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.
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.