Can the percentage of dystrophin fibers be used to predict a clinical benefit? Does one only need 10% or is the level sufficient for a lasting improvement more on the order of 50%?
It isn’t enough to say dystrophin levels are critical for proper muscle function, SRPT will have to come up with a number or some type of matrix. So that if you score above the magic number the prediction is you would have a clinical benefit and if you didn’t reach the cutoff the predication wouldn’t be as favorable.
In my opinion there simply isn’t enough data to be able to make a reasonable prediction. What is the threshold? And I’m not the only one:
“Phase II Principal Investigator Dr Jerry Mendell, Nationwide Children’s Hospital, Columbus, Ohio, agreed that from his experience, functional data like 6MWT is critical for accelerated approval, not biomarker data like dystrophin production alone. He declined to provide an opinion on whether accelerated approval is warranted or not.”
Another moronic assessment - they will need to come up with a "matrix". You could study this drug in 500 boys and not come up with a reliable matrix - every boy is at a different stage of the disease, will metabolize the drug differently, have different phenotypes, etc., etc. The bottom line, which is well documented and well understood, is that DMD is defined as a lack of dystrophin production and so in accordance with the AA protocol, the production of dystrophin is "reasonably likely" to generate a clinical benefit. Will every boy "clinically respond" (as measured by the 6MWT) the same to the same levels of dystrophin production - no. But there is ample evidence that this has at a minimum slowed the progression of the disease, and if Max is any indication, if you get them early enough, perhaps stop it in its tracks (with respect to ambulation). If you are going to anchor the value of Eteplirsen on the 6MWT, how would you ever evalutate its value on a boy aged 6, let alone a boy aged 16. Again, you are looking at it with moron glasses on.
Yes, tredleon, I have argued many times before that there are so many variables to consider with each individual case as to how and why they respond to the drug. Moreover, if the drug could be administered early enough, instead of later, might eteplirsen stop the disease so that these children never have the affects of the disease? It's kind of like treating cancer. If you catch is early enough, it can be treatable. The longer you wait the worse the outcome can be. Srpt used older children in their trial ( GSK/Prosensa used younger) which means the disease had advanced further. Yet, eteplirsen had better results and was much safer. Did anyone actually read the AE's stats on Gsk/Prosensas drug? Most of the children had an AE and many had severe AE's. I don't think the fda will want to delay and/or deny a drug that seems to work and is safe and, if given early enough, could halt the disease. The fda would take such a horrible public image hit if they were to deny the drug. You know that Jenn and the other parents will publicly attack the fda if they continue to delay. The fda wanted a little more data which is acceptable. The company was just simply meeting the fda to see how to proceed with a possible AA. They were not actually applying for AA. The fda let srpt know the additional info they wanted to see. As soon as CG sends this info, which should not take much time at all, the fda will, imo, make a very quick decision to allow them to apply for AA. I think it then becomes a formality to get approval so long as CG shows the manufacturing is in place. The fda is not going to delay this any longer than it has to.