compared to the patients'.  Because there is no standard curve and because of the apparent loading differences (à actin), it becomes an art to estimate the relative dystrophin amount restored by eteplirsen treatment, but with 7 years of doing the same type of experiments at the bench under my belt, I would guesstimate that the true value is about 2-5% of normal.  Certainly not the 20% believed to be necessary to start impacting the disease phenotype. [Correction 10/13/2012: This was an inadvertent mis-characterization of the quoted source, please see the discussion in the Comments section].

Supporting the notion that the Western Blot overestimates restored dystrophin levels, is the RT-PCR experiment on the right.  Again, the larger band which represents the mutated transcript is much more abundant than the re-spliced signal below, indicating that only a minor fraction of the mutant transcripts were re-spliced.  Moreover, smaller PCR products amplify more efficiently compared to larger ones, meaning that the apparent splice correction is an over-estimate.  Similarly, because the mutated and ‘normal’ PCR signals are almost the same (you would expect an mRNA with premature stop codons to be destabilized relative to wild-type), it is likely that the normally spliced bands have reached saturation, further over-estimating the splice correction in the RT-PCR experiment.

Overall, whatever Sarepta’s motives were behind failing to disclose the absolute dystrophin data last week, they clearly provided some of the necessary transparency at the WMSC presentation.  Having said that, I believe the data support the underlying concern that the splice correction may not be enough to be therapeutic.  I would not exclude it, however, as the 20% value, of course, is also an estimate.  Blame a less than rigorous trial design for not knowing for sure for quite some time to come. 


Anonymous said...

The idea that you can quantify the relative amount of a protein by eyeballing a fuzzy picture of a gel in a PDF file is probably the dumbest thing I have ever heard.

Dirk Haussecker said...

Are you then saying that Sarepta reported entirely meaningless data?

Do you agree? said...

Alternative belief and GUESStimate:

(I would add the belief you're referring to is 15 years old and outdated)
More recent belief:

Search "5%"--Lots of positive fibers, Western not >5% of normal, functional improvement

Figure 2b

Protein: I would guess ~10-15% of normal at 48 weeks.

Lane 1 is healthy control. Lane 2 is NOT spillover from Lane 1 because there's too much actin to be that. From the way this gel is loaded, I would GUESS it is Patient 8 loaded at same amount of protein as Lane 1.

The 48-week DYS bands are ~2-3 times the 24-week ones, and the actin is maybe ~half. Guessing ~5 times DYS at 48 weeks than at 24 weeks.

Now going back to Lane 2, if one imagines a DYS band 5X as intense, one can visualize ~10-15% of Lane 1. Of course this is guesswork since everything is saturated.

Not an issue to me. DYS has like a 20-week half-life? Only need to make a little each week to be overall accumulating it and that appears to be what's happening.

Anonymous said...

As parents, we have been told that the reason there are such varying phenotypes is the existence of revertant fibers at very small numbers.

Also - if the performance of the dystrophin is entirely placebo derived, why didn't the delayed treatment group start bouncing back on the 36 week data? Why did they only start bouncing back at the EXACT time that biopsy data suggests dystrophin is being produced?

Lastly - the bottom line is that the data suggests the drug might work. Further, because of the two treated boys that were no longer ambulatory by the time they created dystrophin, we also know the drug needs to be given early enough in the progression to be effective; it makes sense - less muscle to rescue, less improvement. It's not data cherry picking - it's looking at the facts. GSK's data suggests the same - once the boys are past the tipping point, they can't be rescued.

It's therefore no longer OK to doom more boys to losing the use of their legs, arms, diaphragms, hearts while sitting on a placebo arm so that people like you can be 100% satisfied that it works. At some point, you have to let these boys struggle for the surface rather than continuing to hold their heads under the water.

Anonymous said...

PS - are you shorting the stock? If so, you have no right to pretend to be a scientist and analyze the data. I thought pure science had to exclude bias.

Anonymous said...

Sorry Dirk but I believe you have lost your objectivity and you are talking your book. I've followed your blog for a long time and I find you a smart guy but a lousy investor. Ie. Tekmira

John M said...

From your own oft-cited reference: "Animals with less than 20% of wild-type levels displayed intermediate signs of dystrophy, suggesting that even small amounts of dystrophin can help prevent dystrophic processes from arising. However, at least 20% of thé wild-type levels are necessary for a COMPLETE PREVENTION of disease."

Really Dirk?!? You want to portray an increase from 0 to [2 - 5%] of total normal dystrophin as a negative? Even assuming your lowball estimates are correct, and assuming the patient's Dystrophin levels increase no further than the 48-week levels, since "EVEN SMALL AMOUNTS OF DYSTROPHIN CAN HELP PREVENT DYSTROPHIC PROCESSES FROM ARISING," one may conclude that eteplirsen is benefiting these patients significantly! Would you prefer to see a drug with this capability withheld from the market while we continue to search for a drug which can provide dystrophin levels necessary for a "complete prevention of the disease?" Would you rather voice this opinion to a room full of DMD parents, or admit your bias, cover your short, and get back on the right side of humanity?

John M said...

you wrote: "Certainly not the 20% believed to be necessary to start impacting the disease phenotype. "

Again, if you read the citation, 20% is believed to be necessary not to "start impacting the disease," but for "COMPLETE PREVENTION OF THE DISEASE."

If you want to be seen as a scientific spokesperson, behave like one.

Dirk Haussecker said...

Thanks for all the comments and you have convinced me that there is a case that less than 20% dystrophin may well impact disease pathology.

John e.g. makes a fair point that my reference indeed states (somewhat contrary to the abstract) that 20% dystrophin expression levels may PREVENT development of the disease. This also supports the argument that the earlier you treat the more chance at a correction you have.

The caveat, however, is that the same source argues that 20% dystrophin is less effective when different muscle fibers express dystrophin at various levels. So 20% is not 20%, and the re-spliced dystrohin is probably not as active as 'normal' dystrophin.

Having said that, with a trial of that (poor) quality, I believe you have to take financial realities (public interest) into account and I am against paying hundreds of thousands dollars EACH YEAR for a treatment of which it has not been proven that it works. Maybe there needs to be a mechanism that restricts the amount of money pharmaceutical companies can charge for drugs on the market due to Accelerated Approval and once there is more evidence for therapeutic efficacy, the barriers can be removed.

Anonymous said...

Are you a shill for Glaxo? I noticed that you say we "won't know for some time to come". If you're convinced it doesn't work, why don't you just say so. Otherwise what you have here is something that clearly increases dystrophin, that dystrophin increases with time, and is mirrored perfectly by improvements in 6MW. The idea that if it doesn't make a minimum 20% it should not be approved is ridiculous since no one knows what level will have some clinical impact, and there's a high likelihood that even a small increase over time, or given to younger boys, can change the course of the disease. Meanwhile, the drug looks totally safe. Given the safety and the fact that there is some clear increase in dystrophin, should in and of itself, lead to approval under FDA PDUFA V.

Anonymous said...

Wow - I wish I could talk to you in person so that I could personally show you a picture of my son and then kick your ass.

If the FDA grants accelerated approval with a non-blinded confirmatory study, it would take, at most, two years for us to get a certain answer on whether the drug is working or not. Boys who are dying can only last on placebo for so long before the disease will run its course.

So technically, insurance plans would only be paying for the drug for that period of time, at which point the drug can be pulled from market without supportive evidence.

In that route, no one dies needlessly, and insurance plans only pay until evidence discredits benefit if the drug doesn't work.

Keep in mind that this is a highly motivated and highly monitored population - there is not a risk that confirmatory data would be collected.

But thanks for the opinion that my son's not worth the $$ to try and save. Spoken like a true insurance executive. May you some day have your own child with an incurable disease.

Dirk Haussecker said...

John, I can see now that I was wrong to state that it takes 20% to start impacting the disease.

Anonymous said...

My statement should read "there is not a risk that confirmatory data would NOT be collected."

Anonymous said...

And I personally think that the trial design was ingenious - captured an incredible amount of data with limited resources given the beating that stock shorting assholes gave to Sarepta's ability to raise capital.

Please give specifics as to why you think the trial was of poor design.

If they had gone with the original trial design pre Chris G, they would had tested the drug for 12 weeks only, found no dystrophin, and scrapped the whole thing.

You sound like the worst armchair quarterback I have ever heard.

Anonymous said...

Dirk, having lost the scientific argument has now shifted his focus on drug cost..what a way to CYA. Lost all credibility and true intent is to be the lapping dog of shorts.

Anonymous said...


I am sorry to hear about your severe case of "Analysis Paralysis."

You may want to research data on benzodiazepines!

Dirk Haussecker said...

To the DMD parent...I can understand your anxiety of getting access to eteplirsen. Also, in a cancer trial, who wants to be the one taking placebo in a phase III trial and phase II trials strongly suggested efficacy?

But how much did Roche/Genentech make from the use of Avastin in breast cancer before the indication was take off the label? Is it true that Alexion is now charging half a million dollar for a year's worth of treatment for a rare disease? Half a million is the economic output of dozens of adults in most countries.

Where do we draw the line? Why not blame Sarepta for unblinding the study after only 24 weeks if it is so obvious that it takes prolonged dystrophin production to get a therapeutic effect?

Anonymous said...

wow - you are truly an idiot. they unblinded for three reasons, listed in order of importance:
1. Because that's the way the trial was structured originally. When those parents signed the consent form originally, they agreed to the terms that there was a chance of placebo for the first 24 weeks followed by a guarantee that they would receive the drug.
2. Because they hadn't analyzed the data at the time the trial was unblinded. Original estimates were that the trial would need 12 weeks to prove concept - many experts in the field were arguing that high enough doses would produce dystrophin by that time. Muntoni argued that duration was the important factor, and the trial was extended from the original 12 to 24 weeks. I'm sure that all experts involved in the design assumed 24 would be adequate.

I will again reiterate my desire to kick your ass - as many times as you bring up cost as a prohibitive argument to accelerated approval.

Anonymous said...

Sorry - should have stated two reasons, not three.

No one knew for sure that duration would be the key until this trial was done. And I think that everyone thought 24 weeks would be more than enough.

We can't all see the future like you can, apparently.

Anonymous said...

And as my last word, in response to your question, "where do we draw the line?"

Apparently, your response to that question is that we should draw it exactly at your wallet, shorting ass.

Do you agree? said...

Dude you know nothing. The trial wasn't unblinded at 24 weeks even though the patients crossed-over. They were told after their 36 week walk test at the end of the day.

Go home and do your homework and stop spreading crap around. Or go back to your crap school you're teaching at and stop pretending to be an expert. Haven't even heard of it.

Dirk Haussecker said...

Lost the scientific argument? I admitted that 20% to disease impact was wrong. That does not do away with the important question of how much dystrophin was produced. For accelerated approval, in the absence of 'therapeutic proof' (which is the case here), you better have reliable biomarker data.

Anonymous said...

Dirk, appreciate you digging into the data. I sympathize with the parents for whom any option is better than none. At the same time I understand your concerns about allowing a drug into the market without fully understanding the extent to which it is effective. However one has to balance the cost of the drug vs the cost of taking care of the patients. Money is spent on physical therapy, wheelchairs etc that could potentially be saved by this drug and it's upto the insurance companies to figure out what the appropriate cost of the drug would be if there is accelerated approval. I believe it's in our best interest, both financially and ethically, to figure out the best way to use this drug to help these boys. It's clear that the drug has some effect and is safe.

Dirk Haussecker said...

To the DMD parent (if you are really one): you should support lower pricing before efficacy has been formally proven. Lower price = improved access. I sure hope you have a gold-plated healthy insurance. But don't worry, this issue isn't a DMD-specific one, but it is my strong prediction that as the orphan disease/accelerated approval trend is gaining traction, there will be a backlash. Better be pro-active and be responsible with pricing.

Brad Loncar said...


First of all, I want to say that I appreciate your scientific skepticism. I also happen to disagree with it, but skepticism is the foundation of science so I appreciate that you are voicing your opinion. Frankly, the Eteplirsen studies are far from perfect, science rarely is, and therefore the scientific merits of the drug deserve to be debated rigorously.

However, I must say that your argument about the drug not deserving accelerated approval, primarily because of its cost, is incredibly misguided and, I believe, just plain wrong for a variety of reasons. Let me offer my opinion by pointing some things out:

1. As one parent has already commented, accelerated approval, by definition, is only meant to serve as a temporary stopgap until the results from a larger trial can be borne out. In this case, you are talking a couple of years max. I can think of a lot of things we waste money on in this country, but to error on the side of caution by giving these families two years of hope versus two years of helplessness is not one of them.

2. This is a rare disease. Less than two thousand kids will be taking the drug. When you compare that to our population of over 300 million, I think the country can handle the cost just fine for a couple of years. It would be a much different story if this was a cholesterol drug, blood thinner, or even cancer therapy that affected a much larger percentage of the population. However, in this case the cost is essentially not even a rounding error in terms of the overall system.

3. This is a serious, degenerative disease for which there is an unmet need. Two years for these kids is invaluable, and there is little else that they can turn to in the meantime. It is easy for us investors (for full disclosure I am an investor) and scientists to simply say wait a couple of years for the picture to become 100% clear, but put yourself in the shoes of a family who will watch their child’s condition change over that time. I cannot think of a more heartbreaking thing. It’s great to have perfect data in the lab, but you also must consider what these families are going through.

4. This is a genetic disease that affects children. Through no fault of their own, these kids were born with this. If that is not something we can show the utmost compassion towards, I don’t know what is. The FDA has been bending over backwards lately to approve weight-loss drugs, cholesterol drugs, and all sorts of questionable medicines that treat conditions that are the result of poor lifestyle choices. Call me old fashioned, but if we are going to do that, I think we should also show a little more compassion to the helpless as well…especially when you are talking about children.

5. This drug appears to be safe and effective. Though the phase two trial is not perfect and the sample size is in fact small, that also doesn’t mean you should necessarily disregard its signals. This drug clearly seems to be creating dystrophin and, importantly, it also appears to be very safe. Given that, what is the harm in offering it to families who want access to it while the confirmatory trial is taking place? We are more than capable of doing both in an appropriate way. If some sort of safety signal did show itself during the trial, the system will be able to quickly put a halt to it.

In my opinion, this is an easy decision and it is unfortunate to even bring cost into the picture. And btw, as a closing note, also keep in mind that one of the largest contributors to higher drugs prices has been the much more strict and drawn out regulatory process we have turned to over the last 30 or 40 years. Being more flexible on regulation is one of the more concrete and surefire ways to bring down cost over the long-term.

When you consider how high the stakes are in this particular case, I think it is an easy call.

Ralph said...

Thanks for putting the time of analysing this everyone.
Dirk thanks for your time and opinion.
I am interested in knowing your disclosure please. True transparency obliges to disclose before even being asked. It seems like answering that question was avoided earlier in your reply. So do you happen to be short the stock?
Thank you

Anonymous said...


Keep up the good work. You are arguing with people who lost a lot of money on the stock and could care less as to whether or not the drug works. Which it does not. There are other larger issues with the trial as well that have not been identified.

The DMD population is too large for the FDA to approve a drug with only 4 pts worth of data.

The meeting in Perth was a disaster because none of the docs there believe the data, and rightfully so. Dr. Mendell is about as promotional as they come, I have never seen a lead investigator this promotional, it is totally unprofessional.

I wouldn't waste too much energy bickering with these people. Life is too short,

Pdoofus said...

"you would expect an mRNA with premature stop codons to be destabilized relative to wild-type"

This is complete speculation on your part. There are some mutant transcripts that are unstable and others that are not. Without experimental evidence (radiolabeled pulse-chase or other), it's just as reasonable to assume that the mutant transcript is perfectly stable.

Also, as I'm sure you're quite aware, there is not always a direct correlation between mRNA levels and protein levels.

Furthermore, as I'm sure you are quite aware, there is not always a correlation between protein levels and protein activity.

A lot of your skepticism is based more on speculation than fact.

Bottom line: 6mwt trumps all westerns, rt-pcrs and speculation.

Ralph said...

fyi, I have no position in SRPT

Anonymous said...

"The meeting in Perth was a disaster because none of the docs there believe the data, and rightfully so."

this is plain false. you obviously weren't in Perth. My program co-resident was in attendance and confidently stated the debate was healthy but most certainly not a disaster that you and some non-clinician amateurs have stated on twitter.

the only explanation for you making such an inflammatory statement is you have financial skin in the game.

transparency said...

I find it highly suspicious that you continually refuse to reveal your financial interests in this matter.
Are you now or have you been shorting SRPT?

Anonymous said...

"The meeting in Perth was a disaster because none of the docs there believe the data, and rightfully so."

the points of debate were how patients were assigned to treatment groups and magnitude of the signals one can extrapolate from a small sample size.

there was nearly zero questioning of the actual results or the fidelity of the data or if there was an obvious signal.

Anonymous said...

I'd like to start off by saying that I have no financial or personal ties to SRPT or DMD.

I'd like to pose a question. If I told you all that Company X ran a 48 week trial in 8 patients, 25% of which were thrown out due to being "outliers", the study was confounded by unblinding(the ceo can claim it wasn't unblinded till after 36 weeks till he's blue in the face, but that doesn't cut it in the scientific community), the trial was a phase 2 trial.

Tell me if you knew no background stories, weren't financially involved that you would say that these data are robust enough to warrant accelerated approval.

I have do problem with SRPT treating patients under accelerated approval, until they either pass a reasonably powered, controlled phase 3 trial ( the claim that this patient population size is too small to run large trials in needs to look at GSK's trial sizes currently underway so that point is moot with/me), or until they fail said phase 3 and the drug is yanked off the market.

I do however have a problem with a company making money off of the drug until it has been proven effective in a large (relative to ptnt pop; 150-200 should suffice) ph3 trial. If Company X is sure of their product they should have no problem providing drug to patients at cost until final approval is obtained. If company Y can find patients to fill their trials, Company X with a "superior" product should have no problem finding 2-300 patients for an adequate trial.

I don't want to get started down the slippery slope that I think we're heading down already that drug companies can get orphan drugs approved that either haven't been adequately proven(my concern here) or have such minimal efficacy (not my complaint here) and charge patients INSANE prices because they can.

The only people who can argue with SRPT providing drug at cost to patients until an adequately powered, controlled phase 3 proves the drug works (think to yourself how many larger phase 2 trials are stat sig that later on fail pH 3. A TON!)

Just my 2 cents. I apologize for typos and grammar, I'm on my phone and Autocorrect sucks!

Anonymous said...

You lost your credibility by not being objective like a scientist with no bias but rather like a scared short seller trying to manipulate the minds of investors and traders who don't really have a good understanding of the data.

Alan Frazier

Anonymous said...

you are an idiot. glaxo drug works.look at 96 week 6 min walk data. that drug is toxic so they have to run large studies. srpt is safe. why not approve?

transparency said...

From your Oct 4 blog
"Why am I writing this? First of all, I am obviously trying to find any shares to short. "

You buried it, but I found it.
Sounds like you're weighting your conclusions based on $$$

In the future, please preface all articles on stocks and their pipeline drugs with relevant info as to your financial interests.
More honest.

Anonymous said...

The fact that a correction had to be made to the original post clearly indicates the blogger has no expertise in DMD. Given that , I'm surprised at the viciousness of some of the responses. I'm sure the blogger is reasonably good at his work but one can hardly take him seriously when hasty judgements are made which then have to be retracted. If the data is good as many as you hope and think then one hastily written blog should hardly change that view. I know it's just a blog but if one wants to be taken seriously then adequate research has to be done.

Anonymous said...

"It is true that you may fool all of the people some of the time;
you can even fool some of the people all of the time;
but you can’t fool all of the people all of the time."

Every dog has its day and you surely had yours with your misleading the small people.... but now you on are toast on this short and as well as your word in the future will mean zero. I

Thought you were smarter than that ( but that didnt last long ) and able to see the road ahead of you by more than just a few feet...

P.S. you could have saved your reputation by disclosing you got caught on he short side or at least say you are short.

Anonymous said...

At least Dirk has the humility to admit that some people that have done a little more research have corrected him on multiple points. He is doing some jumping from one argument to the next when his original argument falls apart. His original argument.
His original SRPT post:
Sarepta Fails to Report Meaningful Dystrophin Expression Data, Falls Behind Prosensa
This original post misrepresented the Prosensa and Sarepta data and he was corrected on that. And a week later they released the data he wanted and now he has moved on to "It's too expensive." I can see shorting Sarepta if you see something in the technical charts of the stock, but the reasons to short the company for other reasons have been destroyed over the last few months. I outlined some here:

Do you agree? said...

Dirk, I apologize for my harsh words. I got angry because you made everyone look at the obscure reference (from 1997!!) and kept at it after I pointed out that it is outdated by 15 years. Turns out you didn't even read that thing properly yourself...

It does not matter at all what your 1997 reference says. Look at the papers from 2009 and 2010...5% dystrophin is plenty.

Sorry for being mean.

Anonymous said...

To those of you who take Dirk seriously. Note that Dirk repeatedly states in his blog his disclaimer that "This blog expresses only my opinions, they may be flawed and are for entertainment purposes only".

Don't take anything he says seriously, especially that part of his blog where he claims to be a scientist. That claim clearly is for entertainment purposes only.

Anonymous said...

Dirk, stand tall man. Without your
blog there'd be less light, insight and discussion on this field that is offering so much more hope to treat horrible diseases than the offerings big pharma currently have.

good luck to all SRPT and BLT holders, and those needing treatment breakthroughs

Dirk Haussecker said...

Again, about the 20% number: I was trying to find a number by a reputable scientist and thought the abstract by Chamberlain had the information I was looking for and stopped there. But again, the criticism stands that Sarepta has not provided adequate information on the dystrophin produced.

If there is one principle that I honor on this blog: I do not make any statements that as I scientist I know is plain wrong, a lie.

Finally, have I attacked DMD parents for being long the stock or keeping other investors informed (I'm not saying every DMD parent in the study is)? No. Why? Because I can understand them being anxious of getting access to the 'drug' because of their kids alone.

PS: I deleted my financial position, if any, in this (I am not short though), as their details is nobody's business (note: I do not get paid for writing this blog).

Anonymous said...

Not short. But loads of put options huh? LOL

Anonymous said...

As a scientist you know there is a reason it is called 'topline' results. Standard trial results go: Topline announcement, more details at conference and most detailed in peer reviewed publication. Top publications will not accept articles with results already widely distributed. If you know this, yet criticize for releasing only topline data during topline release, while you may not be 'lying' in the strictest definition of the word, you are certainly manipulating the truth, and with manipulation comes question of motive. Please don't feign righteous indignation therefore when your motives are questioned!

Anonymous said...

The sample size issue

First: what is the underlying distribution of the data with DMD (dystrophin positive fibers, 6MWT results) ? In other words, what is the probability distribution of the two variables showing "improvement"? Can any assumption be made about it? Based on normal progression of the disease, isn't it unlikely to witness an improvement in dystrophin pos. fibers and in 6MWT results?

As an example, say the chances of witnessing "improvement" is 1/37, as an example (same chance as a given number be drawn at the roulette). Now, with etiplirsen, we are witnessing an improvement in at least 4 boys, maybe more, out of a sample of 12. So, if the chance of "improvement" were 1/37 for each children based on normal progression of the disease, what are the chances of witnessing at least a 4 out of 12 success rate as only a result of chance?

Imagine playing the roulette: what are the chances that a given number will occur at least 4 out of 12 draws, given that the a "priori" probability of an occurance in any draw is 1 out of 37? The exact probability is, actually, about 0.02%, or 1 occurances in 5.000! (if anybody wants to play with the numbers, using different assumptions, see: vassarstats_net / textbook / ch5apx.html). If you dont trust the formulas, ask a croupier in a casino.

So, critics implicitely saying that the trial's results could be the result of "chance", given the "small sample size", consider this point.
If probability of "improvement" were, say, 1/10 for each children based on normal progression of the disease, chances of witnessing improvement in at least 4 out of 12 boys as a result of chance would be 2.5%, low enough to make the alternative hypothesis -of etiplirsen being effective- significant.

Anonymous said...


Please disclose your financial interests and motives with your articles. Hard to take your work seriously without it.

Anonymous said...

"I deleted my financial position, if any, in this (I am not short though), as their details is nobody's business (note: I do not get paid for writing this blog)."

Actually, they are the business of your readers since it would uncover any bias you may have concerning the subject of your articles. Otherwise how are readers supposed to take your posts seriously. At least that's what a respectable blogger should do.

Anonymous said...

5Drug showed HARM in the intent to treat (ITT) analysis in the 30m/kg group on primary clinical endpoing of 6 min walk distance. I feel badly for parents desperately looking to treat their sons for this terrible disease, but you can't allow companies like Sarepta to exploit these families with false hope, by conveniently excluding the worst performing patients form the analysis of efficacy. The slipperly slope here is way to dangerous.

Anonymous said...

Yes, my son has DMD. He is 9. He was screened for the Sarepta trial, but he walked too far. He is in the placebo arm of the GSK trial, so I know all too well the pain that you are all too willing to inflict upon dozens of families in the name of 100% certainty.

I handed him over to a surgeon so that they could cut him open and again prove that boys don't magically and spontaneously make dystrophin. They're about to do it again.

I have seen videos of the 60% dystrophin kid with my own eyes, and I can tell you that he is a different child than he was 48 weeks ago.

The fact that you are advocating that I spend my limited time advocating for Sarepta to charge a smaller amount for eteplirson for accelerated approval shows what little empathy you truly have. Sorry - I'm too busy taking my son to a hospital so that they can turn him into a lab rat.

Anonymous said...

"I deleted my financial position, if any, in this (I am not short though), as their details is nobody's business (note: I do not get paid for writing this blog)."

That statement is shameful, and absurd, and calls into question everything you say. Of course your position is everybody's business: you are the one who chose to blog about this company and put your opinions in the public domain. Once that choice was made, the obligation to disclose your financial position came with it. That is always a standard practice in financial blogging.

By making this statement you really loose credibility and makes everybody question your true motives for blogging about this, or any other company.

Anonymous said...

And to the comment directly prior to mine: the reason the 2 boys were excluded from analysis was because they had a precipitous decline before they could be expected to have any dystrophin.

They walked somewhere around 250 meters in the 6 minute walk, and if you look at Craig McDonald's natural history data, you will see that this is highly suggestive of coming off one's feet within the next 48 weeks. The drug had nothing to do with it.

Anonymous said...

Wow, some or all of you posting on this board are treating this blogger like he heads the FDA. Seriously?

To get the drug on the market parents and others who support the drug being in the market need to be petitioning the FDA and the DMD medical community. If the FDA does listen to people who speak out against allowing the drug into the market they will listen to prominent DMD specialists not a blogger. I think he said he was going to short the drug. Clearly he has a motive for not being positive about the drug. Why bother spending time trying to convince people who've already made up their minds before they saw all the data? Parents of the kids are better off figuring out if they want the drug given to their kids and if so then how. Investors (short or long) are better off listening to someone who is an actual DMD expert.

Anonymous said...

From an outsiders perspective who has been reading your blog for several years, once you crossed over to the dark side and began shorting stocks, your objectivity has been seriously compromised. Shorting companies attempting to find better treatments for incurable diseases is morally reprehensible. Companies have enough trouble trying to find enough cash for ridiculously expensive clinical trails and when they have to deal with stock manipulation, it makes it near on impossible. Is it any wonder they push the boundaries when they have such limited funds. You have become part of the problem. Tell me, do you scrutinize trial results using SNALP with such critical eye?

Dirk Haussecker said...

My broker never found shares to borrow when I wished to short, and I went long just before the weekend.

Shorting biotechs and the dark side. I once was sympathetic to your thoughts, especially as it regards illegal, manipulative naked shorting. On the other hand, far too many biotech companies are either outright financial scams or managments/BoDs understand them as their personal ATMs. You think these companies are good for the healthcare system? No. They are wasting precious resources and fuel the backlash that I believe will surely come once some of the orphan drug/accelerated approval excesses have played out and a series of drugs will have to be take off the market, either because they do not work, or worse, because of side effects. 50mg/kg morpholinos and they say they do not see side effects. Wonder though what is behind the observed vomiting.

Anonymous said...

So you suggest to delay treatment with Etiplirsen -possibly a couple years or more down the road after a Phase III is completed- because 50% of the patients experienced vomiting? Go tell the parents of the affected kids.

Anonymous said...

Hi, can anyone post the link to the video of the boy with 60% dystrophin that is mentioned a few comments above?


-Hopeful too

Anonymous said...

Reference for video of Max Leclaire:

Regarding the pre-clinical studies, this was an experiment with a beagle in Japan:

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