You don’t know much about clinical trials; really.

FDA’s guidance on endpoints has no relevance to success or failure of trials — only on their approval chances, if any.

Regarding small vs large trials: Most AD trials (except AVXL's) have indeed been very large -- but that is likely because the expected change in endpoints has been small. AVXL was expecting a larger change -- so, went with a smaller trial to save costs. Ultimately, p-value is what really matters (if safety is not an issue).

In either case, with respect to FDA/US, there may be a tiny change of AA (based on biomarker data) -- but otherwise AVXL needs another trial anyway for FDA approval (this new trial will likely be a large trial -- since the smaller one "failed").

Delay in talking with the FDA regarding AD seems to be: Time taken to "analyze" the biomarker data, as I understand from the call (and perhaps, waiting for OLE data). Which means two disappointing things:

1. Primary/secondary end-point data is indeed not pivotal/FDA-approval worthy, even in CM's eyes. Fair enough.
2. Analyzing biomarker data -- takes them 2 years (!) post-completion. That is certainly not reasonable, by any stretch of imagination.

Too bad.

I liked the presentation -- though CM is really a terrible speaker (of course, my benchmark is Douglas of SRPT).
Anyway, he seemed to answer/address my main concern of AD 2b/3 trial -- i.e, of pooled dosage arm vs placebo comparison. He said that as per SAP and titration-protocol, they did the comparison only of "30+50mg" vs Placebo -- and that it is sufficient to deem the trial to be successful.

However, I can not imagine FDA approving a drug based on pooled analysis. How could the dosage be determined? FDA can't approve a drug without any indication of dose. Not sure what EMA is thinking.

But CM is certainly wise enough to know that WGTs don’t move the market — and there is no upside to pleasing them.

To the non-WGT (Ie, the non-blindfolded ones)::

Is it possible that CM doesn’t really think that EMA approval has a chance, but decided to initiate the process anyway .. just to fool the market.

To me it seems like a non-trivial possibility.

FIRST Q is whether the EMA submission will indeed happen. I'm not very confident. My personal probability of an EMA submission happening (ever) is 50%. If it doesn't happen --- I can't imagine it happening anytime before 3-4Q 24. My pessimism is well founded.

Are you for real? I have seen dumb as well as dumber. But always a surprise.

The stock is at a 3 (or maybe more) year low … it was $15 before the disaster in December 2022. The biggest disaster of all!

Haha. You think the FDA reviewers are neurologists? The WS analysts?

Most answers are obvious — we are just hesitant to say it.

At this point, IMO, CM is mulling — what direction to go.

1. Should he wait for EMA low-probability approval for AD, or start a new expensive AD trial as FDA seems (my personal belief; not a fact) to have made amply clear.

2. He is likely thinking about a large Rett trial too.

I really believe — there is very low chance of approval from current trials.

CM may be preparing for another Rett trial.

Another AD trial is too expensive — so he’s likely hesitating. With EMA possibility, I doubt he’ll run another trial.

NDA (for FDA): Not happening. Zero chance, in my eyes.

No, I’m not talking about website changes; I’m talking about AUC.

Exactly. No idea why majority of posters here somehow restrict themselves from saying anything negative about the company — as if it’s a sin and/or is being disloyal to other "friends" out here.

Claiming AVXL's trials were a success — is no different than claiming that 2020 was stolen. Some of the pumpers likely believe thar too.

I have everything invested into Sarepta, but i have no hesitation saying that its both gene-therapy trials "technically failed" (whether it gets approval or not is another story).

They are hiding it since it failed statistical significance. It’s just too obvious (especially after September PR).

Regarding AUC, Avatar’s endpoint was changed last minute from RSBQ-delta to RSBQ-AUC-delta .. with a very elaborate presentation and justification.

Eventually — CM decided to go back to RSBQ in Excellence with the reason being “there is no need to do AUC, because the larger trial should have sufficient statistical power” —- you can find his exact words on one of the earnings CC, when the analyst was stunned that he was switching back. (I was too).

Isn’t it obvious?

Do you know the whole AUC saga?

I do give credence to Sept PR of p<0.025. But there are two big problems: (1) Where is the dose-level data and efficacy? (2) Why the 1.5 years delay in getting FDA in line for an NDA?

For these two reasons, I consider the “true” efficacy results to be questionable.

Regarding what I would recommend— if AVXL is approved. If AVXL is approved, I’d think that I’d have access to much more detailed and complete trial data (which we don’t now) — and the answer would really depend on analysis of that data. Determining before that is shooting in the dark.

Bas: You and me live in different worlds. You should discard my posts — they aren’t meant for you.

I’m not a neurologist. Why would be recommending any drug to anyone?

If I were a neurologist, I would only be considering from the FDA-approved drugs.

After EXCELLENCE failure, I’m seriously questioning my continued investment/holding shares too. I have held for 8 years, so perhaps selling will be a slow/drawn out process.

And, I have been wrong many times when optimistic— I could certainly be wrong being pessimistic here.

The BIGGEST consideration (like 90%, certainly when it comes to FDA) in approving a drug is on EFFICACY. Safety, ease of administration, unmet need — etc play only a secondary role.

Anavex AD drug has questionable/unproven efficacy at this point — only one trial and that trial’s endpoints weren’t convincingly (to put it kindly) met. We don’t even know the dose-level data!

It’s that simple.

That doesn’t mean EMA approval chances are zero, BUT they are minimal IMO. FDA approval chances are near-zero, IMO.

Why so dependent on others? Don’t you have an analytical mind of your own — that you look for (weak) signals like some stranger joining a company ?

They will — during the review.

How does having non-approvable dosage results stop an application to be ineligible?

What would be the difference between eligibility and approval then?

Of course, the dosage result exists. But the fact that CM hasn’t shared it — certainly means that they aren’t great (ie approval worthy). That’s how I interpret his hiding very-material information.

I think the biggest problem with P2b/P3 is not the filed ADL endpoint. The biggest problem is the lack of dosage-arm data, which is highly likely to have a terrible p-value if any at all. FDA can't possibly approve a drug without a dosage recommendation -- and a dosage recommendation can only come from dosage-level data.

First, you really need to understand AA.

Second, you need to understand Sareptr’s failure better — in particular, NSAA endpoint.

Third — most importantly — LAW doesn’t say anything about “primary endpoint” or p<0.05 requirement. All it says is “substantial evidence”. Point being — FDA decides what is substantial evidence, which in almost all cases is TWO successful trials or ONE compelling and successful trial. Again — AA vs ffull approval is the same criteria — just the “endpoints” differ.

You have high expectations.

The problem is not entirely with the 0.063 p number. I have heard FDA say in an AdCom (BMRN's Prosensa drug AdCom in 2015-2016, if you want to look it up) that they do not have a hard line of 0.05 and are willing to approve drugs that have p higher than 0.05 (e.g., 0.07 may be acceptable). BUT, the problem with 2-73's drug is that there is NOTHING ELSE that supports clinical efficacy claim -- EXCELLENCE's other endpoints failed outright (perhaps, p > 0.2 and/or the DELTA was insignificant), AVATAR failed (AVXL had to post-result resort to AUC to save its face). So, looking at the evidence (of any credibility -- i.e, you can only look at PRE-SPECIFIED endpoints of placebo-controlled rails) overall -- the evidence is very very thin, and in all likelihood the drug does NOT WORK (in terms of its impact on RSBQ and/or CGI, at 7-12 weeks period).

One can speculate of reasons behind the failures -- even if the reasons are plausible valid, that doesn't prove the drug will work in absence of those reasons (e.g., placebo benefit).

So, there is no way FDA will be convinced of drug's efficacy from the data (nothing else matters to FDA). IN FACT, even if a future trial succeeds -- AVXL will only have a lot of explaining to do, as to why these previous trials failed (may not be hard to do, but AVXL will need to).

FDA doesn't approve based on hunches/speculations. It needs to be convinced of the evidence (even if the p value is over 0.05) that the drug "works". E.g., recent SRP-9001 trial failed on its primary endpoint. I am (and, the SRPT's CEO and many analysts) are still betting that FDA will still approve the drug (i.e., at least expand the label for AA which has a lower bar on functional efficacy, but also do a full approval) --- because the overall evidence is quite CONVINCING (of course, FDA needs to feel that too -- time will tell).

There is near-ZERO chance of Rett approval anywhere. FDA doesn’t bend its rules based on community; even in Sarepta’s case, it didn’t happen if you really know all the details (I followed it extremely closely).

Chances of AD approval may still be there —- partly because we don’t even know the full data (which could even be favorable).

CM has certainly tried to be very conservative with money — perhaps to the point of being cheap (cheap CROs leading to 6-9 months delay in reporting results).

It didn’t work out. Perhaps he has learnt his lesson.

Again the worst thing about him is that he hides data (worse, even lies) for months and months. Eg, Still — only pooled data for AD.

Regarding AD P2b/P3's endpoints.

I think its fair to assume that THE endpoints measures (in SAP) were EITHER ORs or LSMs (for ADL and Cog).

1) If they were ORs, then clearly the endpoints were met with statistical significance. Barring some unexplained inaccuracies (but I'm willing to trust AVXL on that -- since CM doubled down on it, that there were no errors).

2) If they were LSMs, then to me September PR is reasonably convincing (p < 0.025 for ONE of the endpoints seems very reasonable statistically; I doubt FDA would mind that -- though I haven't seen a precedence).

With the above in mind -- I think maybe AD P2b/P3 wasn't much of a failure. EXCEPT -- there is this issue about the results for each dosage, which AVXL is still hiding... not sure why. I doubt any regulatory agency would approve a drug based on "pooled" data ...

Anyway, contrary to my earlier pessimism, I wouldn't be shocked if FDA were to ALLOW AVXL to file for an NDA -- but here again the biggest doubt seems to come from the fact that AVXL has been silent about it for 1+ years, so that seems to suggest that FDA has said NO (or AVXL hasn't even approached them).

AUC’s choice in Avatar (post-result) is becoming crystal clear now.

Now, CM not having started additional trials in 2023 (as he had guided in 2022) seems like a prudent decision.

At this point, AVXL needs to find ONE success, before squandering away more capital in various/other indications .

I was certainly right about the timing.
6 month delay was never going to lead to positive trial results.
Not sure how bad is AVXL future …

Do you even know the endpoints of Avatar? Were they determined by CM after looking at the data?

Agree with your timelines for EMA and Rett NDA (if at all).

However, I don't believe there will be any FDA NDA submission for AD. Not until a new trial is run.

That’s their skill. IMO, they were just trying to figure out a way forward. Else, why would it take them one whole year to decide to go for EMA — they should have made the decision 1 year ago (it’s not that they have discovered new data).

Anyway, as I said — time will tell. I have low expectations from CM in terms of him showing any urgency.

You really think they have been working on the submission last year? I don’t think so. Time will tell.

You are saying “failed” trial results are not publishable?

Realistically, June 2024.
It would certainly take 6 months for AVXL to prepare the submission (only a few tens of employees — and this is too important for the company). I’ll be shocked if it happens earlier.

My sixth sense tells me the EXCELLENCE data is coming out today or over the next few days (by next week).

You believe that? Enjoy the blindfoldedness.
Did you hear the CCs/reasons for the delay in ALL of the previous trial results.