Dosing levels and durations.

I note that only two dosages are being discussed: a “low dose” of 30mg, and a “strong dose” of 50mg. Both of those are beneath the maximum tolerable dose (MTD) discovered in the Phase 1 study.

But might the proper, most effective dosages actually be determined by the patient’s body size? A 250-pound man is twice the size of a 125-pound woman. Could it be that a 50mg dose might be insufficient for the man, but an overdose for the much smaller women?

Should dosages be based upon patient sizes, with dosages measured in milligrams per kilogram of body weight? If 50mg works for a 250-pound man, that would be a dose of 2.27mg/kg. For the 125-pound woman, that would be a dose of 1.13mg/kg.

Or, more likely, it will be determined that dosages do have to be determined by patient body weight, but the relationship may not be linear. The smaller woman, half the size of the big man, may need a smaller dose, but not linearly by one half.

I would suppose that when the drug goes on pharmacy shelves Anavex will provide informative, well-determined dosage tables or criteria. I doubt blarcamesine tablets will come in only two sizes, “low dose” at 30 mg and “high doses” at 50mg.

Dosages may have to be determined individually with each patient, titrating up from a low starting dose (perhaps at 25mg) in ascending 5 or 10mg intervals; until therapeutic results emerge.

And, dosages may need to be higher at the start of therapy, but dosage reductions work well further into therapy intervals. 50mgs for six months, then 40mg for the following six months, then 30mg on out.

Blarcamesine as a contra-aging agent.

Yes, indeed. Blarcamesine (Anavex 2-73) begins its chemical interactions at the sigma-1 receptor protein, which either in normal (non-pathological) processes, or when in blarcamesine-corrected dysfunction, causes all sorts of good, “downstream” things to happen. Properly functioning sigma-1 receptor proteins modulate, facilitate a diversity of consequent, “downstream” processes, including autophagy (waste-clearing and function restoring processes), effective unwrapping of chromatin around DNA (allowing genetic expression of good genes), proper protein (enzyme) folding, and general cell-keeping processes (homeostasis). All of this without side effects of any consequence, even.

But this should be taken into account. Except in very rare cases, where rare untoward genetic anomalies are in control, in most cases of Parkinson’s and Alzheimer’s diseases people suffering from those diseases, earlier in life, had normalized mental functioning. Then, with age, by whatever mechanisms, Parkinson’s and Alzheimer’s set in, with their attendant mental debilities.

What happens when blarcamesine therapy takes effect? To some degree, perhaps rather completely, patients are restored to a more youthful, normalized mental capacity. Blarcamesine has restored earlier and healthful brain and CNS mechanisms. The drug terminated the pathological disease mechanisms and restored the ones in operation in earlier years.

The key consideration is this. Most drugs target and treat symptoms. Stop the symptoms and the disease is treated (it is presumed). Blarcamesine is not targeted at symptoms. As a sigma-1 receptor ligand (chemical attachment) it is specifically targeted at the attachment points on the sigma-1 protein. With that, by its unique modulation of sigma-1 functions, a wide diversity of good things happen “downstream.”

Simply, the Anavex molecule puts things back together the way they were when healthfully functioning in more youthful periods of life. The drug is not just “anti-aging,” slowing or preventing aging processes. It’s actually “contra-aging,” actually reversing to some degree the aging process. Unique, altogether.

Experts here after blarcamesine approval.

It is so wonderful to ponder the many posted comments on blarcamesine dosings and dosage determinations. Obviously, getting the right dose for each individual Alzheimer's patient is extremely important. Too little creates reduced or absent therapeutic results. Too much? Well....

Fortunately, when the FDA approves blarcamesine as a treatment for Alzheimer's Anavex can enlist the dosing expertise on this stock investment message board. Alzheimer's patients (and their doctors) will benefit so much.

Nothing wild about "wild type" genes.

The term "wild type" can be misunderstood. I don't see that it has been defined or explained.

Simply, in genetics "wild type" means a gene or trait that is normal or typical, commonly or normally present; as opposed to rarer mutant genes, the ones that cause genetic pathologies.

There's nothing "wild" about wild type genes. They are the normal, common ones that most people have.

What Is This “Dispersion Index?"

Page 12 of the Anavex PDF is titled, “Confirmed Reliable Inter-Individual Variability (Dispersion) for the ANAVEX2-73 Phase 2a Study with 32 Patient Cohort.”

Further, it is stated that, “Evaluation of the dispersion index of all the 32 patient[s] of the Phase 2a reveals that above 16 patients, the dispersion index is maintained at a fixed level with the narrowest confidence intervals.”

What might all of this mean? Whatever is “inter-individual variability (dispersion)?”

From another paper, here’s one helpful statement:

“In contrast to individual cognitive performance, the dispersion index is thought to provide an indicator of fairly stable endogenous factors, such as central nervous system (CNS) integrity (MacDonald et al., 2006, 2009), and to be less influenced by situation-dependent factors including fluctuations in stress or sleep (Hultsch et al., 2000).”
[From, De Felice S and Holland CA (2018), Intra-Individual Variability Across Fluid Cognition Can Reveal Qualitatively Different Cognitive Styles of the Aging Brain. Front. Psychol. 9:1973. doi:10.3389/fpsyg.2018.01973]

In essence the dispersion index in this clinical study indicates, at “the narrowest confidence levels,” that blarcamesine maintained “central nervous system (CNS) integrity,” “less influenced by situation-dependent factors including fluctuations in stress or sleep.”

The take away? Even though there were a small number of patients (only 32), the results were not randomly variable, and most importantly, were predictive of results that would emerge from a study with a larger cohort (larger number of patients). The page text makes that claim, that the dispersion index of this small study “allows for meaningful predictions for larger populations.”

As always before, the data and results from every clinical test of blarcamesine, even Phase 1 and Phase 2 trials, are accurately predictive of subsequent Phase 3 trials. The data from the big Phase 3 Alzheimer's clinical trial are going to be exceptionally positive.

Once again, as always, safety and efficacy.

Well, the question, in another form, is, can these early-stage clinical results be accurately extrapolated for the study’s extended 204 weeks; or, on out to the big Phase 3 study that is concluding? The very positive results appeared in the reported, initial 57-week period. Any significance to these results?

In traditional perspectives, all of the conventional cautions and warnings would be in order.

A) A 57-week trial period may be too short to know the outcomes in long-term, chronic treatment regimens. The study is too short.

B) Apparently only 21 individuals participated in the study; a low number. By conventional protocols not enough to determine certainty. Even though the p-values were low and quite acceptable, (most less than 0.05) the study’s determined metrics are certainly not enough to allow the FDA to approve blarcamesine as a new Alzheimer’s therapeutic. That can’t happen until the top line data from the soon to be concluded big Alzheimer’s study are released, said to happen sometime this fall.

But the results of this short study, with only 21 subjects, for me, confirm that the final reports in the big Phase 3 study will be a profound success. For these reasons.

Most drugs acting in the central nervous system have all sorts of untoward side effects. They do provide positive therapeutic outcomes; well and good. But at the same time, because they are acting in the nervous system, they concomitantly change or affect non-targeted things; even outside of the CNS. But that has never been the case in any blarcamesine study, of any size, in any organism.

In no blarcamesine study have there been reports of genetic disruptions; no mutagenesis. Blarcamesine doesn’t change genes, causing cancers or other genetic pathologies.

No endocrine disruptions. Hormones and hormone signaling are unaffected.

Blarcamesine is active in chromosomes, which in many drugs causes adverse outcomes. Instead, blarcamesine favorably facilitates normal gene expression by modulating chromatin mechanics (proper unwrapping of chromatin enclosing DNA, to expose DNA to make proteins).

Lots of other side effects and molecular disruptions in other nerve-acting drugs. Simply, they don’t exist with blarcamesine. Read closely the details on both the murine (lab rodent) and human tests with blarcamesine. What were the reported adverse events, side effects? Only two types have been reported: transient [short-lived] dizziness and headache; all of which abated shortly after dosing began, or dosing levels were reduced (the dose titration process).

Once again, as always before, blarcamesine is both therapeutic (efficacious — it works) and safe (causes no side effects of concern). That’s what happened in this 57-week Phase 2 study in 21 patients with Alzheimer’s. There is no reason, no evidence whatsoever to believe that the results of the big, definitive Phase 3 study soon to be released won’t be the same.

The results of this Phase 2 study are: “Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (?MMSE:P < .039; ?ADCS ADL:P < .063) and COMT p.Leu146fs (?MMSE:P < .039; ?ADCS ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015).”

If these results data were derived from the big Phase 3 study, which is much longer, with many more subjects, anyone want to contend that the FDA would not approve blarcamesine as a new Alzheimer’s therapeutic? Of course not. The numbers; especially compared to existing Standard of Care (SOC) Alzheimer’s drugs; are stunning.

The No-sell Long-term Approach

I find interesting the diversity of investment approaches in the postings on this message board. Most, it appears, regard the taking and holding of an AVXL position as the mechanism with which to make gains by trading. Buy some AVXLs at one price, then sometime later (just a few days or weeks) sell them for a gain. Rinse and repeat. Short-term trading. Day-trading, even.

A smaller number of posters are looking for big value gains when the share price has three, even four digits. The iconic $1249 eventual share price is often posted.

But, what’s my plan? None of the above. I’m all-in, on-going, with no termination. I don’t anticipate ever selling any of my several thousand AVXLs. They will remain in my estate for all of my remaining days and years.

With that investment approach, only two things can happen. Worst, Anavex fails at all three clinical trials and goes bust. Should that happen, I’ll have lost every one of the hard-earned dollars I took from my family budget (from discretionary funds I could afford to direct to my AVXL position, in the past — no longer a budget factor).

Or, Anavex gets approval to sell blarcamesine for at least one CNS disease, and corporate revenues ensue, followed by the distribution of dividends. That’s my AVXL investment goal; take annually-escalating dividends on out. On my spreadsheet I’ve calculated my gains both ways: short-term trading, or long-term dividends. Sure, in the short term — if I could accurately pick favorable buy and sell positions — I’d make a lot of dollars. But from a decadal (ten-year) time frame, I’m WAY ahead holding my position and being rewarded with annual dividends — presuming any one of the clinical trials prompts the FDA to approve blarcamesine.

As a biologist familiar with cellular physiology, genetics, etc. I’m confident that the Anavex science will prove out in the clinical trials. The unique mechanisms of action (MOAs) continue to prove both successful and absent of adverse events (side effects). I am confident in my approach; can wait patiently.

But, if I’m wrong, I’m not hurt. My AVXL purchases were all made several years ago. No dollars are coming out of my current family budget for new AVXL purchases.

When Anavex Life Sciences Corp is a major, global pharmaceutical, let’s all check in 2032 and see which investment approaches have been most successful.

Is Science Translational Medicine a respected journal, read by medical researchers?

Well, it's one of the several journals published by the American Association for the Advancement of Science (AAAS), the premier professional science organization in the US. Pretty much, if you aren't a AAAS member you aren't a practicing scientist in the US. There is not a medical researcher who wouldn't want his or her article published in that journal. In every case such a publication is a resume enhancer.

Here's what AAAS tells about the publication:

https://www.science.org/content/page/stm-information-authors

Medical researchers reading the new article won't discount it at all. Researchers and managers in drug development programs (in pharmaceutical companies) will read and comprehend the article. Unlike some of the expected posters here, external (non-Anavex) medical researchers won't be picking it apart, claiming that it's all wrong. Just the opposite. The evidence for the Anavex drug (blarcamesine) mechanism of action (MOA) becomes ever more solid. Every interested party will have to take Anavex into account. Anavex science is valid; can't be dismissed or discarded. It is going to change things.

Depends....

Well, for me, I'm up 247% with my AVXL position right now.

Well, tons....

Were there one million patients taking blarcamesine, at 50mg per day, that's equivalent to 50,000 grams, 50 kilograms, or 110.2 pounds a day.

For a year, one million blarcamesine patients taking 50mg each day, all together, through the year would consume 18,250 kilograms, or 40,223 pounds; a bit over 20 tons.

Twenty tons per million patients per year.

Reductionist Approach? Or Systems Analysis?

Extremely important concepts, perspectives; which dramatically contrast.
First, the preferred, imposed mandate of medical school training and research — reductionism.

Most phenomena in the natural world, especially those acting in living organisms, are extremely complex. Multitudes of interacting, controlling, or complicating factors. How, then, to make sense of observed phenomena? In modern science and medicine, predominately by reductionism.

Simply, reduce the number of factors being studied to those few central ones that actually produce or affect the effects being observed. Reductionism; make it simple enough to understand. Where possible, discount or disregard supposedly extraneous or peripheral forces or factors that otherwise complicate a clear understanding of what’s being seen. Focus solely on a single, central factor. Complicated phenomena are difficult to accurately understand; too much to discover or explain. Keep it simple, smartypants.

One of the first things every science or medical student learns in constructing a research project that will yield data for a master’s or doctoral thesis. Take a reductionist approach. Answer a question, hypothesis, with data that cannot be questioned. Best way to do that is to form a hypothesis or pose a question for which the answer is incontrovertibly true. Keep it simple! Reductionism.

Of course, biological systems and processes in living organisms are not simple. They are extremely complex. Hence, the utility of a “systems analysis” approach.

A reductionist perspective of Alzheimer’s finds the protein waste hypothesis (beta-amyloids and tau tangles) is the problem offering the simple solution. Two waste proteins accumulate in Alzheimer’s nerves; therefore if they can be destroyed the disease can be successfully treated. Well, how has that reductionist perspective been working out? Might the etiology of the disease be a bit more complex?

The systems approach to Alzheimer’s, where it is discovered that one protein, the sigma-1 receptor, in a complex fashion controls or modulates a diversity of downstream cellular processes. With this receptor’s activation, with unique molecules (owned by Anavex), a diversity of complex normal reaction cascades and processes are facilitated or restored — too complex to actually explain right now. The reductionist will consequently say that the success or mechanisms of blarcamesine therapies cannot be possibly known. Too complex. Therefore, we can’t rely on them. Take blarcamesine off the table as a potential CNS disease therapeutic. If its mechanisms can’t be known, it can’t actually work. End of story. Reductionism must prevail.

Or, test the drug in ample populations of patients with CNS diseases (Phase 2 and 3 clinical studies) and see what happens to their symptoms and any adverse events (side effects). Results data will be diverse; lots of symptoms to measure and assess.

Some data will be very positive. Reductionists will demand “further study,” to more precisely ascertain safety and efficacy; especially seeking the exact chemistries producing each datum. “Yea, but how did that happen? What actually happened? What molecules reacted with what structures in what sequence?

The reductionist imperative will mandate decades of “continuing research.”

A systems analysis approach will ask the question, does the entire system (human health) actually improve with the drug? The precise details of every mechanism are not sought. Rather, does the drug work, safely? If so, bring it to market.

If certain posters are consistent, they will so helpfully tell us how the FDA “prematurely approved” blarcamesine next year. “Still too many unanswered questions.”

Not Just Time But the MOA

That as so, the Anavex-is-ahead time factor. But it's not the real story. Simply, Anavex has a new, formerly unknown, but very positive and safe disease-treating mechanism of action (MOA) that operates within diseased or malfunctioning neurons. It's the company's unique MOA that will win the game.

No one else has sigma-1 receptor activators that can do what the Anavex molecules do. Sure, there are dozens of sigma-1 receptor ligands, molecules that can bind to the sigma-1 protein. But none of them so powerfully activate the receptor's favorable modulation of downstream reaction cascades and processes, all of which are positive, in regard to restoring or maintaining neuron health and function.

Best for Complicated HSP Cases

Thank you. I'm hopeful.

But my form of HSP is only moderately debilitating. Have to use a walker; with some urinary problems resolved with a suprapubic catheter. Otherwise, I can lead a rather normal, productive life.

But there are several dozen HSP genotypes, disease variations. Mine is moderate. But some have "complicated HSP." In these cases the disrupted motor neurons are not just the ones to the adductor muscles in the legs but in motor-control nerves throughout the body. Every muscle is tight and spastic. Everything is compromised by muscular tension. Eating and swallowing can be compromised. Just a horrible genetic disease.

I'm hoping that HSP is Anavex's unrevealed "rare disease" that will be targeted with blarcamesine. As in the case of Rett syndrome, it ideally would be administered to neonates, newborns exhibiting spastic symptoms; with the hope that GABA levels could be maintained, preventing the developmental onset of spasticity.

Someday, HSP

For anyone new to Anavex a close reading of the many pages of the new corporate presentation is in order. Most of the science and application of the Anavex molecules is thoroughly laid out.

https://www.anavex.com/_files/ugd/79bcf7_5ad0bcb5c81b432e9e3fb549f6e21385.pdf

As I’ve posted before, I have a rare central nervous system disease, hereditary spastic paraplegia (HSP). In previous postings on this I noted that I had self-diagnosed the disease; every symptom of my moderate spasticity (in my legs and bladder) matched perfectly with HSP. But recently one of my physicians wanted to genetically confirm the diagnosis. I was correct. A proper genomic analysis of my DNA showed that, indeed, I had one of the more common HSP genotypes.

The spasticity in my leg muscles is caused by a deficiency of gamma-aminobutyric acid, GABA, a neurotransmitter that slows or moderates excessive nerve firing. With its deficiency in the long nerves that control the adductor muscles of my legs normal nerve transmissions can be excessively over-active. Spasticity; tightness.

On the new corporate presentation, on pp. 27 and 28, I read with interest that in girls with Rett syndrome (who also have GABA deficiencies with similar motor neuron dysfunctions) Anavex 2-73 (blarcamesine) tended to restore normal GABA levels and functions.

Consequently, I’m eager, someday, to have my neurologist prescribe Anavex 2-73, off label, for my HSP. With that there is a good likelihood I’ll be able to walk once again without the propping support of my walker.

Or (so much better), after Rett HSP may be tested and proven as a treatment for HSP. It will then be “on-label.”

There are a wide diversity of rare diseases for which Anavex2-73 may eventually prove to be safely therapeutic. All will be later chapters in the ever-expanding Anavex story, after the stories are complete for the Anavex Three, Alzheimer’s, Parkinson’s disease dementia, and Rett syndrome (today). Later? Many others. Activating the sigma-1 receptor protein favorably moderates all sorts of good “downstream” cellular processes that malfunction in CNS and other diseases.

Thanks for this posting.

I found this Missling statement of particular interest:

I believe this is further substantiation of the ease of blarcamesine synthesis; meaning that it can be and may already have been farmed out to a drug supply contractor. Daily 50mg doses won't be expensive to manufacture; works to the benefit of the company, its shareholders, and patients. All-win.

All of the other presented information is positive. Read the material with scrutiny. The Anavex story continues to develop so positively. Great things in the (near) future.

Share Price vs. Dividend Yield

Not only the share price but the dividends to be distributed to shareholders.

Here are some numbers I've punched in my Anavex spreadsheet, projecting my annual dividends after blarcamesine is approved to treat Alzheimer's and/or other CNS diseases. I'll post the numbers, but not the number of shares I own (irrelevant).

Let's start with one billion dollars of annual revenues to Anavex, $1,000,000,000. Just a start; bigger revenues later on.

The crucial datum for dividends is not company revenues but the percent dropdown, the percent of the revenues that actually go out each year as dividends. In my calculations, I'm using a 15% dropdown. With a billion dollars of revenues, 15% of that going out as dividends is $150,000,000; one-hundred-fifty million dollars.

As happens each year, there are always complaints of corporate dilution; new shares have been sold to raise funds, thereby diluting the value of previous shares. Understood. Therefore, in my calculations I'll presume that the eventual number of AVXL shares in trade will be one-hundred million, 100,00,000. Right now, there are 77,410,000 million shares in trade, so my number is very conservative; accounts for subsequent fund-raising dilution.

So, with a billion dollars of revs, with 15% of that going out to shareholders, who in total own one hundred million shares, each share yields $1.50.

Later, with ten billion dollars of revs, each share would yield $15.00 in dividends.

With 30 billion in revs, each share yields $45.00.

If you plan to hold or expand an AVXL position for several years, after blarcamesine becomes the SOC (standard of care) treatment for one or more CNS diseases, simply multiply your number of shares by the three dividends above. With my AVXL position I'm extremely pleased. I can wait five years or longer, should it take that long. Don't think so, however. In two years Anavex Life Sciences Corp could be taking in several billion in early revenues. In ten years? Gonna be fun to see.

Eventually, Far Beyond Today's Anavex Three

Understood; quite reasonable.

But what may be unreasonable is to presume that blarcamesine or Anavex 3-71 will only treat (or prevent) the three presently-targeted diseases: Alzheimer's, Parkinsons's disease dementia, and Rett syndrome.

The unique mechanism of action (MOA), whereby the sigma-1 receptor protein is activated, very likely will yield propitious outcomes for a wide diversity of other diseases or conditions in the central nervous system (CNS). Protein misfolding (of enzymes, et al.) is a core problem of many CNS diseases. The Anavex molecules restore proper protein folding mechanisms. With that, all sorts of maladies can be prevented or reversed; not just the presently targeted Anavex Three.

Christopher Missling's offhand remark some years ago stating that the Anavex story is "like an iceberg" seems to apply. I continue to contend that Anavex has all sorts of yet-unrevealed preclinical data in model test organisms (roundworms, murines, etc.) that show profound and diverse therapeutic successes.

Already, albeit incidental, blarcamesine has shown in human trials to markedly improve sleep, with no side effects. Look it up; the problems of insomnia. Worth many billions if a solution can be found.

But, in ten years?

Ok, then, what would be a projected annual per share dividend be after a buyout? Not everyone takes an AVXL position to sell it at a profit later on. Many are authentic long term investors (not stock traders). After blarcamesine gets approved to treat Alzheimer's, Parkinson's, and Rett, what will the annual dividend be?

If I have a ten-year (decadal) stock investment perspective, will I be better off trading in and out of AVXL; or sit back and accumulate annual dividends? After ten years, in 2032, where will things be, comparing an AVXL trading scenario against a buy and hold and accumulate dividends scheme?

The Time Perspective.

There are several ways of making money by first buying shares of a company.

There is shorting, where shares are "barrowed" (at an expense) from a brokerage, to be sold back at big profit when the share price eventually collapses.

Then, there is day-trading. Buy a stock at a perceived low price, but hold it for only a short time, sometimes for even less than a day. Sell the stock when the trading price goes up a bit. If you consistently make just 1% on such trades, over a year you will be rich.

Then, long-term trading. But some shares, then hold them for months or years, hoping to sell at significantly higher prices far down the road.

Finally, there is the buying of an equity position, shares, to hold them for the foreseeable future. Financial rewards will not be the difference between purchase and sales prices, but the annual dividends each share will yield. That's authentic long-term stock investing.

From the day, about five years ago, I started accumulating my AVXL position (now, several thousands of shares) I knew that I would never sell a share. I'd hold them and be rewarded with their dividends. As things have developed, my anticipated dividends will be far greater than I first imagined.

My AVXL position will remain a holding of my estate, to be passed on my heirs, estate beneficiaries, and philanthropies I'll designate in the estate plan my wife and I will be creating later this summer. I think in decadal time frames, not hours, days, or weeks. In ten years I think I (or my estate) will be way ahead: both in received dividends and also on appreciated share prices.

Seems, fail in murines and no human trials.

Well, I have no interest in scrutinizing murine tests of non-Anavex Alzheimer's drugs. Haven't checked out any of them; what few there might be. Were there preclinical murine tests of Aduhelm (which produced in humans brain swelling), or with Aricept, which in humans merely slows for a period the progression of Alzheimer's, ultimately followed by mortality?

In fact, have there been any new Alzheimer's drugs elevated to human clinical trials that have first failed in murine tests? Failing to be safe and effective in transgenic rats would seem, to me, to preclude any subsequent human trials, even Phase 1.

In the end the only thing that actually counts is safety and efficacy demonstrated in real humans in a proper blinded clinical study.

The Anavex 3-71 Production Cost Factor

It appears that 50mg of blarcamesine will be a standard daily dose for Alzheimer’s. Anavex has patents on the manufacture of this molecule. Unlike many drugs, it is not a complex molecule; the production cost of a daily blarcamesine pill should not be excessive. Fifty cents? Five dollars? I have no idea if it’s in that range. But not likely to be in the hundreds of dollars.

But, then, what about Anavex 3-71? Unlike blarcamesine (Anavex 2-73), it is works in microgram quantities. One microgram is one one-thousandth of a milligram; 1.0 microgram = 0.001 milligrams. There are a thousand micrograms in a milligram. (A milligram is a thousandth of a gram.) “Milli-” means “one-thousandth.” “Micro-” means one millionth. Orders of magnitude stuff.

Does this mean anything? Well, if manufacturing costs are a significant fraction of the total purchase costs of a drug, it would certainly appear that Anavex 2-73 will not be expensive, at least as to its manufacturing costs.

Therefore, Anavex’s profit margin will be large. Make the drug for a few cents or dollars for a daily dose, and sell it at “market rates.” What will be the “market rate” for a drug that successfully treats (I’ll whisper the real term — hold on! — cures) Alzheimer’s or Parkinson’s disease?

Once Again, 3-71 Succeeds

https://79bcf7a1-8b8e-483b-b7cf-f5c5192a6d63.usrfiles.com/ugd/79bcf7_ebfbe5fa6e924647a3272c209977cbe5.pdf?mc_cid=314a22ea6e&mc_eid=39975e48cc

--- The impairment in Tg rats was completely reversed with ANAVEX®3-71 (p ≤ 0.01).

--- ANAVEX®3-71-treated Tg rats performed significantly better than Tg control rats (p ≤ 0.05).

--- This deficit in Tg rats was entirely reversed with ANAVEX®3-71 (p ≤ 0.0001).

Read the data for yourself; unless, of course, you are certain that the effects of a drug acting in a transgenic rat can't possibly reveal how the drug would work in a real human with the same disease genetics. No need to go further. Mice aren't men; rats with human disease genes inserted in them can't possibly predict how a drug targeted at the disease will work in humans. Rats and people both breathe air and utilize oxygen to take up de-energized hydrogens and produce water in cellular respiration. But, beyond that, rats aren't people and human drug studies in them cannot be predictive.

OR, rats and humans, as mammals, have very parallel chemistries and genomics, so if human disease genes (as, in this case, for Alzheimer's) are inserted (gene editing) in a rat, the rat actually gets the disease with all of its human symptoms. Then, a drug is tested in the transgenic rats, to see if it yields any therapeutic benefits. In this case, symptoms were "completely reversed," diseased "rats performed significantly better," and a " deficit in Tg rats was entirely reversed."

Those convinced that these murine (lab rodent) results can't possibly be predictive of human therapies of Anavex 3-71 against Alzheimer's disease will intelligently refrain from taking any position with AVXL shares based upon these new data. Well and good. Play it safe.

The rest of us, however, regard the findings of the transgenic rat study to be very predictive. We gleefully await consequent studies of Anavex 3-71 in humans with Alzheimer's. Our AVXL holdings are even more confidently held and accumulated.

For New Readers --- There Are Many

Why? Because long-time readers of this message board have already seen them?

Is it not a bit presumptuous to presume that no one new to Anavex or this message board ever clicks in?

Actually, like them or not, for those new to Anavex or this message board George's posting of older Anavex information is very informative and helpful. All well referenced.

Don't like them? Very simple. Just click on to the next posting. Are you disconcerted because they have all previously appeared? Or, that the posted information supports the validity and eventual success of Anavex science?

A Zinc Ionophore

Quercetin is a zinc ionophore. It transports zinc ions into cells, where they "poison" various enzymes required for viral replication. With zinc available in the cytosol inside a cell, most viruses are terminated. The zinc attaches to the replication enzymes, bends them out of shape so that they can no longer catalyze various reactions required in viral synthesis.

But if the diet is zinc deficient, there won't be enough to get transported into cells by quercetin. My daily multivitamin provides 30 mgs. Some authorities say 15 to 18 mgs is sufficient.

Since taking 7000IU of vitamin D-3, along with 400mg of magnesium (threonate), along with the quercetin, for many years now, I've not had a single viral disease.

Aren’t We A Bit Biased?

Well, understand (to some degree, however hazy) that because Xena and I have personal debilities that we so hope can be treated (well, fixed) by blarcamesine, it could be argued that readers should not consider our posts; they can’t be fair or untainted. We’ve got health problems we really want blarcamesine to fix. Therefore, there is a likelihood that we are overstating the positives of the drug. Wishful thinking it could be argued.

Or, the studies and clinical reports and posters speak for themselves, without reference to or taint by Xena and myself.

Let the reader discern.

Animal Tests First — Perhaps in the Anavex Can

Of course, one starts by treating various animal models who have well-characterized mitochondrial dysfunctions. At the most elemental level, inducing mitochondrial dysfunctions in the lab roundworm Caenorhabditis elegans, then treating them with blarcamesine would be a start. Perhaps fluoroquinolone antibiotics, such as Cipro, could induce the mitochondrial dysfunction; then, treat with blarcamesine, at various doses and intervals, etc.

Or, use mice who have mitochondrial dysfunctions, either genetic, knock-out, or chemically induced; then treat.

Such research, especially with the roundworm, is not expensive. I would be surprised if Anavex doesn’t already have early data on this. They have copious amounts of trade-secret data on all sorts of diseases and conditions that have never been mentioned, yet. Missling knows there will be a right time to lay out those stories; most likely after the Anavex/blarcamesine MOA (mechanism of action) is thoroughly accepted and understood by the medical community. Everything is working in that direction.

Personally, I understand your fluoroquinolone vulnerabilities. To a degree, I have them too. Other people with my genetic debility, hereditary spastic paraplegia (HSP) have been nearly paralyzed by Cipro. My neurologist told me to list Cipro as an “allergen” in my medical records; never to be administered to me. With HSP, my mitochondria cannot effectively power the synthesis of gamma-aminobutryic acid (GABA) in my nerves. With that deficiency, I have a neurogenic bladder, now requiring the use of a supra-pubic catheter. My legs continue to be spastic, stiff. I must walk using a walking frame. No pain; but great frustration.

I’m eager, someday, to treat my HSP, off label with blarcamesine. It might allow me to walk normally again.

In Each, the Data Tell

Well, I taught advanced placement biology, to smart kids in an upscale college-preparatory high school where parents enrolled their college-bound kids to take courses from me and my colleagues. Credits earned in my classes were applied to college curricula. Kids who passed my advanced-placement biology class got to skip college 101 biology courses; started right off with sophomore-level courses.

But even more significant was my high school’s science research program, where the most talented students devised and conducted real science research projects. I created the program, where local industries, governmental agencies (wildlife, environmental protection), and other professional hosts allowed my students (after school) to conduct research projects — which in most cases provided useful and valid data for the research sponsoring organization.

The organizational sponsors got free research data which they could apply to their operations. The students learned the details, however elementary, of proper science research. When they got their many college scholarships and grants-in-aide, they were ready to step into new learning roles at the college level.

In every case, what’s the question, then, what are the solutions. And finally, are the data supporting the solutions valid? Is the science real, or merely conjectural? On a far more massive scale these are the questions for Anavex and blarcamesine. For Anavex the question is, can blarcamesine treat various CNS diseases? The results of the Phase 3 clinical trials will provide the data. So far, not one hint that the drug will fail. Just the opposite....

Well, actually essential.

Well, let me state, a p-value of 0.05 or smaller is not just "important;" it's absolutely crucial. Any datum <0.05, less than 0.05, means that the result must be tossed out. Not statistically significant or valid. Such a result was probably caused by chance, not an actual mechanism.

Now for many years I've been scrutinizing every paper presenting clinical results from blarcamesine; in both murines (lab rodents) and real humans. The quickest (and most accurate) way to discover if a drug being tested for some positive therapeutic affect actually works, actually does produce positive clinical results, is to check each and every stated p-value. Simply, p-values >0.05 don't appear in papers (studies) of blarcamesine treating CNS or other diseases.

This will be the case, too, when the results of the big blarcamesine against Alzheimer's study appear later this year. The same biochemical mechanisms in action --- already proven.

But What Were the P-Values?

Are the positive data in the new poster merely by chance, not actually caused by blarcamesine; or are they statistically significant, not caused by mere chance?

The chance that chance, itself, caused a result is expressed in the p-value. Accepted practice in biostatistics is that results with a less than one-in-twenty chance of randomly occurring are presumed to be actual, caused by the factor being tested; not mere chance. The one-in-twenty validation cutoff, expressed in the “p-value,” is “0.05.”

So, in the new poster, what were the posted p-values? Are any >["greater than"]0.05, indicating that results may have been by mere chance? I scanned down through the entire poster and copied each presented p-value, all 13:

p-value < 0.005
0.004
0.004
0.004
0.001
0.001
0.001
p = 0.021
p=0.003
p=0.034
p<0.005
p<0.005
p<0.005

Each datum is statistically significant. Each of the positive results was statistically significant; actually caused by blarcamesine, not mere chance.

Blarcamesine actually works.

Not Known --- Fibromyalgia Treatment

I was not familiar with the etiology (causes) of fibromylgia; had to look that up. No one else knows, either. The disease remains a mystery.

So, the ability of blarcamesine to treat this disease remains unknown.

Eventually, practicality will decide the matter.

Indeed, blarcamesine (Anavex 2-73) is likely to transform 21st-century medicine as much or better than penicillin did in the last century. The discovery of both penicillin and blarcamesine were essentially accidental; but that's not what made both of them so phenomenal. Something very different; but something that should be understood.

In both cases, a new therapeutic agent appeared that successfully treated otherwise untreatable conditions. Before penicillin, bacterial infections very often were lethal. Get an infection and just hope that, somehow, the body's innate immune system would be able to fight it off. Very often, even in otherwise very healthy individuals, it didn't.

The question arose, "How can this molecule from a fungus kill bacteria and not normal body cells?" At the time, no way to explain it; it just happened.

And that's the rub in medical practice. If something happens without precise and accurate understanding, by its nature the process must be questioned; even if it works. In the case with penicillin, it was so successful in turning back infections once it was available it was used massively. My mother was a fine nurse, and as a kid back in the mid 1950s I dreaded getting a cough or any indication of "an infection." With that, mother would put the glass syringe and needle in a metal tray in boiling water on the stove. Sterilization. Then, I'd have to "lean over" and get a shot right in my bare hind end.

As you can imagine, I soon became diligent in disguising any cough I had.

At the time, there was little understanding of induction of resistance by over-use of antibiotics. They worked; so use them. Today, we are more informed.

Same phenomenon with blarcamesine; but with far greater objection. Actually, in a petri dish penicillin would be seen restricting the growth of bacteria. It could be seen that it worked. Simply, it did kill or inhibit bacterial activity. Good enough.

But, blarcamesine? It's supposed to successfully treat, without side effects, recalcitrant central nervous system diseases; Alzheimer's, even. That can't happen. Too good to be true. CNS diseases need "strong" drugs to work. Virtually all of them have prominent, sometime even lethal side effects.

The explanation is that the molecule attaches to an obscure protein, the sigma-1 receptor, and then supposedly prompts all sorts of good downstream things to happen; inside of all things neurons. Neurons are the most complicated of all cells; very prone to disabling chemicals, toxins as it were.

So, the perceived problem with blarcamesine is that it does otherwise impossible good things inside the neuron; without upsetting anything. Penicillin killed pathogenic bacteria, by at the time unknown means. Today, blarcamesine fixes malfunctioning brain cells by still questionable mechanisms. Nothing in medical textbooks of their times could explain either penicillin or blarcamesine.

For penicillin and the other antibiotics it took ten years or so (mid-1940s to 50s) to be fully accepted and utilized. Looks like it will be a decade of discovery for blarcamesine, too. But like penicillin, blarcamesine will rise to therapeutic prominence once the Alzheimer's clinical results appear. They will be "too good to be true; can't be believed." But thousands of Alzheimer's patients getting their symptoms suppressed will settle the issue. Practicality will decide the matter. Just as with antibiotics mid-century last, a phenomenal new era in medical science will commence.

Bad Editorial Reviewing

Exactly. There was no nefarious activity or intent on the part of Anavex. A photo got pasted in twice, That's something the journal editors needed to catch before the paper was released. That's what "peer-reviewed" journals are supposed to do; check, review all of the data and graphics the authors submit to the journal.

Editorial negligence; solely. Nothing else.

Anavex Deception?

https://pubpeer.com/publications/0AFF8522141E0FE5395496C78038C2

Apparently, one image of some obscure drug candidate named "Anavex1-41" got replicated. Same image twice. Was that an error, or a deception? The paper appeared in 2009.

Anyone here ever heard of "Anavex 1-41?" I've not seen it in any Anavex clinical trials? I don't recall seeing it in the Anavex list of "pipeline" drugs.

This brings into question everything Anavex, doesn't it? [Sarc]

Seeing Will Be Believing

Xena, I concur. The science is solid, re-confirmed.

But that's not what most equity investors believe or understand.

"Well, I'm not dumping any of my hard-earned dollars into some new, start-up company pushing a new, unknown, unproven drug that fixes CNS diseases. Sure, some new drug fixes nerves with Alzheimer's, Parkinson's disease and a bunch of others, merely swallowed once a day. Won't believe it until I see big Phase 3 study results, which will have to be explained. I know better."

Phase 3 Trials Are the End-All, Be-All

I don't recall the details of this. But, it's standard practice in modern drug testing. Like it or not, no drug gets approved unless there is a big Phase 3 clinical trial demonstrating statistical significance (efficacy) and safety.

Phase 3 Proof for Blarcamesine’s MOA

Well, the Anavex unique, previously-unknown mechanism of action (MOA), how the company’s molecules induce profound therapeutic results, is actually proven, in both animal models with human CNS genes and diseases, and in real humans. But, no, the results of the big Alzheimer’s Phase 3 clinical trial of blarcamesine have not yet been released.

The issue, of course, is, indeed, that blarcamesine “has yet to be proven,” in the minds of both retail and institutional equity investors. It’s a change minds thing, not a matter of molecular science or the MOA. The MOA is valid and proven. Hesitant, questioning, confused, or objecting minds will be changed when the Phase 3 trial results, later this year, are revealed. They will be as good or better than all of the previous early-phase trials. Only a matter of time, not science or MOA.

Everything?

Ok, then, tell what constitute "trade secrets." Those don't have to be revealed.

Too Early for an Anavex Press Release

Steady, exactly.

Were Missling and Anavex to turn right around and on Monday make a big announcement, "Amyloid thesis now dead for Alzheimer's; we have the real solution," Anavex would instantly get lumped in with all the companies that promoted (with billions of dollars spent on research and clinical trials) the induced removal of amyloid accumulations. In every case a complete failure.

None of the pharmaceutical biggies could solve the Alzheimer's problem, after spending decades of time and billions of dollars. Obviously (to most), Alzheimer's is a complicated CNS disease for which there cannot be a simple, orally dosed pill that could ever treat the disease. Just who does Anavex think we, the biotech investment market, are? We know better. Anavex, with its 'barkameseen,' is barking up the wrong tree. Big Pharma can't fix Alzheimer's. Brand new little Anavex has even a smaller chance.

So, yes, as always before, the only thing that will change the game, for both Alzheimer's patients and Anavex Life Sciences Corp will be incontrovertible clinical results, showing with statistical significance that blarcamesine beats the existing SOC (standard of care) Alzheimer's drugs.

Blarcamesine Polytherapy

I, too, read through that gigantic list of cancers in the new patent document. I saw one cancer of particular interest, Waldentrom’s macroglobulinemia (WM), a rare B-cell lymphoma. This was of particular interest because I have that disease. For five years, in my case, it’s been classified by my oncologist as “smoldering;” with low-grade symptoms not yet requiring any of the standard therapies. To help maintain this low-grade symptomatology, I take trans-resveratrol, an over the counter supplement which in Germany is the SOC (standard of care) initial treatment for WM. There is a reasonable likelihood that this will hold the disease in abeyance for many years. Or, the proteins of the disease will spike and I’ll need to take acalibrutinib, twice a day, orally, at a cost of many thousands of dollars a month (have health insurance).

Or, by the time my WM no longer smolders but fires up, perhaps blarcamesine (Anavex 2-73) will be available to treat my blood cancer. Hope so.

Especially, for another reason. With the long list of diseases in the new patent document that blarcamesine might be therapeutic for, I’ll take advantage of this polytherapeutic factor.

I have another morbidity that is not listed, but almost surely will respond favorably to blarcamesine: hereditary spastic paraplegia (HSP). I’ve had my genome analyzed, I definitely have a mild, slowly progressing form of this disease. Specifically, long neurons controlling various leg muscles lack sufficient gamma-aminobutyric acid (GABA). GABA is a neurotransmitter that inhibits over-activity of nerve impulses. Without sufficient GABA in their controlling nerves, the adductor muscles in my legs are tight, spastic, making walking difficult.

But, the girls in the Rett syndrome study showed that blarcamesine increased GABA production. I want that for my HSP. With it, I might be able, once again, to walk around without my walker.

When available, I’ll take blarcamesine to treat my WM, my leukemia; which at the same time may well treat my HSP. Two for the price one.

Two disease treatments at the same time: “polytherapy.” Watch. Once blarcamesine is widely prescribed it will be discovered that the drug treats not only the target disease, but at the same time other comorbidities are resolved. Eventually, blarcamesine will target not only the three central nervous system diseases presently in trial (Rett syndrome, Parkinson’s disease dementia, and Alzheimer’s disease) but an ever-widening catalog of diseases and conditions, which can be resolved by blarcamesine's propitious activation of the sigma-1 receptor protein.

At the same time, it will be discovered that blarcamesine is actually prophylactic; prevents the onset of a host of geriatric diseases and conditions.

New Anavex Patent

Today's new patent application by Anavex indicates further that the company's science is deep, and that they have precise, clear understandings of how it can be uniquely implemented to treat (or even prevent) otherwise recalcitrant central nervous system or other diseases.

The company can't be making up or merely assuming the mechanisms and processes their drugs can use to attain the desired therapeutic outcomes. They have a lot of yet undisclosed data. Some really powerful, new therapeutic things happen; now being patent-protected.