Replies to post #204433 on Anavex Life Sciences Corp (AVXL)

[georgejjl]

High plasma concentration of ANAVEX®2-73
[≥4.0 ng/ml] is correlated with the clinically
administered dose

This [≥4.0 ng/ml] is correlated with the clinically administered oral dose.

Good luck and GOD bless,

[georgejjl]

The S1R agonist ANAVEX®2-73 could potentially
normalize neuroinflammatory processes by several
different mechanisms:
1. Reducing microglia over-activation
2. Reducing inflammatory cytokines
3. Increasing anti-inflammatory cytokines
4. Releasing protective factors, e.g. BDNF
5. Protect against inflammatory molecules

https://www.anavex.com/wp-content/uploads/2019/07/Anavex-Microbiota-Presentation-AAIC-July-2019-1.pdf

[Doc328]

Why don't we do a trial for an A2-73/19-144 patch (eg. on arm) and dodge the whole gut absorption issue?

A273 is a small lipophilic molecule (logP=3.87) so it could readily be made into a patch with any generic patch matrix. However, before doing so, they would need to do some mouse studies followed by phase 1 to determine the dose of the patch to get the level above 4 ng/ml in the blood and then finally a phase 3 for approval. There are potential advantages --- bypasses gut, maybe less dizziness but also disadvantage -- patients prefer pills, old people skin with easy bruising, possible irritability, stability generally better with pills, etc). They are already down the oral path and will continue for better or worse. PDD results should be available 1Q2020. If Anave273 ever gets approved, a patch might be considered if a need exists.

Unfortunately, because the gut data was only on a single sample +/- 18 months after initiating and there was no correlation to MMSE, I don't think any conclusions about A273 and the gut absorption can be made at this time.

Is part of the treatment also happening in the gut?

Probably not as they did IV and oral crossover in part A of the small 2a study. However, the gut associated lymphatic tissue makes up 2/3 of the immune system in the body so its not a settled point. In the CNS, Neurons, astroglia, oligodendrocytes and microglia express Sigma1 receptors. Peritoneal macrophages (I'm not sure if macrophages int eh GALT, though), similar in many ways to microglia express S1R so sigma-1 agonists might have some action in the gut.