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Then, even bigger things to follow.
Interesting that we have been discussing homeostasis as long as we have. Looking like the FDA may soon be convinced as well.
And, it's safe.
I failed to mention in any way the utter safety of the Anavex drugs. Almost all of the drugs acting in the central nervous system have side effects of varying degrees, "adverse events" (AEs).
In any of the clinical tests of the Anavex sigma-1 receptor drugs, whether in murines (lab rodents) or in real humans, no obviating AEs have ever appeared, An infrequent circumstance among brain-acting drugs. Another Anavex positive.
Why Anavex Is Different
A consideration of how and why blarcamesine (Anavex 2-73) and Anavex 3-71 are markedly different CNS and other disease therapies.
First, the two major disease therapy targets for the Anavex drugs, Alzheimer’s and Parkinson’s diseases, are diseases or conditions that present themselves, have their onsets later in life. In most cases, people with the targeted diseases were in health in the first portions of their lives. Then, at middle or older age, any of the various disease symptoms appeared. In regard to the unique mechanisms of action (MOAs) of the Anavex drugs (which, among other things, are sigma-1 receptor protein activators), this is extremely significant.
Let’s start with Alzheimer’s disease. Twelve-year olds don’t get the disease. A very few, with a particular genetic propensity get it starting in their twenties or thirties. The vast majority first experience the disease’s symptoms after middle age, starting in the fifties, sixties, or seventies. Most commonly, Alzheimer’s is a geriatric disease, occurring in older people.
The same is true for the various forms of Parkinson’s disease.
With this typical scenario of symptomatic initiation, how can the Anavex drugs work, particularly in comparison to recognized and commonly used SOC (standard of care) drugs? Will the Anavex drugs treat these CNS (central nervous system) diseases the same way as conventional, existing drugs, or not?
Very much, not.
First, a diagnosis of either Alzheimer’s or Parkinson’s disease is ominous. Conventional, available treatments can only slow the lethal progression of those diseases. And most often, not very successfully. Simply, none of the existing drugs are able to effectively or safely restore a youthful, healthful state of neuron (nerve-cell) physiology. Although some welcome treatment outcomes may happen, the underlying, causative neuropathology lethally continues. Existing drugs for Alzheimer’s or Parkinson’s inevitably fail. Patients die.
How, then, could this be different with the Anavex drugs? How could they terminate or chronically suppress the disease-causing biochemical anomalies in each of the two big CNS diseases? No other drugs have been able to do this. Specifically, how can the Anavex drugs make this happen?
The key? Unique, propitious activation of the sigma-1 receptor protein. Anavex 2-73 (blarcamesine) and Anavex 3-71 easily cross the blood/brain barrier, enter neurons, and then bind to the sigma-1 receptor protein on the surface or edge of the endoplasmic reticulum. With that, all sorts of good things are initiated in the neuron.
When properly functioning or activated, the sigma-1 receptor protein (the Sig-1R) modulates, controls a diversity of processes within the neuron. “...Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems.”
https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(16)00004-3.pdf
Simply, activation of the sigma-1 receptor by the Anavex drugs fixes bad things happening in diseased neurons. They restore “homeostasis,” the ability of the cell to properly control its biochemical function in a steady state, the “homeo-” process.
In the case of neurons with Alzheimer’s or Parkinson’s, homeostasis (“same status”) no longer occurs. In the case of Alzheimer’s, waste proteins, beta-amyloids or tau plaques, accumulate, disrupting normal nerve cell signaling and operation. Alzheimer’s symptoms result (cognitive impairment, etc.). In Parkinson’s, other biochemical disruptions occur — all because neurons can no longer work as they did in more youthful years. Activation of the sigma-1 receptor by either of the Anavex molecules restores normalized homeostasis.
One of the most important and significant outcomes of Anavex sigma-1 receptor activation is the proper folding of various enzyme proteins. Virtually every chemical reaction within a living cell is controlled and modulated by a specific enzyme. Enzymes are proteins, complex and detailed key-like structures. Like a key, if they get bent out of shape (as can happen in older age), they can’t catalyze chemical reactions. This happens in neurons being clogged with beta-amyloid waste proteins. Normally, enzymes are synthesized in ribosomes, then bent into their proper shapes. Simply, properly-activated sigma-1 receptor proteins modulate, facilitate proper enzyme structures. With that, waste-clearing enzymes are active and waste proteins cannot accumulate and cause the symptoms of Alzheimer’s. Similar processes are involved in Parkinson’s.
Propitious activation of the sigma-1 receptor facilitates a diversity of other good cellular functions, too lengthy to describe here. But in each of these outcomes, uniquely, they are controlled upstream, at the start of reaction sequences or pathways, thereby making “downstream” functions work. This is exactly why the Anavex molecules are so effective. Instead of trying to fix already broken things happening “downstream” within the neuron, they fix wrong things at their start, at the upstream, top, or start of reaction cascades or processes.
To certain degrees, this also works with genetic anomalies present at birth, such as the horrible symptoms of Rett syndrome.
As the story of the Anavex molecules begins rapidly to become recognized and depicted, notice the universal involvement of the Anavex drug’s activation of the sigma-1 receptor protein. That’s where the remarkably phenomenal therapeutic results will emanate from. Propitious activation of the sigma-1 receptor protein is the Anavex story. This year and next, with the completion of the on-going clinical trials (Rett syndrome, Parkinson’s disease dementia, and Alzheimer’s) the world will learn of — and benefit from — the company’s unique, proprietary science.
Looking out....
Educational Video News Release ... Currently running 24/7 on a closed loop in a number of BP Research Departments.
Edison and Adams
Hello, I’d like to speak to Mr. Ansel Adams.” The reply came back, “Speaking”
No, "bad" science is the "problem."
Complete denial imo most likely due to NO partnership.
Credentials? Or performance?
I know he felt slighted by the MD community as he felt disrespected, in his interactions with them,....
Schwab, too.
Charles Schwab states that at 4pm 1,075,276 AVXL shares had been traded during the day.
Schwab, too.
Schwab, too, has 1,075,276 listed as Anavex's trade volume for the day.
No Genetic Correction, But Possible Moderation
Is it your understanding that 2-73 can be used in pregnancy to correct chromosome X to prevent rare diseases like Fragile X syndrome and others that occur?
But, far greater....
...the potential exists for an unlimited disease altering treatment literally.
Draw One's Conclusions
Thank you for posting this abstract; which especially includes this excerpt:
The long-lasting effect of Anavex 3-71 in preventing cognitive decline of McGill-R-Thy1-APP rats, even after a wash-out period would suggest some preventative, disease-modifying, properties of the compound over the AD-like amyloid pathology.
Carcinogenicity Won't Be A Factor
Tests for carcinogenicity (cancer-causing) and genomic disruptions are standard preclinical tests for proposed new drugs, conducted in a host of organisms. If they haven't been conducted and their results are not available to the FDA, chances of a New Drug Approval are essentially nil.
The Ames Test is the first one, followed by lower animal exposures of the proposed drug, such as tests on Caenorhabditis elegans, a common lab nematode. Then, long-term tests in animals (lab mice, rats). Finally, there is the monitoring of any genomic disruptions (mutations, changes in DNA) in the Phase 1 human trials.
Search all of the literature on blarcamesine in organisms, whether bacteria or animals. I've never seen a single discovery or incident of blarcamesine-induced or -associated carcinogenicity or induction of mutations of any sort. If any are published, please post them.
To the contrary, blarcamesine's favorable modulation of gene expression by its enhancement of chromatin functions tends to obviate against the aberrant mechanisms involved in the genetics of neoplasms (cancers). The FDA review board will be impressed with the absence of evidence or incidents of any carcinogenicity related to blarcamesine.
Actually, many approved drugs are known to be associated with or to induce cancers. Nonetheless, their therapeutic benefits outweigh the infrequent hazards of the drug's cancers.
Stunning.
Tanya’s body was far looser, she tends to get quite tight. She seemed to be far more aware of things. Where she was looking around, far more interested in the things around her. Her legs, for example were operating far better on her own. She needs two care givers to walk her but her legs were operating far better on her own. You didn’t have to pull her along, she was quite willing to do it herself, but, holding on to the two carers.
No Concerns
I, too, have been buying AVXLs since 2017, in small incremental lots. Yes, the share price has been up and down over that time. Today, the share price, like the market itself, is trending down. Right now, I have it at $7.70. My holding is worth 2.6x what I paid for it. I’m settled and satisfied.
But let’s check back at the end of 2023. Or, even better, at the end of 2026, when millions suffering from various CNS diseases are being successfully treated with blarcamesine.
Now, or then?
I’d rather suffer paper losses now than risk not owning any stock when there’s a surprise PR one morning that the FDA has approved the drug for Rett, etc.
Give us further guidance, please.
Preclinical studies in murines can be indicative of response in humans and encourage clinical trials, but they far from offers guarantees of success in humans as experienced biotech investors and biologist will know - well from experience .
Eventual veterinary applications.
I think the S1-R is far more than a Human Health drug.
Check back when human trials are completed.
Don't forget what Dr. Randi Hagerman said about 2-73 and her expectations of a 2-73 Fragile X trial.
Merely a letter. Next, clinical proof.
falconer--comment on recent peer reviewed Fragile X publication ???? Thanks !!
Nope. Not likely.
Maybe the Amyloid buildup thesis(root Cause of AD) will finally get the factual assessment it needs.
New Evidence for Blarcamesine-induced Autophagy for Alzheimer’s
Evidence mounts. Alzheimer’s is not caused by “amyloid buildup outside of brain cells.” A new paper finds that in Alzheimer’s, lysosomes, filled with acidic enzymes involved in the routine breakdown, removal, and recycling of metabolic waste from everyday cell reactions, are dysfunctional.
https://www.eurekalert.org/news-releases/954383
This particular autophagy, removal of wastes inside cells, is compromised, which allows the accumulation of toxic wastes inside the cells, thereby disrupting normal cell functions. In brain cells, Alzheimer’s results.
Here are the definitive statements:
“Our results for the first time sources neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears,” says study lead investigator Ju-Hyun Lee, PhD.
“Previously, the working hypothesis mostly attributed the damage observed in Alzheimer’s disease to what came after amyloid buildup outside of brain cells, not before and from within neurons,” says Lee, a research assistant professor in the Department of Psychiatry and NYU Langone Health and research scientist at Nathan Kline.
“This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression, because the brain cells are already crippled before the plaques fully form outside the cell,” says study senior investigator Ralph Nixon, MD, PhD.
“Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons,” says Nixon, a professor in the Department of Psychiatry and the Department of Cell Biology at NYU Langone, as well as director of the Center for Dementia Research at Nathan Kline.
Download or use an installed spreadsheet program.
"Punch it out on a spreadsheet"--so where to find spreadsheet---no see here !!
Quick bucks? Or long term investment?
my point is that even with the setup as it is I don't see how share price can sustain higher if there is no imminent approval.
This is a new biotech stock. No guarantees.
As doc had mentioned there is not even any guarantee that we are powered enough for approval in AD; PD is going to take a while, and RETT which was touted as getting approval by mid 2022 is now looking at mid 2023 at best. How is that going to translate to a higher share price.
Punch it out on a spreadsheet.
Calculate both the high and low possibilities.
I’ve created a detailed spreadsheet into which I’ve added various ranges of potential Anavex data. One column has a lengthy list of potential diseases and conditions any of the Anavex drugs may eventually treat (or prevent). In the next range of columns the numbers of cases of each disease in various countries and regions of the world. Then, in the next columns potential annual revenues from each of the numerous patients. In the last columns, arithmetic products when the appropriate cells have been multiplied. In the next to last column, resultant AVXL share price calculations. In the last column, the resultant value if my AVXL position for each disease or condition.
I’ve tried to rank the diseases by probability of sales approval, from the ones yielding the lowest annual revenues (such as Rett) on down to those with the biggest annual revenues (prophylactic and anti-aging applications).
In all cases, to get a picture of the ranges of possibilities, I’ve got lowest-possible numbers on up to highest-possible numbers (where such a range could be possible).
Of course, the far-right column calculates the worth of my modest AVXL position for each disease, condition, and application. At the lowest right is the sum-total value.
For those not moderately skilled in spreadsheet creation, none of this has value. But all calculations are elementary arithmetic. Cell A-1 times cell B-1, etc.
And, yes, my spreadsheet lays out numbers in the range of those just posted by JWC3. Far too big to quote here; not believable. I have only a few thousand shares of AVXL, purchased over the years (at an average base price of $2.91), knowing full well that sooner or later Anavex Life Sciences Corp could go bust; that I could lose my entire investment in the company. Diligently, I’ve used only fractions of the discretionary dollars in my budget. If Anavex goes bust, my life is unchanged.
If blarcamesine gets approved for just one or two diseases, the beneficiaries of my estate will be well rewarded. If most or all of the listed diseases and conditions get approved, my estate will have generational wealth, much of which will go to appropriate philanthropies.
Again, the potential blarcamesine prophylaxis factor.
All 53M 60yo will be taking A 2-73 soon, all living longer and feeling better!
Clinical testing of blarcamesine for insomnia.
In Pharma trials, is it possible to submit a NDA based on secondary endpoint being successful? Sleep in all of these trials has always been a secondary endpoint,....
New; psychiatric and psychopathology applications for blarcamesine.
I wonder if treating the insomnia would decrease Alzheimers's agitation.
An insomnia backdoor for blarcamesine against Alzheimer’s?
Wouldn’t this be curious, where sooner or later (well, later) blarcamesine is tested in a big double-blind clinical trial to gain regulatory authorization to sell and use blarcamesine to treat just the insomnia of Alzheimer’s? The new patent suggests this could be possible.
In that case, the only thing that needs to be shown (in the clinical trial) is that blarcamesine moderates or even eliminates the insomnia problems associated with Alzheimer’s disease. All of the other progressing symptoms of the disease would be unaddressed and play no part in the drug’s therapeutic use approval. Sleep, only, would need to be improved. Big Pharma could continue its Holy Grail quest for a drug that treats beta-amyloids, tau tangles, etc.
Of course, after a few months of thousands of Alzheimer’s patients getting restful blarcamesine sleep, it will be astonishingly noted that other disease symptoms have begun to abate. “Getting good sleep really helps Alzheimer’s patients” it will be proclaimed.
Of course, the patients will have to continue with their daily blarcamesine pills; otherwise, the Alzheimer’s would “return.”
The amyloid causation motif would continue unabated. But blarcamesine for Alzheimer’s insomnia would become the standard of care. Who’da thought?
Now more strongly, the Anavex insomnia treatment factor.
Another Anavex milestone. The new patent, using blarcamesine (Anavex 2-73), directs the drug to treat the insomnia typical (and causative?) of Alzheimer's disease. But read further through the patent in the 10 "Examples." Applications beyond Alzheimer's.
Of course, there are existing drugs for insomnia. But their side effects are almost as bad (or worse) than the effects of the insomnia being treated. With Anavex 2-73, no side effects.
Ponder the market size of Anavex 2-73 when used for those with the insomnia of Alzheimer's, and all the other conditions noted in the ten Examples.
Some time ago I claimed that the treatment of the various forms of insomnia would be a major revenue source for Anavex. This patent moves things decidedly in that direction. (Yes, there must be big human trials. They will happen.)
Thanks. That clarifies the issue.
My issue is not with the science. It’s with senior (mis)management and the clubby BOD.
Except, of course, for Anavex.
Just because something hasn’t worked yet doesn’t mean it won’t.
Yes, thanks for posting those papers. Here’s the “biochecking” I did.
In the first paper, I found this statement to be definitive: “Sigma receptors (sRs) are considered promising targets for treating different heterogeneous medical conditions, including cancer. (6-8)”
In the second paper, I found this statement to be instructive:
“Human mammary adenocarcinoma, colon carcinoma and melanoma cell proliferation was inhibited by sigma-1R ligands, such as haloperidol, DTG and SKF-10047, in vitro cell culture experiments (13).“ Might blarcamesine, as a unique sigma-1 ligand, actually be therapeutic for the referenced cancers? Needs to be tested.
In the third paper the topic was investigated using off the lab shelf, self-sustaining human breast cancer cells (MCF-41 cultures). This statement is revealing:
“The sigma-1R proliferative function was examined by comparing the proliferation rates of a sigma-1R-overexpressing line, MCF-41 with a sigma-1R-defective line, MCF-7, in culture media with various serum concentrations. The results demonstrated that MCF-41 cells grew significantly faster compared with MCF-7 cells, indicating a proliferation-enhancing receptor function.”
Clearly, in this in vitro (lab dish) study, certain sigma-1 receptor ligands (blarcamesine was not tested) induced cancer proliferation. For blarcamesine, this needs study. Someone needs to culture MCF-41 human breast cancer cells in the presence of blarcamesine, to determine how that molecule might affect MCF-41 cell cultures. Only three possibilities. It promotes their growth. It inhibits their growth. Or, has no effects on them. Won’t be a difficult study to conduct, as MCF-41 cell lines can be purchased and cultured. Let’s see how that study turns out.
Of course, if positive, the blarcamesine label might well make this statement, “Not for use in women with breast cancers, particularly of the MCF-41 genotype.”
The fourth paper stated:
“It has been demonstrated that sigma1R is involved in proliferation and adhesion of cancer cells.” Very important statement, raising the specific question, does blarcamesine involve itself in the proliferation and adhesion of cancer cells?
As typical in such discussions, I state, “Further studies are needed.” Bring ‘em on, someone. Obviously, no one has found definitive blarcamesine-induced cancers in any test animal. All of the studies above were in vitro, in lab dish studies. Let’s learn of blarcamesine-induced cancers in real organisms. Given the extensive murine and other animal tests of blarcamesine, curious that no cancers have yet been reported. Very likely, the molecule’s unique activation if the sigma-1 receptor actually suppresses oncogenic mechanisms and processes; it restores youthful, healthful homeostasis.
So far, no blarcamesine oncology results from real animals, human or otherwise. Let’s see what develops.
Researchers haven’t found blarcamesine cancers.
SIGMAR1 protects healthy gene expression through Chromatin Remodeling
(pre-transcription
That should be cancer protective by reducing the number of errors in transcription which are thought to be a source of cancer mutations.
The ‘potential’ carcinogenicity risk of blarcamesine.
The risk of over-expressing S1R might need careful consideration
How so?
A potential truth is that the long term side effect of A2-73 could be increased risk of cancer.
Extremely important new technology.
This is a patent [not an application] for the (a) diagnostic-treatment process or method which will be used to examine, measure, diagnose, analyze, treat, then reanalyze pt. changes and to iteratively resolve pts. CNS disease(s) /disorders and symptoms.
Yes, but one thing will be terminated.
My only change would be to use the word completed rather than terminated regarding the Phase 2b/3 early Alzheimer's trial. terminated has a negative connotation.
My Reasons
What odds are you giving for successful phase 2b/3 AD?