Amelioration of Inflammatory Markers in Duchennes..
An often overlooked pathological endpoint of treatment with eteplirsen is the reduction of inflammatory markers CD3, CD4 and CD8. This ties together the additional dystrophin produced, proper incorporation of said dystrophin into dystrophin-associated glycoprotein complexes, clinical improvement via cowers and 6MWT, and overall improvement of muscle pathophysiology. The following was from a recent presentation, "Moreover, novel dystrophin expression was accompanied by a significant reduction of inflammatory cell infiltrates in the two highest dose cohorts, including CD3 ( p=0.01 ), CD4 and CD8 inflammation markers, suggesting an alteration in the underlying degenerative disease process". This is biochemical proof that eteplirsen is improving the diseased state known as muscular dystrophy. Can someone please inform the FDA!
It does make you wonder what the heck is going on at the FDA. This new data on inflammatory markers is really impressive, as is the entire body of Eteplirsen data. In fact, this is simply the sort of data that you would expect to be generated by a drug that works, and works well. Why it is taking so long for the FDA hierarchy to grasp and accept the fact that Eteplirsen works is beyond me. There really is no excuse.
I think the FDA is taking their time because they know that regardless of how quickly they make up their minds, SRPT won't be in a position to meet the manufacturing needs until the end of the year. You would have to believe if they are digging into the data as deeply as people assume, when the finally give the nod to file for AA, there won't be much more to look at, so the decision (which even under a priority review is 6months, instead of the regular review of 10 months) won't take more than a few months. That has been my argument all along - why not tell SRPT to submit for AA - by the time the FDA has to make a decision, they will have another 6 months of 6MWT data - if it is stable, it is a no-brainer, if there are signs of deterioration, then they have an out to ask for a Phase III first - what's wrong with that game plan?
Bionerd51 - With your background and understanding of the MOA of eteplirsen, as well as the nuances of positive discovery in the scientific literature, I hope the DMD community is open to your expert opinion and guidance in how best to communicate with and educate FDA w/ regard to these findings. Your input is very much appreciated here.
The biochemical improvement via inflammatory markers occurred in the 30 and 50mg/kgs cohorts. This data I have not seen before. I believe it was part of the Congressional presentation by participating experts in the field.