fox - this is the point I have been trying to make the last couple of days - is the decline in 6MWT the result of continued muscle deterioration (implying Etep is not working) or is it the inability of the remaining healthy muscle tissue to keep up with the height and weight increases as they age. I can't imagine any trial being able to conclusively answer that issue. If you only enroll boys that already have substantial damage to their muscles, you will never know what is driving their progress over 2-3 years. The only way to know if Etep will provide long-term benefit is to start treating boys as early as possible and see how they progress, but that could be a 7-10 year trial issue. Better to get the drug approved, provide it to as many boys as possible and do as much post-approval study as possible.
Appreciate the sentiment, but not sure why you think we will see a spike towards the end of the year - filing the NDA won't be noteworthy and I can't imagine anything out of the WMS presentation that is going to change the minds of the naysayers. It is my firm belief that Etep and its clinical path is completely misunderstood by a good chunk of the investment community - they either believe (like pasteur) that the data from a 12-patient extension study is not sufficient to for approval or that if Etep really worked that the boys would be improving, as opposed to struggling to maintain stability. IOW people don't understand the AA process or DMD natural history (particularly as it relates to boys in the 7+ age group). I expect that the only thing that is going to convince these naysayers is when the advisory committee experts set them straight and give the FDA no choice but to grant AA, and that won't happen until mid-2015. Maybe if you get a 4th biopsy and/or there is some individual detail in the 144 week data that provides some nuance to the overall story you could see some recovery by the end of the year, but the Etep story will more likely play out in 2015. The wild card will be some groundbreaking pre-clinical data and/or a lucrative venture deal in some indication that hasn't been announced, yet.
jkad - I think it is clear that deterioration begins as soon as they are born - it just doesn't become recognizable until they are diagnosed at age 4-5. The more I think about this, the more I believe that there is a constant struggle going on between remaining functional muscle and the demands placed on that muscle from these boys continuing to grow, until at age 7+ function starts to deteriorate at a greater and greater pace. The fact that Etep has seemingly stalled/delayed their deterioration at a point where they should be rapidly declining due to substantial accumulated damage is very meaningful and not to be dismissed, even if these boys should continue to slide.
I guess when you boil it down, there are three potential scenarios at work with the declines experienced by the boys at w144 - (1) Etep has had absolutely no impact on the boys muscles and they continue to deteriorate, but due to the odds of enrollment and the natural variability in the population, two lost ambulation immediately, 6 on treatment showed stability for 120 weeks and then started to deteriorate and 4 placebo-delayed started to deteriorate then stabilized for 72 weeks and then started to deteriorate (2) Etep has had some impact on their muscles and has slowed the deterioration of their muscle function or (3) Etep has stopped the deterioration of their muscles, leading to an initial stabilization, but the salvaged muscle mass in their legs is not enough to stabilized them as they age and add weight and height. IMO, scenario one makes no sense - Etep is having some effect and between scenario 2 & 3 it is a toss up. The individual data would help make sense of this - if there are some boys that have in fact improved at w144, that goes a long way toward making the case that the drug is working and the variability is due to the existing muscle damage at the time of enrollment.
bb - The dosage is automatically upped as the kids grow - they are dosed based on their weight. The key point in the equation is once the muscle tissue is destroyed by the disease it cannot be recovered. The company is caught in this paradigm of trying to prove the drug works on patients that are already damaged from the disease, because testing it on younger boys would take too long to show a benefits - if you tested it on 5-6 year olds you would have a 5-7 year trial to prove no deterioration in their 6MWT. Testing it on 7-9 year olds shortens the equation but brings in the risk of having patients with too much damage (the twins) or if the damage is stopped, may not have enough functioning muscle mass to be stable as they grow.
winter - that is the point at issue - are the increasing "rates of decline" in the 6MWT evidence that Etep is only slowing progression in the deterioration of their muscles or is a case of the boys remaining leg muscles that are being maintained by Etep are not healthy enough to carry the load as the boys age and gain height and weight? There is probably no way of answering that question conclusively and the only way to know whether starting treatment earlier will salvage enough healthy muscle to get them through to adulthood with no significant loss of function is to actually get the drug approved and start treating boys as early as possible.
All these comments throwing Etep's ability to "cure" into the trash are way off base. If the twins that lost ambulation end up living into their 50's with no severe deterioration of their lungs, heart, arms, etc. going forward, would that be considered a "cure". Nothing is going to be able to restore the muscle that has been lost to this disease, so every boy's "cure" is going to be relative to how much damage has been done before they start treatment. For some, it will be confined to a wheelchair, for some it may be using a walker as they age and hopefully for those that start treatment early it will be walking to their grave at ripe old age. The less obvious and cruel potential "cure" will be for the boys that have lost most of their physical functions, where treating them with Etep may simply drag out the suffering they endure to the end - what would you do as a parent?
Dosage already is varied by body weight - the 30mg and 50 mg dosages used in the trial are per kg of body weight.
CG commented on that in the past - the twins were by far the tallest boys in the trial and height is one of the predictors in determining how quickly DMD boys lose ambulation - their deteriorating muscles can't keep up with weight and leverage of their growing limbs. That is playing out more slowly with the rest of the Etep boys - how much muscle was saved, how will the muscle grow in relation to their bones, etc.
The Becker's comparison is missing the point in this case. CG has spoken many times on the hope that Etep will convert exon51 boys into the milder Beckers form of DMD, but that would be when the boy starts on Etep before significant muscle damage has already taken place - that is not the case here. What drove the twins to lose ambulation and what will ultimately determine the long-term prospects for the remaining 10 boys on Etep is how much healthy muscle tissue remains that can be salvaged by Etep and how will that muscle tissue grow/perform as the boys age. The prospect of converting boys into Beckers patients can only be tested by starting them well before age 7 and tracking their progress into their late teens - a 15 year trial is not realistic, so the only way to realize the Beckers hope is to get Etep approved and get boys on the drug as soon as possible.
If everything you said was true, then the FDA would not have told SRPT to file for AA or have given them alternative paths to approval. Are we to believe the FDA is going to take them all the way to the goal line and then say, "the data over 168 weeks is very compelling and the experts all agree that the drug is effective, but if we include the twins, then statistical significance for the original 48 week data is lost, so sorry"? You have a mental block here - take a pill or something, but give it a rest, already!
pasteur - you're like a rabid dog that won't let go of a bone - we get it already - everybody knows, the twins lost ambulation and their 6MWT results are excluded from the results. As the FDA has communicated to the company, they will supposedly be acting in good faith with the AA regs and be as flexible as possible in analyzing the available data. Everybody but you seems to understand that Etep will not restore lost muscle function, so when you are enrolling patients on the precipice of losing ambulation and it takes 12-24 weeks for meaningful levels of dystrophin to be produced, you run the risk that some boys will not be able to perform the 6MWT. Does that mean Etep is not working for them or that boys that have lost ambulation can't benefit from the drug? I'm not sure why, but don't seem to be able to grasp the AA regs and how they relate to the Etep clinical path.
I agree - as AF noted today, the 144 week data is either good or doubtful depending on whether you believe that all or most of the enrolled boys should be in wheelchairs by now or that the "variability" of the disease is enough to explain the relative stability of the boys in 6MWT and pulmonary function. I am not convinced that the FDA, by opening the AA submission door, has given up on their variability rationalization. When all the boys were stable, it was a slam dunk to say 10 out of 10 does not represent variability - it represents a working drug. If the breakdown is as copp portrayed (3 better, 3 marginally worse and 4 moderately worse), does that open the door for the FDA to fall back into their ignorant position? You would hope the adcomm and cleaner natural history analysis would convince them otherwise, but it may no longer be a slam dunk.
That data doesn't exist - it is considered unethical in trials of this nature to deny placebo arm patients the drug for longer than a period deemed necessary to show a treatment effect - in this case that was 24 weeks. Part of it boils down to the practicality of keeping placebo patients in the trial - why would you subject your boy to all the testing if they had no chance to get the drug, so parents would sign their boy up for the trial and then drop out after they were randomized to the placebo arm.
grey - While under most circumstances, continued stable results in an extension trial would not be considered material, I am having a hard time agreeing with that position when it comes to Etep. Given the slow, progressive nature of the disease and the uncertainty surrounding Etep's long-term effectiveness (particularly in the 7+ age group), every clinical readout should be considered material for SRPT, especially because the FDA has told them how important the data will be for the upcoming AA. If they are truly under an embargo due to their presentation commitment at WMS in Oct, that's fine, but that does not prevent them from disclosing that the 144 week testing has been completed and there are no SAEs or significant changes in the boys' 6MWT results. I agree with the premise that if the results presented a material negative change in the clinical efficacy or safety, they would have to disclose that immediately, but the idea that we have to wait until Oct to get any official word from the company on the 144 week results is ridiculous.
jrrt - I'm going from the individual 6MWT data tables in the latest presentations - those show 6 patients in the treated group and only 4 patients in the placebo delayed group, so the twins must have been in the placebo delayed group.
The other aspect of this non-issue raised about the Willis twins is that if there were to be any of the patients in the trial that were expected to show some level of deterioration, it would be these two boys. It is clear from the rapid deterioration of their leg strength early in the trial (they were in the placebo-delayed arm and lost ambulation by week 36-48) that the existing damage to their muscles was greater than the other boys in the trial - why would this damage be limited to their leg muscles? They could also have significant damage in their arm muscles that doesn't present itself as clinically obvious as it did in their leg muscles w the loss of ambulation. As they age and their bones grow, does the remaining healthy arm muscle tissue grow normally and allow them maintain their function or is it too damaged to grow normally and keep up with the additional weight and length of their arms, hands, etc. and do they lose functionality?
IOW, it is ridiculous to expect that there are two distinct outcomes with DMD boys on Etep - retain full functionality and lose all functionality. There will naturally be a full range of potential outcomes, depending on when treatment starts, existing muscle damage, dosage, etc., etc. We can hope that all the boys in the Etep trial were started early enough to maintain the function that they started with as they age, but that probably will not be the case. The hope is that if you start them early enough, they will live the life of a Becker patient - that hope cannot be tested in the current trial and the only way to realize that hope is to get all Exon 51 DMD boys on Etep as soon as possible.
A number of posters have tossed out the idea that the Etep results should be viewed in a context similar to a cancer trial - i.e. benefit is typically proven with well less than 100% of the patients having a response to the drug. While there is some merit in this thinking, it also distorts the picture by missing a key factor that Etep's clinical path has in its favor. The merit is obviously in the fact that we know that Etep is not a "cure" in the sense that a patient already having material muscle damage from DMD will not be able to recover that damage, so the "response" to Etep as measured by clinical benefit to motor function will not be 100% in a patient population of boys aged 7+ years - they already have substantial muscle damage that may not allow them to improve or even stabilize. Ultimately, the clinical benefit that is most important is survival, but trying to measure the impact of Etep on survival would take too long and be grossly unethical (assuming you had a placebo arm). This set of circumstances is exactly why the accelerated approval rules were written - the ability to measure clinical benefit is difficult in the short-term (not only due to the slow, progressive nature of the disease, but also the lack of a large patient population) and is why you can't compare Etep's results in the same context as a cancer drug. Most cancers are progressive enough to kill their victims within a couple of years and most cancers have a current standard of care that provides some benefit, so the ability to measure clinical benefit is typically very concrete. Etep should not and will not be held to that same standard in an accelerated approval setting.