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I was reading the report presented by PTC Therapeutics at the recent American Academy of Neurology Meeting, on April 16.
I am a lawyer, not a scientist, but I think that anybody using common sense will agree that these results show that Ataluren at a low dose is a remarkable success in terms of improving the health of the DMD boys who have a stop codon type of mutation. The results show that the 57 boys who were given the lower dose walked - on average - only 13 meteres less at week # 48 as compared with their baseline during the so called "6 minute walk test", while the placebo group and the higher dose group walked 42 meters less! The difference between low dose Ataluren and placebo was 29 meters!

However, because the sponsors of the trial and the FDA had agreed that the outcome would be considered a success only if there was a 30 meter difference, the whole thing was shut down and the extension trials were cancelled. The difference between the desired goal and the actual result was only one meter!! I simply cannot believe that a medical breakthrough like this is about to be dumped because someone fails to see the writing on the wall: Ataluren at a low dose IS a success, because: (a) as already shown during Phase 2a, the drug manages to produce dystrophin; (b) as a result of the presence of dystrophin, the boys' muscles die at a slower rate (I wish the muscles stayed 100% healthy, but slowing the progress of a deadly disease should be hailed as an indisputable achievement); (c) as a result of the above, and after taking the drug for almost one year, these boys manage to walk approximately twice as much in 6 minutes as those on placebo; (d) if such a good outcome is measured JUST relying on one highly debatable end point such as the 6MWT, simple commons sense would dictate that the alleviating/ameliorating/life-prolonging properties of Ataluren must surely be as impressive in crucial areas such as the functioning of the respiratory system and that of the heart. Sorry to throw all this out in such a disorderly way. I hope these type of questions will be asked on May 27th!.
What is worse is that the pre-determination of how dystrophin introduction behaves in DMD muscle in humans is most likely flawed. Who is to say that 48 weeks is the magic number? We know that dystrophin production takes a long time due to its size, the question is how much is needed to help muscle? What if doubling that to 96 weeks would have had an outcome of a positive number of meters. The timeframe is way to short to understand how dystrophin introduction behaves. I want to see their DNA and muscle biopsy results at the 48 week. If it shows an increase in dystrophin production then the trial should continue. My son produces dystrophin but he has got something else wrong at the binding sites. His symptoms are less aggressive but he has been producing dystrophin since birth so he has that advantage. 48 weeks is too short of a period - dystrophin production is key and so is the length of time that dystrophin production is allowed. I don't understand this trial or its outcome, it makes no sense at all to stop it based on some pre-determination that has no standing because any way you look at it, it's a guess plain and simple and not based on any historical facts because I don't think anyone else produced dystrophin in DMD boys yet.
I agree with Franco. When I saw these results I said that the most sensible approach will be to continue this trial and collect more data. Have they looked at the biopsy data yet? IMO dystrophyn expression is what we all need to focus on at this point. We know all the pros and cons, we know that the FDA want to see functional improvement etc. etc. etc. Bottom line is that after 48 weeks this slows the disease progression and there is no other drug on the market doing that (there is NO other DMD disease modifying drug on the market period!). I am looking forward to the May 27 conference call!

MarcosDad said:
What is worse is that the pre-determination of how dystrophin introduction behaves in DMD muscle in humans is most likely flawed. Who is to say that 48 weeks is the magic number? We know that dystrophin production takes a long time due to its size, the question is how much is needed to help muscle? What if doubling that to 96 weeks would have had an outcome of a positive number of meters. The timeframe is way to short to understand how dystrophin introduction behaves. I want to see their DNA and muscle biopsy results at the 48 week. If it shows an increase in dystrophin production then the trial should continue. My son produces dystrophin but he has got something else wrong at the binding sites. His symptoms are less aggressive but he has been producing dystrophin since birth so he has that advantage. 48 weeks is too short of a period - dystrophin production is key and so is the length of time that dystrophin production is allowed. I don't understand this trial or its outcome, it makes no sense at all to stop it based on some pre-determination that has no standing because any way you look at it, it's a guess plain and simple and not based on any historical facts because I don't think anyone else produced dystrophin in DMD boys yet.
Thank you Marcos and Ofelia. I agree with you 100%, and it seems to me that what we are saying is so sensible that someone out there will have to wake up and realize that by stalling this crucial trial they might be condemning the ONLY real, tangible scientifically successful drug ever devised so far for DMD. It is not only that the 6MWT by itself should have never been "THE" threshold for a thumbs down or thumbs up on Ataluren, as Marcos and many others have said. It is also that if you pick the 6MWT as one of several useful measures to take into account, it turns out that the low dose group did just great on that particular test!! The distance they were able to walk in 6 minutes was only 13 meters shorter at the end of the 48 week trial, as compared with a reduction of 42 meters for the placebo boys. Had those boys managed to walk 12 meters less after 48 weeks instead of 13, we would not even be discussing this, and instead of that we would be hearing praises to PTC from all over the world.... Sounds crazy to me...
Another question is why not restart the suspended nonambulatory trial ASAP as it has different end points ie cardiac fx and PFT's, they only need to change to the lower dose, this trial is paid for by MDA, they don't need to go back to the FDA, it is unblinded so they can see the data right away and possibly get very help information and these are 18 year old or older young men who do not have time to wait. Cheri, mother of Jacob who was in the nonambulatory trial.

Bernardo A. Iriberri said:
Thank you Marcos and Ofelia. I agree with you 100%, and it seems to me that what we are saying is so sensible that someone out there will have to wake up and realize that by stalling this crucial trial they might be condemning the ONLY real, tangible scientifically successful drug ever devised so far for DMD. It is not only that the 6MWT by itself should have never been "THE" threshold for a thumbs down or thumbs up on Ataluren, as Marcos and many others have said. It is also that if you pick the 6MWT as one of several useful measures to take into account, it turns out that the low dose group did just great on that particular test!! The distance they were able to walk in 6 minutes was only 13 meters shorter at the end of the 48 week trial, as compared with a reduction of 42 meters for the placebo boys. Had those boys managed to walk 12 meters less after 48 weeks instead of 13, we would not even be discussing this, and instead of that we would be hearing praises to PTC from all over the world.... Sounds crazy to me...
Very good points Cheri. I hope all of them are raised during the conference call. I won't be able to attend.

Cheri Gunvalson said:
Another question is why not restart the suspended nonambulatory trial ASAP as it has different end points ie cardiac fx and PFT's, they only need to change to the lower dose, this trial is paid for by MDA, they don't need to go back to the FDA, it is unblinded so they can see the data right away and possibly get very help information and these are 18 year old or older young men who do not have time to wait. Cheri, mother of Jacob who was in the nonambulatory trial.

Bernardo A. Iriberri said:
Thank you Marcos and Ofelia. I agree with you 100%, and it seems to me that what we are saying is so sensible that someone out there will have to wake up and realize that by stalling this crucial trial they might be condemning the ONLY real, tangible scientifically successful drug ever devised so far for DMD. It is not only that the 6MWT by itself should have never been "THE" threshold for a thumbs down or thumbs up on Ataluren, as Marcos and many others have said. It is also that if you pick the 6MWT as one of several useful measures to take into account, it turns out that the low dose group did just great on that particular test!! The distance they were able to walk in 6 minutes was only 13 meters shorter at the end of the 48 week trial, as compared with a reduction of 42 meters for the placebo boys. Had those boys managed to walk 12 meters less after 48 weeks instead of 13, we would not even be discussing this, and instead of that we would be hearing praises to PTC from all over the world.... Sounds crazy to me...
The most disturbing piece of all of this to me is how apparent it is that our generation of boys is already considered collateral damage in the attempt to find a cure.
Dear All

I am the father of a 12 yrs old boy with DMD from Cyprus. My son has deletion as the mutation. So we are not expecting that Alaluren will help my boy, but I am very dissapointed that all these months and years of research from PTC are just thrown away just based on 6MWT!! What about other results? What about muscle biopsy results? What about dystrophin levels? PTC should have a look at these info also.

I am afraid that the problem is something else... Money!! PTC may "want" to stop these trials because they see no "real financial benefit" from Alaluren? Can we think of that? Maybe the 6MWT is just an excuse for stopping the development of Alaluren?

Greg
I think if there's any way PTC can get a return on their multi-million dollar investment, they're pursuing it aggressively.

There's a huge financial payoff for an approved Ataluren therapy. The license to distribute would be worth hundreds of millions of dollars, extrapolating from the amount that GSK has agreed to pay for exon skipping and the number of patients each therapy could help.

I can't see PTC walking away from this while there's a chance it can result in a therapy. Some of the points raised here sure seem to indicate it can result in a therapy. I'm sure these points aren't lost on them. I listened to the last conference call, I didn't hear anything that indicated they were giving up on Ataluren. I'm looking forward to hearing what they have to say next week.
I agree. We have to keep in mind that these companies are in it for profit. I know that it does not sound good, but that is the difference b/w a company and an academic institution, they want/need to make a profit.

Question is: do they have the urgency in mind when making plans? They can make money in 2-3 years but our sons need something now, o/w as Mindy said, this generation is collateral damage. Unfortunately, I do not think that saving this generation of boys makes the top of a company's agenda. Look at Prosensa/GSK, starting a trial beginning of 2010 became mid 2010 and now late 2010...one year delay does not prove that they really take into account the urgency AND we are not talking about safety anymore at this point, these drugs are proven safe, so they cannot play the safety card.


Keith Van Houten said:
I think if there's any way PTC can get a return on their multi-million dollar investment, they're pursuing it aggressively.

There's a huge financial payoff for an approved Ataluren therapy. The license to distribute would be worth hundreds of millions of dollars, extrapolating from the amount that GSK has agreed to pay for exon skipping and the number of patients each therapy could help.

I can't see PTC walking away from this while there's a chance it can result in a therapy. Some of the points raised here sure seem to indicate it can result in a therapy. I'm sure these points aren't lost on them. I listened to the last conference call, I didn't hear anything that indicated they were giving up on Ataluren. I'm looking forward to hearing what they have to say next week.
The economics of Duchenne has always been difficult due to the small population. Ataluren only got as far as it has because it potentially impacts many other diseases, most of which are more profitable. Drugs that only help Duchenne (like utrophin upregulators) will always face financial hurdles. Unfortunately, as science makes advances, the financial constraints have and will become more apparent and frustrating. I have been following all of this for over 12 years (son is now 14 and still walking). PTC, and it's joint venturers and investors, will not risk the success of this drug for Duchenne. My take on the low versus high dose is that the high dose might be producing an immune response to the dystrophin. No one knows how much dystrophin will be needed to improve function; and no one knows if we can restore a sufficient amount of dystrophin without triggering an immune response. If Ataluren is to be properly evaluated, we will need to know what % of dystrophin was produced in various muscles, and whether there is evidence of the body attacking the newly produced dystrophin. I am surprised we have no major statements regarding whether or not there was immune response to dystrophin at higher doses (if there was none, they should state that fact). If there is an immune response, these dystrophin replacement strategies will be set back even further. I have always thought utrophin is the only hope for boys alive today. But, as can be seen, upregulation is not easy from either a scientific or a financial viewpoint.

Unfortunately, nothing will happen overnight. Just look at the timlines for drugs for the most lucrative of diseases. I share your frustrations and have lived through them. More frustrating than the failure to get dystrophin in the muscle is the failure to pinpoint key downstream pathologies that might be targeted by existing drugs. As of today, we still depend on deflazacort and supplements.
I have not seen any data to suggest a possible immune response because I don't believe it has been an issue with ataluren. Not all the boys in the trials had zero dystrophin pre ataluren some had natural dystrophin present. I believe the boys with some dystrophin may do better on the drug because they would not have as far to go to get to a theraputic level. I hope our sons can get back on the drug soon so this can be evaluated better.


aid:
The economics of Duchenne has always been difficult due to the small population. Ataluren only got as far as it has because it potentially impacts many other diseases, most of which are more profitable. Drugs that only help Duchenne (like utrophin upregulators) will always face financial hurdles. Unfortunately, as science makes advances, the financial constraints have and will become more apparent and frustrating. I have been following all of this for over 12 years (son is now 14 and still walking). PTC, and it's joint venturers and investors, will not risk the success of this drug for Duchenne. My take on the low versus high dose is that the high dose might be producing an immune response to the dystrophin. No one knows how much dystrophin will be needed to improve function; and no one knows if we can restore a sufficient amount of dystrophin without triggering an immune response. If Ataluren is to be properly evaluated, we will need to know what % of dystrophin was produced in various muscles, and whether there is evidence of the body attacking the newly produced dystrophin. I am surprised we have no major statements regarding whether or not there was immune response to dystrophin at higher doses (if there was none, they should state that fact). If there is an immune response, these dystrophin replacement strategies will be set back even further. I have always thought utrophin is the only hope for boys alive today. But, as can be seen, upregulation is not easy from either a scientific or a financial viewpoint.

Unfortunately, nothing will happen overnight. Just look at the timlines for drugs for the most lucrative of diseases. I share your frustrations and have lived through them. More frustrating than the failure to get dystrophin in the muscle is the failure to pinpoint key downstream pathologies that might be targeted by existing drugs. As of today, we still depend on deflazacort and supplements.

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