Anavex Life Sciences Corp (AVXL)

[Investor2014]

Anavex have never really explained why A2-73 would work, when many other even higher affinity S1R agonists have been tried and are in use e.g. Donepezil/Aricept without bringing about amazing if any results.

Assuming the whole FKBP12 preamble holds water and further assuming A2-73 is in fact also an antagonist of FKBP12, then as the article says Anavex might just have stumbled on a fortuitous molecule.

It is like that with many drugs. Their actual MoA is not fully understood, but to that end who cares, not many incl. the FDA et al.

I think Donepezil is a great example of a drug where the developers did not see or even realise that in fact its limited benefits likely comes from it being a S1R agonists among other activities, but evidently not in a too fortuitous configuration.

Only time and trial results will tell, soon'ish.

Anavex2-73 is a S1R agonist with moderate affinity and has produced impressive clinical results from double-blinded studies treating Rett syndrome and Parkinson disease dementia. Currently it is in a phase II/III trial for Alzheimer’s disease. However, neither the scientific nor the investment communities are fully endorsing the clinical results or the potential in AD treatment. Granted, there are thousands of agonists of S1R with higher affinities than that of Anavex2-73 and none of them have been proven to have significant clinical applications. Is Anavex2-73 unique?


Figure 2. Possible binding mode of Anavex2-73 to the active site of FKBP12.

Agonism to S1R will provide temporary relief of ER stress (ISR) and we can expect short-term improvement in symptoms resulting from AD. However, a sustained response requires blunting the source of inflammation, necroptosis. From a structural perspective, Anavex2-73 features a phenyl group (Benzene) adjacent to a 5-membered ring, a structural similarity to that of Phe-Pro dipeptide. FKBP12 recognizes and prefers a substrate with sequence containing Phe-Pro for catalyzing the isomerization of the corresponding peptide bond³?. We suspect that Anavex2-73 is an inhibitor of FKBP12 and subsequently conducted preliminary docking experiments. The results indicate that Anavex2-73 might be an inhibitor of FKBP12 (Figure 2) with reasonable affinity, likely in the nanomolar range. Granted, wet lab experiments are needed to confirm or disprove the docking studies, as docking alone does produce artifacts. However, the fit to the active site is intriguing, especially the impressive hydrophobic interactions between Anavex2-73 and the active site without steric strains. Further laboratory investigation is warranted to obtain binding affinities. Maybe it is too condescending to ask “Did Anavex stumble onto the right compound”?