Anavex Life Sciences Corp (AVXL)

[apostrophe]

re:"but at least Donepezil is known to remove plaque (regardless of the stance of it actually being helplful or not). "

Um. sorry to contradict, but donepezil does not actually remove plaque. It slowed down accumulation of certain plaque components in mice that were engineered to develop CNS disease. There was "signicantly less accumulation" at the end of the test period compared to no treatment, but it didn't actually remove any.

"...we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition ... Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Abeta(1-40) and Abeta(1-42), Abeta plaque number, and burden at the study end point in Tg2576 mice. "

http://www.ncbi.nlm.nih.gov/pubmed/19799879

These narrowly focused researchers end with the rather conventional wisdom conclusion that if some is good maybe more is better. But in human practice there are some problems that show up, besides, plaque removal probably not being the right answer anyway.

Firstoff, donepezil's intended function is for use as an acetylcholinesterase inhibitor. Acetylcholine is produced and serves as a neuromodulator in the brain. It's level is regulated, held to a limit by production of acetylcholinesterase which nuetralizes ( or we might say "-erases", excess acetylcholine to maintain a balance (homeostasis). Brain cells calling in sick with AD evidently slack off on acetylcholine production, so the idea was to keep the existing acetylcholine from getting nuetralized by removing the limiter.

Meanwhile it turns out donepezil also engages in some receptor binding, outside its original purpose. There are a lot of different kinds of receptors. It may well be it chanced to bind to something that unterferes with Abeta(1-40) and Abeta(1-42). But what is known is that it also inadverdantly activates M2 and M3 receptors. M3 triggers nausea and vomitting side effect (among other things) but what I find notable is that M2 shuts down acetylcholine production as part of the regulation mechanism. This would suggest a reason why donepezil stops working after a while. Maybe ok to provide a low dose initial boost but with new production shut down, existing acetylcholine gradually diffuses away and it becomes self-defeating at that point.

2-73 instead puts the cells in a kind of maintenance mode or enhanced survival state via the S1 receptor while avoiding the M2 and M3. It also doesn't screw around with the acetylcholine system which simply needs proper regulation restored, as well as maintained in other parts not sick with AD, whereas donepezil circulates everywhere with its effects.

Another thing to keep in mind:

"The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease.[26][46] Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore, mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1?E9), are no more impaired than the oligomer only mice.[47]"

https://en.wikipedia.org/wiki/Amyloid_beta

In the context of biochemistry, an oligomer usually refers to a macromolecular complex formed by non-covalent bonding of a few macromolecules like proteins (or nucleic acids). Of relevance is that with AD, protein assembly is screwed up. Anavex's approach is to correct the process resulting in misfolded proteins.

One can spend hours reading (and writing) about it. Some further reading is below that I found interesting in regard to protein misfolding. Suffice to say that the extensive prior research done to develop 2-73 and its specific targets differs greatly from the current soc/plaque mania and will continue to succeed as others fail, (imo) :

https://en.wikipedia.org/wiki/Aggresome