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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...
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.
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