Replies to post #336600 on Anavex Life Sciences Corp (AVXL)

[LBSR TO DA MOON]

If there was a company out there who had the same thoughts that you have, IMO AVXL would have definitely received a takeover offer by now. I certainly hope your predictions come to fruition...

...but it does seem to me like the AD chances of success are at least 90 percent. (My gut feel is iffier, but that is where the numbers point.) And the theory of efficacy, I believe, will apply equally to both Rett and AD.
So considering all this, I think 90 percent is a reasonable prediction for AVATAR's success.

[nidan7500]

boi568:Another excellent post...thx-

Most of my confidence arises from the previous Rett trial results which, as we know, hit its endpoints. This trial is using the same population as the first; the only difference is an increased dose. There is no evidence available that increasing a dose of 2-73 (within tolerance limits) will do anything other than increase efficacy.
We don't need an increased efficacy to pass the trial, we just need to avoid a drop below the endpoints. We survived the interim peek safety check.

Beyond that, we have biomarker consistency between PDD and Rett, even though the traditional etiology of these conditions appears qualitatively distinct -- that is, unless you accept the radical idea of a previously unexplored upstream cause. We have that too, in theory and now to an early degree in practice.

By analogy, you can look at PDD and AD. There is a 70 percent correspondence there for episodic memory. There are stats on the chances of success moving from a Phase 2 to a Phase 3 trial, which I believe Missling cited -- using precision medicine -- at 68 percent. If I remember my research correctly, safety issues account for 17 percent of failures in Phase 3 and commercial concerns another 5 percent; these risks are very minimized, if not eliminated. I can't parse all the overlaps involved in these elements, but it does seem to me like the AD chances of success are at least 90 percent. (My gut feel is iffier, but that is where the numbers point.) And the theory of efficacy, I believe, will apply equally to both Rett and AD.

So considering all this, I think 90 percent is a reasonable prediction for AVATAR's success.

[Investor2014]

Most of my confidence arises from the previous Rett trial results which, as we know, hit its endpoints. This trial is using the same population as the first; the only difference is an increased dose. There is no evidence available that increasing a dose of 2-73 (within tolerance limits) will do anything other than increase efficacy.

I need to see the AVATAR data to aliviate my concern that there was quite a lot of placebo response in the U.S. Rett trial.

This was recently discussed also with Doc328 chiming in on the reliability of RSBQ and its sentivity to bias being questionaire based. I think we saw an amount of that in the data.

Yet of course overall the trial showed stat sig outcome, so a repeat of that and especially with further distance between placebo and the higher AVATAR dose would bolster my confidence considerably.

[Investor2014]

We only have a small open label trial in AD so far.

We all agree that Aduhelm is good at reducing its plaque biomarker target, but it does not translate to much clinically meaningful efficacy.

The Anavex S1 mRNA biomarker is good at showing A2-73 is engaging with its S1R target through its increased expression.

We don’t yet know for certain how well that increased S1R expression translates to the classic endpoints in the various potentially pivotal trials, which is why we are running them.

I beleive you are also refering to this:

Previously reported cognitive outcome measures from this study relevant to Alzheimer’s disease presented at CTAD 2020 observed statistically significant improvement of CDR system Episodic Memory of +42.22 between ANAVEX®2-73 high dose and placebo, which was dose-dependent (p = 0.003).7 CDR system Episodic Memory has been shown to be highly correlated (70%) with the ADAS-Cog score (r = 0.7).8 The calculated corresponding ADAS-Cog mean change from baseline score is -1.9 (improvement) for patients in the high dose group, an 8% mean improvement from baseline to 14 weeks.

The implied correlation of one specific CDR System measure to the P2b/3 AD primary endpoint is suggestive, just like the S1 mRNA expression likely is.

To me this cannot translate into anything like 90% certainty that the P2b/3 trial will have a succesful readout with stat sig endpoints.

If it does turn out as we, Anavex and patients hope we will have beaten Biogen's Aduhelm and PERHAPS have established a new S1 Biomarker.

Still not sure of the latter though because as we know not all S1R agonists are the same, but common to them all may be a measureable enhancement to the S1 mRNA expression at varying levels of correlation to actual clinically meaningful outcomes - again much like reduction of amyloid plaque as an MoA target does not.

In biotech/biology it is rarely as simple as a back of a napkin extrapolation - by all means entertain them, but don't rely on them for investment purposes.