I have read the notes on Friday's call with PTC, which were posted yesterday on PPMD's main website, especially Sharon Hesterlee's useful comments. I've also read Pat Furlong's blog and her words about this community's own "hurricane" are indeed moving to all of us.


I thought it might be interesting to share with you the outcome of a quick search of Ataluren's clinical trials in the Government website www.clinicaltrials.gov, and the status of these trials as reported there. This has to do with the difference between suspension and termination, a distinction whose practical consequences I do not really grasp (my son was not in the trials, even though he has a stop codon mutation; we live in Argentina).


There are five DMD-BMD related trials of PTC124 listed there, including the Phase II trial completed in 2007, which does not count for these purposes.


As far as I can tell by looking at each individual entry, only one trial has been actually suspended. It's the Phase 2a trial for non-ambulatory boys (#  NCT01009294). The estimated completion date for this trial was mid 2011.


The Phase 2b Trial (# NCT00592553) is shown as "completed" (neither terminated nor suspended), and its results - as we know - are being presented as not successful, because there is no statistically significant improvement in the 6MWT (the primary end-point measure that was defined for this study).


The Phase 2b Extension Trial (# NCT00847379) is reported as "terminated". The primary outcome measure of this particular study was not the 6MWT, but rather the "long-term safety of PTC124 in boys with nonsense-mutation DMD/BMD, as determined by adverse events and laboratory abnormalities". Ambulation, together with a number of other parameters, was listed among the secondary outcome measures to be looked for in this extension trial.


Finally, the Phase 2a Extension Study (# NCT00759876) is also shown as "terminated". The primary outcome measure looked for in this trial was "long-term safety". Again, as in the Phase 2b Extension, ambulation was described here as one of the secondary outcome measures.


The first question that I would be tempted to ask is why have the Extension Trials (both 2a and 2b) been terminated, when the 6MWT was not their primary outcome measure?


Was it absolutely necessary or otherwise mandatory to stop those trials, which were supposed to go on for two years, even though they were looking for "long-term safety" as primary results and they included very important secondary measures, such as cardiac and respiratory function?


As for the non-ambulatory boys, whose trial has been suspended, appart form cardiac and respiratory function, other extremely important secondary outcome measures included Upper extremity function;  Upper extremity range of motion; Upper extremity muscle strength, as welll as Activities of Daily Living and Muscle Dystrophin Expression  and CK levels.


I guess that it all boils down to what exactly do they mean when they say that the results must be"clinically meaningful". Duchenne Muscular Dystrophy is essentially a cell-killing disease. What cells does it kill? Muscular cells; first skeletal muscles and then the diaphragm and the heart. Why does DMD kill muscular cells? Because, due to the absence of dystrophin the cells are unprotected and all sorts of lethal chemicals flow in, causing necrosis and preventing regeneration. What happens when these cells die? The boys suffer a gradual physical deterioration, which is first noticed in their ability to run, climb stairs and ultimately walk. However, the deterioration does not stop there, and soon they cannot raise their arms, comb their hair, etc.


In other words, the "primary outcome measure" or primary end-point for a drug that looked like the first potentially serious cure for a deadly disease such as DMD should have been "detention or reversion of muscular cell necrosis", as shown in biopsies taken before, during and after the trials. If necrosis is stopped or reverted, the boy will live!! (isn't that a significant clinical result?).


To me, basing the whole thing on the 6MWT for an experimental drug whose aim has all along been to restore the production of dystrophin, so that in turn cell necrosis stops or is reverted, would be more or less like evaluating the efficacy of a lung cancer drug by asking the patients to sing the aria of an opera and see how they perform.


Sorry about such a long post, but I've been following PTC124's evolution for more than 7 years. My son was then 11 and he walked with a funny gait. Now is 19, he's been wheelchair bound for a little over three years and his overall strength is going away daily.


I know that Dr. Peltz and his team must also be emotionally affected by this sad outcome, and I hope that they will not throw the towel yet.









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I think what they mean by "clinically meaningful" is this. Maybe the drug did in fact increase dystrophin production, but if that does not translate into any physical improvement, then so what ? If my son makes dystrophin but it does not mean any physical difference, then it does not seem to be worth it. Let's move on to something that makes a difference in dystophin AND in the physical abilities of the boys.

Well, certainly the question is not only if the genes are expressing dystrophin as result of Ataluren, but - most crucially - if by this mechanism the muscular cells stop being destroyed by leakes, or even if as a consequence of reading through the premature stop codon a regeneration of muscle tissue is possible. These are the truly important results, because if the individual cells stop dying the boys will live!!. If, as a bonus, the boys are able to walk faster that's great, but this should have never been the final aim (I think it wasn'tt when PTC first started announcing its research on DMD back in 2002 or 2003). To me, the rate of progress in cell necrosis before and after Ataluren is as much a physical and measurable pattern as anything else. To me, if the drug succeeds in stopping the progress of the disease, its discoverers should be awarded the Nobel Prize and we should be eternally grateful to them. I was not expecting a miracle potion that could make my son walk again; I was hoping for a medicine that could stop his physical deterioration, perhaps until another line of research becomes even more successful, if not for my own son for the younger generations.
Bernard, very well written post.

First off, I would guess that the extension trials would be cancelled because you don't need safety data (the primary objective of those trials) on a drug that doesn't achieve its primary outcome (6MWT).

Your main issue seems to be the 6MWT being used as the primary outcome, rather than something like increased dystrophin production, or a slowing of muscle necrosis. Sharon goes into that in her notes, and I think Tamara's point in this thread is well taken as well. How much dystrophin is enough? How much slowing of necrosis is enough? In the end, it's really about seeing some difference in function between patients that take the drug and those that don't. Is the 6MWT the best indicator of that? Maybe not. It seems to be the best we have at this point, though.

I have confidence that PTC and Genzyme are not giving up on Ataluren. I think there's an altruistic aspect of working with our boys that will keep them on the case. Perhaps even more powerful is the financial aspect. A lot of money has been invested, and there's a lot of money to be made if this becomes an approved therapy. If there's a way that the primary endpoint for the drug can be reworked or changed - perhaps to one of the previous secondary outcomes that show promise in the data - you can bet they'll do that. I would also imagine that if there's an avenue for regulatory approval in another country - they'll pursue that. They're not doing this work out of charity, and it's not some kind of endless academic exercise. Their work results in a therapy they can sell - or they go out of business. Make no mistake - they want this to proceed if there's any way possible at all - probably not as bad as we do - but they've got some substantial motivation as well.

I agree with you that it has to be very emotional and disappointing to the people that were working on this. They've invested a lot of their heart and soul in this. They know us. They know our boys and the position we're in. They're not giving up. They said so, and I believe them. I thank God for people like them every day...
Thank you very much Keith. We'll see what happens next.
Hi everyone,

Tamara, Keith, and Bernardo - you all make great points. Since the news, I have been reading everything I can find on Ataluren and the 2b trial, and you all expressed my reactions perfectly. Why is the 6MWT the primary outcome as opposed to a cellular or molecular effect? Were these boys and young men on the drug long enough to show an effect? Where are the data for the other measures and why are they stopping the trial before analyzing all measures?

From what I could tell, and please correct me if I'm wrong because I'm not as well-versed on the topic as a lot of people on this site are, but the primary outcome was dictated by the FDA. The FDA has the same sentiment as Tamara's post above - if there is no improvement (or in this case, maintenance) of actual physical performance - then anything else is moot.

I personally do not agree with this point. As we all know, these boys are not dying from the inability to walk, but from heart and lung failure. Just because there is no obvious improvement in walking distance, it does not mean there are no other important effects. The human body is incomprehensibly complex, and no possibilities should be ruled out so easily. It could be that because the leg muscles are the largest in the body, the effects of a modest increase in dystrophin will have the smallest effect because of a small degree of penetration into the tissue - maybe heart function is being improved as we speak. It could be that the drug has the strongest effects if given earlier, before significant degeneration. It could be that the body actively sequesters dystrophin to more essential muscles to keep itself alive (the body is pretty darn good at adapting to internal and external states to survive). It could be that after not having dystrophin for so long, the body is creating antibodies to the protein, and the drug could be more effective with a mild immune suppressant. It could be a million things! To me, it seems the primary endpoints should only be heart function, lung function, and life expectancy - that's what we all care about in the end.

I do in fact feel that if they only know what they have told us, this trial was ended prematurely. There are obviously some boys in the trial that are seeing a benefit, and those boys need to be more closely examined to see how and why their bodies are responding positively. Now, the fact that I feel the trial should not have ended is from the perspective of someone with an affected brother-in-law. I'm not saying PTC was irresponsible in their actions - as Keith explained, they have a huge interest too - so I'm sure they have some reason to halt the trial, whether it by monetary or something else. In the end, they probably know best on how to run their business, and if they need to work on the data more before spending more money, that will ultimately benefit us in the end, if they can stay afloat long enough to see through the development of this drug.

My heart goes out to everyone here - though I can't possibly understand what you are going through as parents, I feel so incredibly frustrated that I can't do anything. I am in the building right across the street from CHOP - but because I am in the neuroscience program at Penn, there is not much I can do in studying muscle tissue.

Let’s hope that PTC can realize which avenue to best explore in a timely manner. Hope is far from gone!
Actually, I do not think that there is any doubt in the minds of the scientists working in the field that producing enough dystrophin will produce functional improvement. It has been shown in large animals that this is the case even with exon skipping where the dystrophin produced in not full length. When a very high dose of morpholinos was used and a large quantity of dystrophin was produced, one could easily see the difference in the 6MWT surrogate b/w the treated and untreated dogs. What is not clear at this point is how much dystrophin represents enough to see the improvement. Hence it is difficult to use % dystropin as an endpoint now. That and the fact that the FDA would like to measure function/improvement. That is why I think that the most important data to analyze is the biopsy data.

I have no idea what Ataluren's future is for DMD (the PTC group was not clear at all when asked the question proving that they do not know either until all data is analyzed), but there is very important information in this data for other possible treatments in the pipeline, exon skipping, gene therapy etc. I hope they analyze this data sooner rather than later and present the results.

Tamara Walters said:
I think what they mean by "clinically meaningful" is this. Maybe the drug did in fact increase dystrophin production, but if that does not translate into any physical improvement, then so what ? If my son makes dystrophin but it does not mean any physical difference, then it does not seem to be worth it. Let's move on to something that makes a difference in dystophin AND in the physical abilities of the boys.

Thank you Shane and Ofelia for your valuable input. Let's hope that PTC finds some histologically important information when they finish sorting out their data from the biopsies, and that they can then convince the FDA about possibly expanding or changing the definition of the primary end-point. I assume that in hemophilia that is induced by a stop codon mutation, things will be much more clear cut por Ataluren than in DMD. Either the clotting factor is expressed (and bleedings stop), or they don't. I don't know about cystic fibrosis. In DMD, as Shane says, boys and men do not die "from their inability to walk but from lung and heart failure", so if Ataluren manages to stop the necrosis of muscular cells then it ultimately becomes a life-saving drug!!. Regards to all.

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