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Sarepta Therapeutics, Inc. Message Board

  • wggm wggm Dec 3, 2013 7:28 PM Flag

    How would you explain the Drisa 1/2 results if you were SRPT?

    I suspect that the FDA is thinking in part that the Drisa's p1/2 trial had a small N and very promising results, but failed the P3, so we should require a P3 for Etep. I know all the arguments about the different safety profile and dystrophin production, but just focusing on the Drisa p1/2, if you were CG and talking to the FDA and they said the Etep results were consistent with the Drisa p1/2 results, is there anything you can say about it other than it was a fluke? I think it would be extremely important if you could show that the Drisa p1/2 results were consistent with Sarepta's views or could otherwise be explained away, because I believe that is what is giving the FDA comfort in their assertions about natural history.

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    • You missed the entire point. much like FDA. Sigh.

      1. MOA--Mode of Action: Drisp and Eterp have the same mode of action: by producing more dystrohpin, the drug will delay the DMD deterioration. Do you understand this? If so, move on.
      2. Drisp P1/p2: only 29% treated boys show increased dystrophin, yes, only 29% on western blot, while Eterp shows 100% by western blot. That's a 4-fold difference.
      3. So Drisp P1/P2 can be explained by their MOA to a degree of 29%. The rest is unexplainable, which can be attributed to their inclusion criteria and variability. Drisp P2 is only stat sig at 24 week. It's no longer stat sig at 48-wk and beyond. Eterp can explain their p1/p2 success by their MOD to a degree of 100%. Nothing unexplainable here. Stat sig at 96-week and hopefully beyond when they release more data. Huge difference here.
      4. Drisp P3 had a different inclusion criteria than P1/P2. Assuming they still have a MOA of 29%, then at best you should see 29% improvement by design. The rest is due to variability. When you start out with a puny treatment effect, variability will bury the effect easily. Also, P3 had more drug holidays, which may indeed lowered the dystrophin increase rate to below 29%. Dose-limiting toxicity is what you need to know.

      So in summary, Drisp P1/P2 have very poor results(not stat sig at 48-wk and beyond) compare to Eterp P2(stat sig at 96-week+) . Drisp shows poor MOA rate at 29% dystrophin increase, while Eterp shows 100%.

      Case closed.

      • 1 Reply to carrix_fool
      • Carrix, I think you missed the part of my question where I said I know about the dystropin and all the other stuff. I am only talking about how this study supports the FDA's view of natural history. You have a group of boys in the study that are now 3 to 15 years old who have remained relatively stable and up and running. That is not supposed to happen. Is there something about the boys in Drisa's p1/2 that would explain why they remained stable for far longer than the models that SRPT is using would have predicted? I don't agree with the FDA's conclusions, but if you don't believe etep is producing functional dystrophin, all you are left with is that the etep boys remained stable for a lot longer than they should have (I am ignoring the placebo kids who declined and then stabilized at a lower level). That seems no more impressive than the kids in the Drisa p1/2.

    • Their phase I/II enrolled a group with different natural history than was enrolled in their phase III. Due perhaps to difficulty in finding enough subjects from this rare disease group to enroll in the larger phase III, they included more subjects likely to do well without their drug.

      • 1 Reply to paris1785
      • I don't have the information in front of me, but even if they started out better, my recollection is that they are now 13 to 15 years old and still going strong. How is that consistent with the natural history that Sarepta is trying to present? I am playing devil's advocate. I want to hear why I should ignore this data when thinking about natural history, because I really believe the FDA has this study in the back of their minds. Again, I am only focused on how this undermines natural history claims.

    • If they were real scientists it wouldn't need explaining. Thinks about it this way. What if Etep hadn't been tested and you look at the drisa data. Now predict Eteps result. What do you get? Answer nothing-can't be done. Its no different after you test Etep. Nothing to do with each other. They should Know that.

      • 1 Reply to thigrlsrk
      • Wait a minute. You can certainly point to the boys in the Etep p2 who were on placebo who declined and then stabilized once on Etep, but I am talking about natural history. Part of the argument in favor of AA is that you have a group of DMD boys who should not be stable for two years and therefore the drug must be working. Well, says the FDA, the Drisa p1/2 also had a small group of DMD boys, and they stayed pretty stable for even longer on Drisa, and that drug didn't work, so you assumptions about natural history aren't correct or there is enough variation such that the stability of the Etep trial kids does not prove anything. Again, I know there are other reasons to grant Etep AA, I am just focusing on how the Drisa p1/2 supports the FDA's assertions on natural history.

 
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