Replies to post #279012 on Anavex Life Sciences Corp (AVXL)

[jimmy_mcyoloswag]

My 2 cents FWIW:

The ryanodine receptor is a large target, many side effects to be expected. The evidence of this study indicates Alz effectiveness by addressing a phenomenon also seen in Alz. I would count this as second degree evidence, not direct. Twice removed, if you will.

At the same time this adds further evidence to my personal theory that dysfunction of mitochondrial and ER associated calcium homeostasis is a key player in neurodegenerative diseases.

Incidentally, S1r activation addresses this, specifically, elegantly and apparently by original function, on an as needed basis (think fire truck):

https://www.cell.com/cell/fulltext/S0092-8674(07)01099-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867407010999%3Fshowall%3Dtrue

[falconer66a]

Looks very promising.

This new Alzheimer's treatment, at least in mice, looks very promising.

It's a heart drug, carvediol, brand name Coreg, among others, which is used to treat high blood pressure, congestive heart failure, and left ventricular dysfunction. For those cardiovascular indications, it does have a number of side effects. Whether those would appear at dosages to treat Alzheimer's in humans is unknown.

For mice with Alzheimer's, with the accumulations of amyloid ß (A-beta), the waste protein that disrupts normal neuron signaling, thereby disrupting cognition, carvediol acted upon the ryanodine receptor, causing it to work properly. It's a calcium transport moderator, and in Alzheimer's is over-active. The heart drug kept this calcium transport moderator from over activity. After a time, the affected neurons functioned normally. “We couldn’t tell the drug-treated disease models and the healthy models apart.”

First, of course, will this be the outcome in humans? Very, very high probability. For the involved molecules, parallel chemistries in all mammals.

Would the drug, then, be a competitor for blarcamesine? Quite possibly. For Alzheimer's, blarcamesine also facilitates normalized calcium transport within the organelles of the neuron, thereby allowing the clearance of accumulated waste proteins, not only the beta-amyloids, but also the tau protein wastes.

No doubt, because carvediol is already FDA-approved, off-label treatments for Alzheimer's will be tried, closely monitored, of course, by the prescribing physicians. It sure looks better than any of the always-failed antibody drugs that have been tried time and again for over a decade.

But, here is a significant difference between the mechanism of action (MOA) of carvediol, compared to blarcamesine. Carvediol, in its activation of the ryanodine receptor, is working a bit "downstream" in the disease process. Blarcamesine, in its activation of the sigma-1 receptor protein, also facilitates optimized calcium transport (as apparently does carvediol), but far more significantly, upstream, it also restores mitochondrial function and proper protein folding in the endoplasmic reticulum. For the restoration of various homeostatic processes (such as autophagy), far more important than just calcium moderation.

Carvediol fixes one Alzheimer's pathogenic process, disrupted calcium transport between the organelles of the neuron. Very fine. Blarcamesine (perhaps even more optimally) fixes that and the many other biochemical anomalies in Alzheimer's neurons. Blarcamesine treats the Alzheimer's neuron more completely.

Of course, the duration of efficacious treatment with both drugs is not entirely known. Will carvediol be able to continue effective therapy chronically, over time? Or, will the underlying pathologies eventually overpower it (perhaps by tau protein accumulations, apparently not addressed by carvediol)?

The same question, of course, is asked of blarcamesine. But given the many, many months (well, years) that some Anavex clinical trial participants have been taking the drug, it appears not to lose efficacy after chronic treatment.

I notice that carvediol (Coreg) is sold by GlaxoSmithKline. I won't be liquidating any of my AVXL position to own some GlaxoSmithKline shares.

[Doc328]

They found that the racemic carvedilol (which is the drug Coreg, now available as a generic for as cheap as $4/month) was ineffective but the R-carvedilol enantiomer was effective in the mouse AD models. Racemic carvedilol is a 50:50 mixture of R- and L- enantiomers.

Very interesting, however, R-carvedilol is not commercially available so patients won't be able to be trialed in the doctor's office. Enantiomers are considered NCE's but do have a faster regulatory pathway through the FDA than a true new chemical entity as they can piggyback on existing safety data. With promising results and assured safety, I hope some company does a study.