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Why the rest periods?
The on-off blarcamesine (Anavex 2-73) dosing schedules in today’s patent application are most interesting. The company wouldn’t be laying this out unless it had data and experiences indicating efficacy.
According to the patent application, the drug will be given at full strength for an initial period, a few days or a week or so; followed by a “rest period.” This on-off dosing schedule then continues for a year or more.
How come? Why not just give a daily dose, without interruption, without “rest periods?” Far more convenient. There could be several reasons. Choose the one you thinks fits best.
1) After the first, initial dosing period, the drug loses efficacy; no longer suppresses or turns off Alzheimer’s symptoms. The cellular structures or processes the drug controls become saturated, so they need a rest period for the drug to clear and be able to resume efficacy when dosing re-starts.
2) For whatever exact mechanistic reason is at play, perhaps unknown, Anavex has discovered that intermittent dosings at the intervals laid out in the patent application actually work best, give the best therapeutic results.
3) As shown in early Phase 1 clinical trials, and in murines (lab rodents), continual, unvarying dosings do work; but symptomatic improvement curves flatten after long periods of continuous dosings. With dose rest periods, the drug maintains continuing high, uninterrupted levels of therapeutic efficacy.
4) For whatever reason(s), intermittent dosing simply works; so, with the rest periods, dosing costs are reduced by about a half, or more.
With many drugs there are at the start “loading doses,” strong doses that load biological systems to where they can be properly modulated by the drug. Then, after the loading period, lower, chronic (time-continuing) dosages are administered. This has not been mentioned for blarcamesine. This phenomenon would be investigated with dosage “titrations” in human clinical trials, where dosages are low at the start, but incrementally increased until therapeutic results appear. Then, that dosage level is continued.
After long durations of such symptomatic relief, some clinicians might then want to titrate down, to see if results continue at lower dosage levels.
Anavex 2-73 safety.
For those unfamiliar with the human clinical data showing profound safety of blarcamesine (Anavex 2-73), here, in the patent application, is a summary of the safety data from Phase 1 human trials:
Based on the frequency and intensity of non-treatment emergent adverse events (TEAEs) the maximum tolerable dose (MTD) and the minimum intolerable dose (MID) were defined as 55 mg and 60 mg, respectively. A highest doses, observed adverse events included moderate and reversible dizziness and headache, common in drugs that target the central nervous system. Blood pressure and resting heart rate and other clinical parameters such as vital signs and 12-lead electrocardiogram (ECG) did not show any clinically relevant or dose-dependent changes. The QT interval and QTcB also did not reveal any clinically significant changes. The pharmacokinetics of ANAVEX2-73 was found to be suitable for daily oral dosing.
Some 8th-grade Anavex arithmetic.
There have been any number of posts laying out potential numbers for Anavex revenues, and how those might connect to shares and dividends. On my spreadsheet, I did some elemental arithmetic, to see how various numbers connect to the AVXLs I own.
First, I wanted to figure out how much of a year’s annual sales revenues by Anavex Life Sciences Corp would be valued by each outstanding share. To do this, first calculate a per share value. Divide the annual revenues datum by the number of outstanding shares (presently, at the full authorized number: 75,710,000).
Then, let's imagine that in 2023 Anavex takes in $20 million dollars in sales revenue. For each share, that would be $20,000,000 over (divided by) 75,710,000. That would be $0.246 per share, a bit over 24 cents.
One's personal value, based upon one's AVXL share position, is calculated by multiplying that per-share datum times the number shares owned.
On a spreadsheet or table, one can visualize the numbers at various annual revenues. Simply create a stacked, incremental list of potential annual revs, from, say, $10,000,000 on up to (but not limited by) $100,000,000.
Then, presume some reasonable “drop down” figure, the percent of annual revenues that drop down, get distributed as per share dividends. If the per share drop down is 20%, multiply the per share annual revs datum times 0.2 (which is 20%). In this case, $0.246 x 0.2 = $0.0492, a bit less than a nickle per share.
Of course, in an early year, say, 2023, when the company is still expanding, with revenues of only $10 or $20 million dollars, there is not likely to be any dividend; all after-costs dollars get re-invested. But at some time in the future, revenues will generate dividends. Use these 8th-grade arithmetic protocols to visualize the new numbers. When blarcamesine (or, later, Anavex 3-71) is treating millions with various CNS diseases, the numbers get big.
Later, if either Anavex drug becomes a standard, near universal middle-age geriatric disease prophylactic, with many tens of millions taking the drug each day, every year, the numbers get pretty astounding.
The most astounding figures, however, are when either Anavex drug, more distantly in the future, is discovered to prevent or treat not only geriatric-onset CNS diseases, but when consumed by young adults they prevent all sorts of other pathologies, such as autism, cardiovascular conditions, cancers, etc.
Will any of this happen? For most (understandably, respectfully), all of the above is risky speculation, upon which no AVXL investment decisions should be made; wait until Anavex actually has some annual revenues, which won’t happen until they get authorization to actually sell one of their drugs.
Personally, I don’t make high-risk stock purchases. I do have a moderate AVXL position, at a per-share cost basis of $2.67. My entire AVXL position has been purchased over many years, all with discretionary money in my budget. If Anavex goes bust, I’m not hurt at all. If it succeeds, as I anticipate, based upon low clinical trial p values, very positive symptomatic suppression results, and uniform and universal safety outcomes, I (well, my estate) will be well-rewarded.
All of these projected numbers are guesses, but informed, calculated ones. With your own calculator or spreadsheet, punch in your own numbers. Interesting, at least, if not informative yet.
Of course, these projective calculations are of little value or application for those who are in the AVXL game to make dollars by trading; buy low, sell high, etc. Takes more than 8th-grade arithmetic to make that work. I’ll let the traders tell their stories on that. I’ll just sit back and watch, until at least 2023, the year I predicted (I think accurately) that would be Anavex’s first year of real revs; when the company’s future becomes secure and assured.
Any resulting new AVXL positions?
3 days ago SAVA was around $118, today it closed at $58.35
The Rett trial will end before 2022 (https://www.clinicaltrials.gov/ct2/show/NCT04304482). That CNS disease will then be treated with blarcamesine, showing that blarcamesine fixes otherwise recalcitrant CNS dysfunctions. That will elevate the AVXL share price, many months before the Alzheimer's study is completed and the FDA then approves blarcamesine for that big disease.
Check my posting. I referred to the "Alzheimer’s/CNS play," not just Alzheimer's alone. A single blarcamesine success for any of the three it's being tested on, Rett syndrome, Parkinson's disease dementia, or Alzheimer's, will validate the drug and the company. No stopping either the share price or corporate revenues thereafter.
Yes, another problem.
Their antibiotic may stop damage, but it is unlikely to repair damage;
RedShoulder listed the five in-play CNS drug biotechs. Worth considering them all, below:
1. SAVA, Cassava Sciences Inc.
Their Alzheimer’s/CNS play: Simufilam
How it works: “Simufilam is a proprietary, small molecule (oral) drug that restores the normal shape and function of altered filamin A (FLNA), a scaffolding protein, in the brain.”
https://www.cassavasciences.com/simufilam
Their problem(s): Legal petition to stop FDA trial of the drug; alleged factual misrepresentations.
https://www.glancylaw.com/cases/cassava-sciences-inc/
2. ANVS, Annovis Bio Inc.
Their Alzheimer’s/CNS play: ANVS401
Their problem(s): In clinical trial results, efficacy scores are not statistically significant compared to placebo.
https://seekingalpha.com/news/3721385-annovis-bio-anvs-loses-nearly-half-after-presenting-alzheimers-drug-data-at-aaic-2021
3. CRTX, Cortexyme Inc.
Their Alzheimer’s/CNS play: atuzaginstat (COR388)
Their problem(s): The main phase2/3 clinical trial is yet on-going; no results until the end of 2021. The drug suppresses an oral bacterium, Porphyromonas gingivalis, of presently dubious involvement with Alzheimer’s in the brain or nervous system.
https://dementia-monster.blogspot.com/2021/01/if-not-ban2041-what-about-atuzaginstat.html
4. BIIB, Biogen Inc.
Their Alzheimer’s/CNS play: Aduhlem
Their problem(s): Multitudinous. Simply, the drug just doesn’t work, is exorbitantly expensive, has side effects (brain bleeding), and the FDA approval process is under question.
https://chicago.suntimes.com/2021/7/13/22574122/aduhelm-fda-investigation-alzheimers-patients-deserve-full-truth-editorial
5. AVXL, Anavex Life Sciences Corp
Their Alzheimer’s/CNS play: blarcamesine (Anavex 2-73)
Their problem(s): No human clinical data yet available to submit to the FDA; trials yet on-going, won’t finish until late 2021 or into 2022.
Ok, then, who would intelligently decide to plunk down a portion of one’s equity investment funds on any of these Alzheimer’s/CNS plays? On the face of the commonly-available information, not a wise thing to do.
Here, many of us who have scrutinized the science of all of these have seen that the problems of the first four company’s are deep and unresolved; most likely never to be. Not so for Anavex, however. So far, no clinical data that the FDA can ponder, but an abundance of pre-clinical murine and human safety and tolerability data which indicate that the results from the three on-going clinical trials, Rett syndrome, Parkinson’s disease dementia, and Alzheimer’s will be entirely positive; allowing FDA approval of blarcamesine.
For most, who don’t understand or have no confidence the in science of each of these companies, a wait and see stance is advised. Wait until the FDA approves a company’s new drug before committing personal dollars to own a bit of the company.
But if the understood science is both good and accurate, buying in before FDA approval happens, some time in the future (for Anavex, in 2022 or 2023), ultimate financial rewards (value gains) will be significant.
Personally, the only game I’ll play in is Anavex. I’ve purchased my pre-season tickets, will attend the Home Opener the day the FDA approves blarcamesine, probably first for Rett syndrome. Then, big road games for Parkinson’s disease dementia, and finally the 2023 CNS World Series victory with Alzheimer’s.
Salubrious: "health-giving"
Yes! At the start of the causal chain.
The "magic" is moving upstream in the causal chain. It appears Blarcamesine may do just that.
Tells of blarcamesine cellular salubriosity.
I am waiting for you knowledgeable posters to address this technical article from Italy that Kentucky posted yesterday.
There’s a molecule that will do that.
I sure could use something to calm my neurons down and stop the neurorigidity.
Nope, it's not.
It's not a neuropathy miracle cure.
Not Until Rett Results
there is no news that can move this up..
Blarcamesine BS (salubriosity).
Salubrious: favorable for or promoting health or a healthful condition; adjective salubriosity.
Accurately and concisely conveying the traits, functions, and outcomes of blarcamesine therapy can require some pretty long, involved phrases or sentences. This proprietary Anavex molecule simply does so much, with so many good things in cells, especially neurons.
Of course, to date, little of this has yet been known, recognized, understood, or accepted by either investor or medical communities. They’ve regarded Anavex topics to be just BS.
Actually, that acronym does apply, if properly understood. I hereby suggest a bit of real Anavex BS, Blarcamesine Salubriosity; noting that the molecule is so particularly salubrious; health-giving.
Rett; then Fragile X; then Autism?
The incidence of Fragile x is about 5x that of Rett.
Published in Nature's Scientific Reports.
Publication of a paper in the prestigious 'Nature' is a real win for the company.
My error.
The article is not published in the flagship journal Nature, but an associated journal.
Yes, trial results will move the stock.
Nothing to move this stock until Rett approval or alz data, probably nothing this year.
In Nature, no less.
Readers should understand that the new paper, telling of new, affirming data and findings about blarcamesine treating CNS conditions, in both transgenic mice and real humans, appears in Nature, one of the two biggest, most respected journals of science research globally. Nature is centered in Europe, The other one, Science, of the American Association for the Advancement of Science, is centered in the US.
Every researcher in the world dreams of getting a paper published in either of these journals. There is no better journal to be listed on one's resume or curriculum vitae. Rejection rates for both journals are very high; editors select only the best papers, having the most important and significant information.
In regards to blarcamesine, let the reader discern.
From the new paper’s abstract. Rather definitive:
The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.
It’s for new viewers.
Some have taken offense at George's frequent postings of Anavex science information.
Take note. What George posts is solid information, facts, dealing with Anavex. Those of us who’ve been reading this message board for some time (now, for years), know and are aware of the information George and some others post. But many site visitors are new, trying to learn about Anavex Life Sciences Corp and their molecules.
As though this were a trial, George sets the Anavex information openly on the table, as “evidence,” allowing and promoting examination and cross-examination of it.
Again, George, thank you for continuing to post useful and informative science data on blarcamesine. New viewers need to learn of it; examine it themselves. New viewers can’t easily find or access such information. You’ve done the good work for them. Continue....
A competitor gone?
Well, now what? If some proposed Alzheimer’s drug — what was it, ‘Simulflam’ — gets eliminated, what is blarcamesine going to be negatively compared to? Blarcamesine’s just gotta be worse than other new drugs, from other real, pharmaceutical companies.
Is the company well-named?
When I first learned of the company’s name, “Cassava,” I thought it curious, at least.
Cassava, Manihot esculenta, is a tropical root crop, producing massive amounts of carbohydrates, including tapioca.
But before cassava roots can be eaten, they must be carefully macerated and washed, to clear toxic chemicals that if allowed to remain, produce cyanide. Improperly processed or ill-prepared cassava is rather poisonous.
Why would someone name a drug company, of all things, for a tropical root that is, of itself, toxic, poisonous, with cyanide as its toxin?
Ok, there's real evidence.
The drug works and it's only a matter of time before that's 100% proven
Once again, what's the evidence of error?
What you've described about blarcamesine is wrong.
Evidence of blarcamesine dysfunction cheerfully invited.
--again an excellent explanation of what we have---thank you !!!
Temporary, short-period benefits; or permanent ones?
...the effect of simufilam is temporary, and then patients continue to decline -- similar to (but presumably safer and a bit more efficacious than) Aricept.
Just a matter of time.
Some ignorantly chose to dismiss facts until some other "experts" review them.
Are facts facts?
The problem at the moment is this hasn't yet passed peer review.
Some will win, others lose.
Did that help?
Speak for yourself.
And we don't even know if 3-71 is efficacious in human disease yet,....
The chemistry is un-complicated.
What Anavex organic chemists? I don't see any on staff....
Big Pharma won’t wait. They’ve failed already.
You certainly know enough organic chemistry to know that as soon as 273 delivers its p3 results, every BP in the country will be looking at various isomers that are technically and legally different chemicals, but close enough to 273 to produce similar results.
For yet another CNS disease, blarcamesine works.
Peer Reviewed paper regarding Blarcamesine for the treatment of fragile X syndrome and other autism disorders.... https://www.researchsquare.com/article/rs-189177/v1
There will be no useful competition.
...273's overall market share could diminish as competitors come on line,....
The market won’t make Anavex 2-73.
Market wants to know 273 works for alz....
Shape ain’t right for toxicity.
This [the molecule’s unique molecular structure] may explain why blarcamasine seems to have no side effects: It is suited to interact with a target that has a unique structure, and the inference would be that blarcamasine cannot interact with other proteins because they are too different in kind from the S1R.
Two perspectives: Before or after an FDA decision.
I hope this is sarcasm [My statement that “Until the FDA approves the drug, it is categorically and unconditionally unsafe and ineffective. Period. ”]
Of course...
Don’t dismiss the placebo or even nocebo effect.
No, it’s the stock message board effect.
-" very high rollover rate into the open-label study which was over 95% which is extremely high."----what is significance of this ??? Why do patients want to stay on the drug ???