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I like the idea, but unfortunately whatever simple-actions I can think of (eg reveal ADL mean-change) — I just can’t imagine CM doing that even on his dead body.
Another upgrade?
Oh, you are believing that it will be RSBQ-AUC. You don’t think he’ll do a threshold-based responder analysis over RSBQ-AUC?!
What are the endpoints/outcome-measures of the upcoming EXCELLENCE trial?
Do we have any clarity on that? Or it’s a crapshoot?
Beautiful trading action.
Will possibly explode tomorrow. If I were still a short-term trader, I would buy it right now.
one issue, end points were tweaked to suit the data
Selvaraju is a credible name in biotech, in my limited understanding. His upgrade is certainly post-DD from him. It only means that WS isn’t completely trashing AVXL yet.
Exactly — because the flaws were extremely obvious. Have you read the 12/1 PR? Which company starts off with threshold-based metrics?
Todays upgrade from Selvaraju.
It’s a big deal.
Thats not how FDA is flexible. All I can suggest is to listen to the following FDA presentation for SRPT's AdCom in 2016. You'll hear exactly how FDA thinks about even AA (in short, they do NOT compromise on the definition of what "substantial evidence" means -- but for AA they are willing to use a surrogate marker or intermediate clinical endpoint). Unfortunately, I can't find the AdCom video -- it used to be available till recently.
I’m telling you how the FDA works, and not what is the “right” way to judge how a drug works.
Specific example: A study shows that 20% of the treated patients “improve”, while the 80% of treated patients behave “similarly” to the placebo patients.
In this case, the mean-change for the whole group should be positive. But let’s say the p-value for the whole group is very bad .. say 0.2.
For the above example, FDA will not approve. Definitely not. If you think otherwise, then I suggest you find a relevant precedence that proves your point (Ie a drug that was approved by FDA with a study showing super-responders without improvement of the whole group). .
I’m sure the surrogate marker must have been evaluated for the whole group of treated patients. What subgroup are you talking about?
I will take the opposite side of view. How can any regulator deny a safe drug which stops a 100% fatal disease progression in 1 out 5 patients and revert the disease in 1 out 15 patients?
Thanks. COVID can only be measured in terms if number of infections (esp considering the current tests available — which are only binary).
I guess a more appropriate Q would be: Has FDA ever considered OR as a basis for approval (even in conjunction with n), even when mean-delta change was a plausible metric?
I would seriously doubt it. Because OR fundamentally ignores a lot. Eg, in this case, how do the non-responders compare? You can’t ignore this.
Irrespective of the above, how could AVXL presume that FDA will be ok with ORs? Certainly, FDA didn’t give them a formal OK. OR has obvious flaws — and wasting 7 years of P2b effort on just a dubious measure would be very stupid. Maybe, CM did change from mean-delta to ORs then. We may never find out …
Perhaps. The potential will be much better reflected in the stock price — if CM is replaced.
Could FDA accept OR metrics as basis for approval (assuming that they were indeed pre-specified)?
I doubt it. Is there a precedence? I don’t know if any. If there is no precedence, what argument can FDA have against it (if let’s say # of improved patients is sufficiently high)?
One thing at a time, JKS. I am not at p-values yet.
1. Is it possible that OR outcomes was the intention all along, and they were specified as such in the SAP?
2. If yes, would FDA find these measures sufficient for approval?
Which part is impossible? That there is no SAP? There certainly is, as per CM in the CC.
Is it possible, that CM has been telling the full truth? Ie, the OR measures were truly the outcome measure intended all along (Ie in SAP, communicated to FDA, not necessarily approved).
I’d say it’s possible. And, if that’s the case — would FDA accept these for approval? I don’t have a strong argument against it.
One shouldn’t preclude the above possibility. There is no reason to believe it’s less likely than the currently prevailing presumption.
Every single PUBLIC company can be taken over.
So, a CEO should delay start of trials — so as to maximize the speculative impact on share price?! Wow.
Anshu i disagree with your valuation for buyout. There is no way if even 20 percent improve on drug that this will only be worth 2 billion.
Confirmatory trial HAS to be a well-controlled trial. OLE will never work for it.
You think the CEO does any better?
Appended to the post.
Every question must be answered, every data point a stunning masterpiece of clarity. No equivocating
No, I seriously doubt that CEO gets it.
TLR may be released — many times — but would it really clarify matters? Would it be presented like most credible companies do? Would it leave the market only all the more confused?
If the upcoming TLR really makes things crystal clear — whether good or bad — I’ll be stunned!! But, very happy.
Which side do you want to be?
Negatives:
1. CEO goofs up TLD releases, possibly, even twisting the truth, hiding key data points, changing endpoints. THREE times.
2. FDA may require P3 for AD.
Positives.
1. Just based on what is publicly known, the company can be bought out for $15-20, IMO.
2. Considering ADs drug failures to date, FDA may give AVXL a chance to file and review based on P2b/3 results. CDR-SB and Cog endpoints were certainly positively met. Upcoming data details may be positive. If FDA is open/sympathetic, AA can’t be ruled out.
3. Rett data’s positives are difficult to dispute (I also believe Avatar’s RSBQ-delra was very positive, even though CM didn’t disclose). So, post-excellence, approval should be on the cards.
I’m stuck on the long side; hoping for the positives, infuriated by negative #1.
I seriously doubt it!!
Yes, positives noted. But, have you completely missed the point of the negatives — which really need to be repeated over and over again (here, media, analysts, everywhere) until the thick-skinned CEO gets it!!
Yes, but for safety reasons the drug should have been used on sufficient many patients across trials. I don’t think that’s an issue for 2-73.
AD drugs typically use very large trials because they are expecting the difference in effect to be small — in which case you need a larger trial (to get low p value).
How is it that CM is the only one in the whole wide world who think’s differently? Listen to his reply to S Roy in the CC. Unbelievable—he thinks the whole world is a fool.
Why not short BIIB then?
Awesome update.
I hope CM gets it right this time!
Do you realize that showing mean-change if ADCS-ADL takes 5 mins, and this is something being pointed out by everyone relevant as conspicuously missing?
What do you assume the reason to be — except that CM is making a fool of everyone else (but actually himself).
BioChecker: I feel your energy is being uselessly wasted in your posts. I know you are frustrated and upset. I was too — but am better now. Do you think it would be more meaningful to instead do something about the frustration?
The only thing I can think of is to write a letter to the board. Do you think that’s a meaningful exercise? We could pool in together to write — but perhaps, we need numbers (number of people or total number/length-held of shares) to make impact?
Agree, high-level. However, you can’t deny that CEO’s job is also to communicate effectively with the investors — they are indirectly providing the funds to run the company.
A few weeks or 1-2 months of delay is not going to change anything .. neither would I consider it much if a miss.
Is there a material deadline that AVXL has missed significantly .. ie 3+ months .. for reasons internal? I can’t recall.
That WS/investors don’t believe his claims.