not that long ago he put chances of AA at 15%. then after PDUFA delay and request for PROMOVI biopsies he called that concillatory by FDA and he upped AA to 45%. now this morning he has read the tea leaves on the changes to ESSENCE, he seems to be predicting AA will happen in 3Q16, so he has upped his odds for approval yet again, of course all assuming ESSENCE biopsies show stat sig increase in D
And i admit, a threshold for fold increase may not be the correct way to look at it. Obviously a simpler way of looking at it: is systemic rescue of dystrophin taking place? Will be interesting to see how the fda defines that. But i dont know how you set 1%, 3%, 10% as the threshold for systemic rescue of D. It seems to me it will be a function of fold increase......we shall see
You make many good points but Janneys Debjit in a note today claimed that SRPT management has told him that the fda has asked for PROMOVI WB D data but has not asked for PROMOVI 6 MWT data. Now either debjit or srpt could be full of it, but if they are correct then the fda is not looking for correlation between D and 6 MWT as a threshold for AA as you suggest. If that is the case AA all comes down to what is good enough D data for fda? Is it 1%, is it 3% etc? Or is it fold increase? Since srpt has proven exon skipping, mRNA production, increased D + fibers in animal andor human models AND you combine that with Woodcocks quote:
"there is agreement that the drug does achieve primary pharmacodynamic effect," and i really believe a stat. significant fold increase over baseline is what JW is looking for. We shall see
I dont know, he got really bearish until today for a few weeks. I agree he is clearly one of the better analysts but he needs to weigh the entirety of the data and think more independently about that data. Its all just a game to these guys
Did you see Debjits note? I have been wondering about the correlation he mentions. I think he quotes srpt management. If this is true it s huge
"Management remains confident on the likely mechanistic validation of eteplirsen, especially since the agency is not asking for a correlation with 6MWT. "
If this is true, what management claims, this is very very bullish imo
Contd, its pretty clear, unlike most of the most extreme bears, JW does not appear to believe etep is a placebo or sugar pill. Bears should keep that in mind
"there is agreement that the drug does achieve primary pharmacodynamic effect," imo this was a tip of the hat to the DMD experts letter and open hearing testimony. The problem is you cant approve a drug on a letter as sufficient data obviously. Add to that 201/202 was determined by adcom panel , in a close 6-7 vote, not to be adequate and well controlled. But it seems clear to me the D data in PROMOVI was collected in an adequate and well controlled manner. Just compare and contrast the D methods in 201/202 to PROMOVI, its quite stark. So once JWs quote can be verified by an adequate and well controlled study, will these boys finally see AA??
Contd if they werent slightly unsure of something they easily could have waited til after AA. Lets see the D data , it better (and imo should) be good
1) SRPT is confident in AA, otherwise they would be asking for more but 2) they are unsure of something: either they do not know yet exact WB dystrophin #s or they dont know exactly how fda will react to that data. Nothing has changed in my mind from yesterday: ie SRPT can get AA but they have to produce the data
Details on price are very important, but my guess is some institutional investor is going to make a ton of money or lose a ton of money.....hmmmmmm......
Heres from his twit longer, good stuff from adcom:
no votes on the AA question and their post-voting commentary.
---Glen Nuckolls, PhD: Mentions different patients, different muscles, “and I don’t find that this fits the definition of an adequate and well-controlled study.”
---Caleb Alexander MD and professor of Epidemiology and Medicine: “I had concerns about the techniques,whereby dystrophin was measured, the relatively modest or very modest absolute amounts of dystrophin produced, as well as the absence of more scientifically rigorous selection and management of controls to allow for what I felt would be comparisons that would lead me to be more confident.”
---Dr. Richard Kryscio (Biostats Professor): “I don’t think the studies were well-controlled…using different tissue samples…” “I was concerned about lack of correlation…” between dystrophin levels and substantial clinical benefit in individual patients.
---Dr. Onyike: "The questions [regarding accelerated approval and standard approval] twice mention well controlled and as you’ve heard repeatedly people have said that they had trouble with the controls so this well controlled phrase in a sense tips or constrains the question."
---Aaron Kesselheim MD (Division of pharmacoepidemiology and pharmacoeconomics): He divided question into 4 parts. “For me the induces production part was the easiest. It clearly does seem to me to induce production.” “studies that were provided by the applicant were not adequate and well-controlled” And again he is also bothered by lack of “correlation” between clinical outcome (acknowledged walking benefit just as Kryscio did) and numerical levels of dystrophin in each indiv. patient’s case who did seem to benefit.
You are correct, we dont know what the results will be. But there is little reason to expect they will be much different than the data from 201/202. As far as i can tell, in terms of the adcom vote on AA it was 6-7. And many of those 7 who voted against stated they thought D was being produced but cited lack of adequate and well controlled studies for why they voted no. Promovi data will be adequate and well controlled. Aftter that its difficult to predict what dunn, woodcock, califf et al will do . But mad scientist on twitter wrote up a great summary of the adcom panelists quotes on the D data and their vote on AA. Beyond his turrets syndrome, its a good read.
Mad_scientist has a nice twit longer summary on twitter. Check out his posts. He summarizes the quotes from adcom. The panelists questioned the D #s because they didnt feel they were obtained and compared to baseline in a well controlled fashion. I agree with him and i also think the Promovi D #s will be obtained in an adequate and well controlled fashion
Art krieg has said sugar is not the answer for these boys. They are already gaining too much weight from steroids . As you know, he has said the next increase in efficacy will come from ppmo
That is a great question! Of course at baseline , that is before treatment, so no bias. But the question remains, did srpt cherry pick those first 13 boys at 48 weeks? Its possible! But maybe the fda has decided that they will do AA on just 13 boys, ie even if cherry picked, it is still a positive effect on a high enough % of boys. And then full approval would be contigent on looking at a fuller data set?