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No preclinical hints or evidence of problems.
... if [Rett and other] results don't come in as great as I expect they will, then I believe it would contradict all of the previous trials that I mentioned above.
Blarcamesine against ALS.
...you mention" primary lateral sclerosis, PLS, "-do you think 2-73 could also be beneficial for those suffering with ALS ??
Research on certain gene mutations suggests that changes in the processing of RNA molecules may lead to ALS-related motor neuron degeneration. RNA molecules are involved with the production of molecules in the cell and with gene activity.
Other gene mutations indicate there may be defects in protein recycling—a naturally occurring process in which malfunctioning proteins are broken down and used to build new working ones. Still others point to possible defects in the structure and shape of motor neurons, as well as increased susceptibility to environmental toxins.
Gabapentin Not Effective For HSP
Are you using GABAPENTIN?
Two other CNS diseases blarcamesine will treat.
...the normalization of GABA/glutamate [by blarcamesine therapy] could then be used as a surrogate endpoint across other diseases which hallmark imbalanced GABA/glutamate levels.
But, only trial outcomes count.
But, what can it prove if the patient (or his advisors) think the drug is working? or just thinks it is advisable to continue, working or not.
Mothers can tell.
If the roll over follows a blinded trial, and the patient, families, doctors and investigators don't know if the participant was receiving the drug or the placebo, they don't usually have much clarity on whether the drug is working or the placebo is working.
Big end of day trades.
Can anyone explain the significance and process in the big, >100k share trades right at the end of each day's trading for the last many days?
Who might be doing this? Why just before the trading day closes?
????
But it’s just ‘nonsense.’
I don’t think our deep knowledge posters have given this news [of profound Anavex 3-71 efficacy] the broad spectrum of interpretation which such clinical data deserves..
After Rett Results, Anticipatory AVXL Purchases
The company will announce topline data from the Alzheimer's trial by 2H 2022.
This will be the most important event in the lifecycle of this company.
Missling Phrases of Impact
Anavex CEO Missling made these statements this morning: AVATAR results are "Virtually around the corner"... and "we are very excited"....
1) Results "around the corner." I'm presuming they will be released in a few weeks or less. Makes no difference whether in a week or a month. Girls with Rett syndrome will still need blarcamesine therapy. Whether results are delayed or not, the market for blarcamesine against Rett syndrome will be unchanged.
2) Excitement of Anavex officials. First, if results are forthcoming, at least to some degree they must be known to insiders; hence, the proclaimed excitement. Making such a statement when the results are actually not positive raises investment advice questions from the company. SEC violation stuff. Missling knows about all of that, avoids such complications. Hence..., the Rett data will be good.
For the first time in several years, from the discretionary funds portion of my budget, I've instructed my bank to send funds to my brokerage. When they get there, I'll be monitoring the AVXL share price closely; intend to expand my holding.
Only if....
Rett Data is important! Rett Data will be here “very shortly.” Stock Price above $100 could be here by spring break!
Full potentials not yet recognized or discovered.
One day, you will be amazed how everything has changed...
Next few weeks, months, or years?
That [Anavex 3-71 as an approved drug] may be true but in 10 years ? The world will be so different ….
Off by a thousand.
Should the PR say micrograms instead of milligrams?
As predicted, Anavex 3-71 next for Alzheimer’s
Based on these results, and ANAVEX®3-71 pre-clinical profile, the Company intends to advance ANAVEX®3-71 into a biomarker-driven clinical development dementia program for the treatment of FTD, schizophrenias and Alzheimer’s disease,....
ANAVEX®3-71 was well tolerated in all cohorts receiving ANAVEX®3-71 in single doses ranging from 5 mg to 200 mg daily with no serious adverse events (SAEs) and no significant lab abnormalities in any subject. In the study, ANAVEX®3-71 exhibited linear pharmacokinetics. Its pharmacokinetics was also dose proportional for doses up to 160 mg. Gender had no effect on the PK of the drug and food had no effect on the bioavailability of ANAVEX®3-71. The study also met the secondary objective of characterizing the effect of ANAVEX®3-71 on electrocardiogram (ECG) parameters. There were no clinically significant ECG parameters throughout the study. Participant QTcF measures were normal across all dose groups with no difference between ANAVEX®3-71 and Placebo.
Anavex 3-71 Against Alzheimer’s
AF710B [Anavex 3-71] long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats [McGill-R-Thy1-APP transgenic Alzheimer’s rats]. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232171/#B88-ijms-22-06359
Let me interpret what is stated in this abstract of a study of Anavex 3-71 in transgenic (gene-inserted) rats with consequent Alzheimer’s disease.
Treatment with Anavex 3-71 was “long-term,” not for just a few days or so. Most significantly this dosing “reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology.” Simply, the rats had advanced cases of Alzheimer’s, but the Anavex drug “reverted” the “cognitive deficits.” The disrupted or disturbed thinking abilities of the rats were turned around. At the end of treatment their cognitive abilities tended toward normal.
What would be the impact if that were to happen in humans with Alzheimer’ disease? Appears very obvious, then, that if Anavex 3-71 treatment were begun at the first diagnosis of Alzheimer’s, cognition could be “reverted” back to normalcy.
Then, “these effects were maintained following a 5-week interruption of the treatment.” What does that mean? First, five weeks in the life of a rat would be equivalent to many months or several years in a human. “One rat month is comparable to three human years.”
https://www.researchgate.net/publication/268409698_The_Laboratory_Rat_Relating_Its_Age_With_Human's
Five rat weeks would then be equivalent in humans to about 3 yrs, 9 months. Imagine, taking a drug that prevents or reverses Alzheimer’s for a useful period, say six months, then going off it for over three years while it continues to work. The take-away is this. Anavex 3-71 binds to the sigma-1 receptor protein and stays attached for lengthy periods of time, all the while modulating and facilitating favorable cell processes.
It is then very plausible that if/when Anavex 3-71 becomes available as a CNS disease therapeutic, after an initial “loading dose” treatment period, the drug will be taken intermittently, at yet to be determined longer intervals. Perhaps subsequent dosings will be each week, on Mondays and Tuesdays.
Clearly, the drug is not rapidly cleared from the cell. In cellular autophagy Anavex 3-71 is chemically regarded as a normal endogenous cellular chemical; not a waste or toxin that must be cleared.
Additionally, as mentioned previously, Anavex 3-71 is dosed in microgram, not milligram masses. A milligram is a thousandth of a gram, a millionth of a gram. Anavex 3-71 doses are a thousandth of those of Anavex 2-73 (blarcamesine). Not much is needed. It readily crosses the blood-brain barrier and enters cells, where, as this study shows, it is not digested or excreted as a waste or toxin.
Coupled with the drug’s profound efficacies and safety, nothing more could be hoped for. An ideal drug, dare I project.
Of course, for human therapeutics all of this will have to be tested and proved in proper clinical trials, some years away. First, it will be blarcamesine in the on-going Phase 3 Alzheimer’s trial. That will not be end of Anavex clinical trials for Alzheimer’s. Anavex 3-71 will be called up from the minor leagues to see how it can play in the Alzheimer’s big leagues. As above, all pre-clinical data are profoundly favorable. In 2022 and 2023 blarcamesine will be the Anavex star. After that, and even better, will be Anavex 3-71.
The same, either way.
Hammond joined us last as a VP, in July. This was a promotion.
The New Positions at Anavex. How come?
And if they have seen it [unreleased clinical data] and it is not positive, why would they accept a position in a company with a failed drug?
Anavex is unique.
...there are other S2 receptor companies and MJFF is supporting them as well - AVXL is not unique
Thank you.
Well, it appears your training and expertise is exemplary. Many readers will turn to you for cogent renderings on how the Anavex molecules actually affect (if they do) the sigma-1 receptor protein's modulation of cellular processes. Advanced training and experiences in finance, somehow, must lend themselves to accurate assessments of Anavex biology. No magic or beans about any of this. Bankers know more than anyone about so many topics; including how various molecules might affect reaction cascades in neurons.
We are privileged to be enlightened by your knowledge. Look forward to your analyses of the upcoming Rett trial results.
Is Anavex ‘faking it to make it?’ Or...?
I just read this, about the “entrepreneur” who was just convicted of defrauding big investors in her technology that was supposed to detect diseases in a drop of blood. The article claimed that the person was “conveying a boundless optimism regardless of whether its warranted or not, known as "fake it 'til you make it."”
Well, that raises the question, doesn’t it? Are either Anavex (Dr. Christopher Missling) or its apologists (such as me) conveying boundless optimism, with the hope of faking it until the drug makes it?
The two seminal questions. Is the science of blarcamesine real? In humans with CNS diseases will the drug actually treat those diseases, without obviating or severe side effects? Of course, the results of the three clinical trials will answer that question.
Then, on the basis of those clinical results, will the FDA then approve blarcamesine for therapeutic uses?
Exactly how anyone’s “enthusiasm” would change or affect either of those actions is unclear. Certainly, because of the control arm and double-blindedness of the clinical trials, anyone’s ‘boundless optimism’ will not play a part in therapeutic outcomes.
The FDA (except for Aduhelm, perhaps) is unlikely to factor enthusiasm in a drug’s approval.
All other things aside, only two things are involved in the success of Anavex Life Sciences Corp: successful therapeutic outcomes in at least one of the three clinical trials; and consequent FDA approval of blarcamesine.
All of us, here, can go back and forth on a landscape full of contentions and questions. But only two things really count: clinical results, and consequent FDA approval.
Potential AVXL Outcomes
What comes out of the entire exercise is that AVXL is one of the few stocks that can really have an enormously wide group of possible outcomes, with lots of great possibilities.
An AVXL Future Values Spreadsheet
These ultimate smart investors [those who have strongly-held AVXL positions, who don’t trade] will leave a fortune to their heirs.
Yes, merely 'nonsense.' Gotta be SO careful.
Yes, be very careful about ‘nonsense’ in regard to Anavex 2-73. Here’s the ‘nonsense’ the author was 'pumping' in the article. I’ve bold-faced particularly nonsensical statements:
NAVEX2-73: The leading sigma-1 agonist under development is ANAVEX2-73, an amino-tetrahydrofuran derivative and mixed muscarinic/sigma-1 receptor agonist.16 At present, 3 active clinical trials involve ANAVEX2-73: one for Parkinson disease with dementia and 2 for Alzheimer disease.17 Another clinical trial for Rett syndrome is planned, announced in October 2018 by manufacturer Anavex Life Sciences.
The most advanced data for ANAVEX2-73 come from a completed phase 2a trial involving patients with Alzheimer disease.18,19 The study involved 32 patients with mild to moderate disease, with baseline Mini-Mental State Examination (MMSE) scores between 16 and 28. The initial 5 weeks of the study involved crossover from oral to intravenous administration, followed by a year of oral therapy. Primary endpoints focused on safety, dose, and tolerability, while secondary endpoints evaluated efficacy measured by MMSE, Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory, and electroencephalography (EEG)/event-related potentials (ERPs). After 1 year, multivariable analysis showed a strong relationship between high doses (30 mg and 50 mg) and improved responses compared with patients who received low doses (3 mg and 5 mg) and had poor responses. The agent was very well tolerated, with no serious or clinically significant adverse effects.
The extended period of this trial has been ongoing for 3 years. The most recent findings echoed earlier reports, namely that the high-dose group continued to show significantly better responses in functional and cognitive endpoints than patients treated with low doses. The investigators also highlighted 2 genomic biomarkers that continued to be significantly associated with responses: SIGMAR1 and COMT. The former suggests that sigma-1 activation is a critical component of patient responses. In a press release issued by Anavex, Harald Hampel, MD, PhD, professor at the Sorbonne in Paris reflected on the biomarker findings: “These results further confirm the impact of actionable genetic variants that were previously identified through a full, unbiased genomic analysis of ANAVEX2-73 in Alzheimer’s disease, raising optimism for the future of biomarker-guided precision medicine to effectively combat this devastating disease.”
Blarcamesine; in the steps of Lister, Semmelweis, Pasteur, et al.
The colleges hammer into them [doctors in training] the chain of command protocol, each dutifully honoring the prior and successor.
You didn't get it.
So over the weekend without any trading we open at $1000 pps on Monday?
A Year-End AVXL Value Analysis
For those of us who held 12-month AVXL positions, we had these numbers. My Schwab account says that a year ago AVXL closed at $5.12. Today, ending 2021, it closed at $17.33.
For the year (2021), that’s a gain of 3.38x, or a 338% gain.
If in coming years the annual gains will be, say, 300% (3x), starting with an AVXL holding worth $1000 on Monday, the first trading day of 2022, here’s a table of position values for the coming five years:
......Date.....Position Value...$ Gain from 2021
Jan 1, 2022......$1,000................0
Jan 1, 2023......$3,000.............$2,000
Jan 1, 2024......$9,000.............$8,000
Jan 1, 2025.....$27,000...........$26,000
Jan 1, 2026.....$81.000...........$80,000
Was the holding of an Anavex equity position for the year 2021 rewarding? With a value increase of 338% it surely was.
Will there be equivalent increases in coming years? That will be for each equity owner to observe. The science of the Anavex molecules can certainly allow equal or greater gains. Successfully treating or preventing the CNS diseases being targeted by the company will increase the annual multipliers significantly. By 2026 add one or two more digits.
With my very moderate AVXL position, I've got a few thousand shares with an average cost basis of $2.67, I have a 548% gain, over about five years. A year from today, I don't expect a share of AVXL will be traded at either $17.33, today's closing price, or even twice that. Much larger; all dependent on the clinical trial results in 2022, and the prospects of FDA approvals. Was pleased watching my AVXL value gains in 2021. They will be much greater in 2022.
The Missling Effect
Drug discovery does not have fixed callendar deadlines.
All of this must be ridiculous.
Anavex 2–73 also helps other cellular dysfunctions including proteostasis, autophagy and neuroinflammation that are present in neurodegenerative and neurodevelopmental disorders.129,130 It has been efficacious in animal models and human studies in Rett syndrome (unpublished), studies in Alzheimer Disease, in Parkinson's Disease Dementia (unpublished) and most recently in rescuing hyperactivity and other behaviors in the KO FXS mouse.127,131,132
In 2022, which disappears, blarcamesine or Aduhelm?
Biogen couldn't even imagine Anavex as a possible solution or future deadly competitor. They were going down with their amyloid ship and are now looking for a tow.
They know...and understand.
Could it be BIIB and its BOD understands what is going to happen in 2022-3 time period with the Anavex proof of concept that the BIIB magic is gone come 2024?
Million-Dollar Trade at the Close
Looks like, right at the close, there was a transaction trading about 75,000 shares. If those traded at the closing price of $17.73, the transaction totaled $1,329,750. Whew.
Any thoughts or explanations about this? A bit bigger than most trades (by an order of magnitude or two).
Such helpful, informative information.
Biotech companies I’m familiar with make a point of showcasing.....
Thank you for your comments and observations.
Accurately, you stated:
Another thought I have, that I didn't see in your talk, is the belief that there are different consequences to be achieved by different agonists, ligands or activators; and that the actual result of activation of sr1 will differ depending on the cell function and location.
Furthermore, I'm not clear yet what part the muscarine receptors play, except I do think they are significant. They already are active elements in other drugs.
Yes, not just neurons.
...sigma-1 receptors are not only found in the CNS space but also through out the body...
Good scrutiny and understanding of Anavex science.
I have followed closely company developments most every step of the way in the last 6 years--all of which have been very very positive with zero negatives--another example-Dr.Randi Hagerman--Of Fragile X foundation and Univ.of California hospital--who had very positive comments on 2-73 after participating in the Rett Syndrome trial. Falconer your scientific contributions here just add reasons as to why I am invested here--much appreciated !!!
The Anavex record; and future.
I just checked my records, to see when I bought my first Anavex Life Science Corp shares; May 2016. In the following years I’ve continued to buy more, when I have some discretionary budget dollars.
Now, for over six years, I’ve closely followed and scrutinized the particular (even peculiar) science of the Anavex molecules, trying to determine if it’s legitimate. Can blarcamesine (Anavex 2-72) really provide the multitude of therapeutic benefits imputed to it? Safely, without side effects?
All of that depends on just how the molecule works in cells. Until the last two years or so, how (or if) blarcamesine can work to resolve any of the central nervous system (CNS) diseases Anavex is targeting was legitimately questioned. The molecule’s “MOA,” mechanism of action, was both unknown and questioned. The early preclinical therapeutic results, in both murines (lab rodents) and humans were simply too good to be true. Too many things got fixed (or prevented), without any expected side effects. Virtually all drugs acting powerfully in the CNS have untoward side effects. None of those with blarcamesine.
Again, too good to be true.
But in the last two years or so the various mechanisms of action of blarcamesine in cells, in neurons in particular, have been discovered and elucidated. A number of detailed, definitive papers have been (independently) published, showing how this single small molecule is able to modulate, promote, and restore a diversity of cell processes, bringing functional health to the neurons and the tissues and organs they control.
Here’s the important fact, being evermore substantiated in both murine and human trials, in vitro (in isolated cells in glassware) and in vivo (in living organisms, murines and humans). So far, it has been discovered that blarcamesine, when attached as a ligand to the sigma-1 receptor protein in neurons, causes, facilitates a wide diversity of “downstream” processes in the cell; many of which are “cell-keeping” (homeostatic) processes. With restored or modulated homeostasis, cells, especially neurons, can function normally. Diseases and conditions are obviated. Health is restored or promoted.
But this is the even greater fact. Simply, just how many diseases and conditions can be either fixed or prevented by blarcamesine’s activation of the sigma-1 receptor protein is not yet known. It is becoming ever more clear that propitious activation of the sigma-1 receptor is not a fix for just three CNS diseases. It favorably modulates just a host of downstream chemical reaction cascades and processes that provide health to both cells and organs.
The prediction is this. Sigma-1 receptor activation biology will continue to be investigated and elucidated. Sigma-1 receptor activation biology is a new Big Thing; previously unrecognized.
Some have castigated Anavex’s long list of “pipeline” diseases blarcamesine might treat (or prevent). Too good to be true. No small molecule (molecular weight 281) can possibly have so many modulating or controlling effects within a cell.
Let’s watch. Continued investigations of the molecule almost surely will discover even more things it controls or modulates. Blarcamesine (and its analogues Anavex owns) is destined to be a major, even revolutionizing therapeutic in coming years. First with Rett syndrome, Parkinson’s disease dementia, and Alzheimer’s. But after that, a widening diversity of human (and veterinary) diseases and conditions. By the end of the 2020s, medicine will not be the same. Nor will human health.
For the consideration by all, we welcome contrary posts, telling specifically why little or none of what I’ve conjectured can or will occur. Let’s see the contrary Anavex science. Lay it out for us, please.
Best time to sell AVXL.
I respect for his thought [Warren Buffet’s] that, if you get the right stock, the best time to sell is never.
Advice; well taken.
Be investors, folks. Ignore the nonsense.
Correct. There will be no competition.
In any event, I don't believe that adevex is 2 - 73 [sic] is really in direct competition with aduhelm.