Replies to post #180178 on Anavex Life Sciences Corp (AVXL)

[MycroftHolmes]

A very interesting study, thank you

Cheers

Mycroft

[OFP]

Sigma 1 Study

Thanks for the link. I think you undersold that one ;)
Very interesting.

The full report is available for free here: https://www.cell.com/cell-reports/pdf/S2211-1247(18)31981-8.pdf

[sokol]

Re: Choline, see this:

Msg 15583 of 31285 at 6/27/2016 10:10:44 PM by

libertyhound

The following message was updated on 6/27/2016 10:12:45 PM.


In response to msg 15580 by Rob Cos view thread
Re: JMP last night- development- stage names that we believe offer compelling value for the biotech investor. Also rare opportunity to acquire large caps at < 1 x's growth....
"Alzheimers is one of the most intractable diseases known to medicine, and chipping away at this devastating illness could go a long way toward reinstituting confidence amongst investors (and hopefully, the generalist) that no problem is too large for current medical science to resolve or beat back. Further, the general consensus is that a successful Alzheimer’s disease drug could become the largest selling drug on the planet, outstripping sales of Ibrance (Pfizer, PFE, NC) and immune checkpoint inhibitors like Opdivo (Bristol-Myers Squibb, BMY, NC)."


*Considering the 'very' preliminary early indications of astounding efficacy, it is possible that AVXL (MC of ~ $250M), currently trialing their A2-73 in Australia, may be long-shot favorite to watch for Alzheimer's - they don't really appear to be pursuing the 'chipping away' (read incremental improvements) approach though.....seem more aligned with going for the Holy Grail approach; their approach is NOT a variation of the popular plaque reduction route.

From a 5/10/16 SA piece by Lane Simonian

"Moreover, science seems to back the early results. Alzheimer's is most likely a disease caused by oxidative stress which can probably be treated with certain antioxidants. Anavex 2-73 partially fits this bill as by impeding the interaction between PSD 95 and neuronal nitric oxide synthase, it reduces the formation of peroxynitrite (ONOO-). Peroxynitrite inhibits the uptake of choline, the enzyme choline acetyltransferase, and the release of acetylcholine through muscarinic acetylcholine receptors which prevents the retrieval of short-term memories and it activates caspase 3 causing the death of neurons. (Image one, Image two, and Study.)

If Anavex 2-73 reduces the formation of peroxynitrite sufficiently it would prevent the further decline in acetylcholine and the death of neurons. In short it would stop the progression of Alzheimer's disease. If it partially reverses the damage done by peroxynitrite, it would increase acetylcholine levels (and thus the retrieval of short-term memory) and the regeneration of neurons in the hippocampus. In short, it would partially reverse Alzheimer's disease. The early data suggests the latter is what is happening with Anavex 2-73."


*No idea whether his (Lane Simonian) interpretation of the 'apparent' mechanism of action is fully correct, but the very preliminary 'results' appear to indicate a trend for unheard of efficacy - their trial is for early Alzheimer's btw, and further 12 week and possibly 26 week results are expected at the upcoming late July AAIC Alzheimer's Conference.

BTW - A2-73 was recently awarded ODD for Infantile Spasms and Rett Syndrome, ODD to their A3-73 for Frontotemporal Dementia, and have reported astounding pre-clinical results for epilepsy.....M.J.Fox Foundation is also fully funding a pre-clinical (animal) study of A2-73 for Parkinson's.

Assuming the AAIC results further confirm efficacy of A2-73 in early Alzheimer's, my guess is BTD will likely follow within a few months.

https://www.investorvillage.com/smbd.asp?mb=17701&mn=15583&pt=msg&mid=16128001

See also: Should You Boost Your Choline

http://www.berkeleywellness.com/supplements/vitamins/article/should-you-boost-your-choline

[Investor2014]

The paper says "Choline links receptors and cholinergic synaptic activity, through Sigma-1 receptors, to enhanced Ca2+ release through IP3 receptors."

The main intended MOA of donepezil is as a cholinesterase inhibitor, but also the Donepezil molecule is a high affinity S1R agonist. Makes me wonder if it sort of shoots itself in the foot, but rescues itself a bit so that what little effect it has is due to a balance of S1R agonism.

Obviously I am thinking here we may understand why A2-73 OVERPERFORMS Donepezil in the S1R agonism department.

Also ref:

In the present study, we examined the interaction of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-inden-1-one hydrochloride (donepezil), a potent cholinesterase inhibitor, with two additional therapeutically relevant targets, N-methyl-d-aspartate (NMDA) and sigma(1) receptors. Donepezil blocked the responses of recombinant NMDA receptors expressed in Xenopus oocytes. The blockade was voltage-dependent, suggesting a channel blocker mechanism of action, and was not competitive at either the l-glutamate or glycine binding sites. The low potency of donepezil (IC(50) = 0.7-3 mM) suggests that NMDA receptor blockade does not contribute to the therapeutic actions of donepezil. Of potential therapeutic relevance, donepezil binds to the sigma(1) receptor with high affinity (K(i) = 14.6 nM) in an in vitro preparation (Neurosci Lett 260:5-8, 1999). Thus, we sought to determine whether an interaction with the sigma(1) receptor may occur in vivo under physiologically relevant conditions by evaluating the sigma(1) receptor dependence effects of donepezil in behavioral tasks. Donepezil showed antidepressant-like activity in the mouse-forced swimming test as did the sigma(1) receptor agonist igmesine. This effect was not displayed by the other cholinesterase inhibitors, rivastigmine and tacrine. The donepezil and igmesine effects were blocked by preadministration of the sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) and an in vivo antisense probe treatment. The memory-enhancing effect of donepezil was also investigated. All cholinesterase inhibitors attenuated dizocilpine-induced learning impairments. However, only the donepezil and igmesine effects were blocked by BD1047 or the antisense treatment. Therefore, donepezil behaved as an effective sigma(1) receptor agonist on these behavioral responses, and an interaction of the drug with the sigma(1) receptor must be considered in its pharmacological actions.

Way out of my depths here, so comments welcome.