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"Secrets" perhaps only to those who never took or paid attention to a freshman biology course.
I'm revealing nothing that any of my former high school biology students would have learned.
All standard, well-understood biology.
What's not understood is just how, and how well, the Anavex molecules re-connect the cellular organelles.
But that's not important, even to the world-class molecular chemists studying the Anavex molecules. For owners of the intellectual property (patents, etc.) of the molecules, or for prescribing clinicians, or, for treated patients, or for AVXL investors, the only things that matter are: a) is it safe (few or no side effects), and b) does it work, does it stop or reverse symptomatic progression of Alzheimer’s?
We know what's important. No side effects; and the stuff works. Other knowledge or understand is superfluous.
The misfolded proteins at the root cause(s) of Alzheimer's and the other Anavex-targeted diseases are not the amalyoid complexes or tau tangles. Both of those are proteins, but they are not functional; primarily protein wastes, that in normally functioning (homeostatic) cells are cleared, not allowed to accumulate.
The proteins the Anavex molecules facilitate are enzymes. Enzymes are complex, precisely-folded proteins that cause chemical reactions to occur. When the right chemical reactions are occuring --- only when the right enzymes are present --- cells function properly. Few cellular reactions can occur without the proper reaction-mediating enzymes. DNA controls the making of enzymes, which, in turn, control cell chemistry.
Interestingly, many (perhaps most) poisons, particularly heavy metals, are lethal because they bind to essential respiratory enzymes, stopping respiration, the conversion of sugars or other feedstocks into ATP the mitochondria. Without mitochondrial production of adenosine triphosphate (ATP), human cells die.
If enzymes are misfolded, they can no longer bind to the molecular substrates that the enzyme controls. Enzymes are like molecular keys, the substrates like locks. The enzymes temporaroy bind to the two substrate molecules, causing them to bind together or react.
Enzymes are folded in the rough endoplsamic reticula, which, normally, are connected to mitochondria, which supply ATP, powering all of the reactions needed to fold the enzymes. In Alzheimer's, rough endoplsamic reticula have pathologically disconnected from the mitochondria, so new enzymes are misshaped, badly folded. They no longer properly control normal cell reactions, just as a bent key won't turn a lock.
Anavex2-73, wonderously, in low concentrations, and without side effects of consequence, re-connects the rough endoplasmic reticula with the mitochondria. Neuron homeostasis, normal chemistry, is restored. Properly-folded enzymes can then dissemble and eject toxic waste proteins such as amalyoid plauqes and tau tangles. Neurons function normally; Alzheimer's symptoms are checked or abated (or, if administered early-on, prevented).
I've added range bars to indicate how the Anavex2-73 cognition chart would have looked like if at least one participant would have not responded positively to the drug, if symptomatic worsening would have progressed typically. Notice how the lower range bar descends as the trial progresses, indicating at least one person untreated by A2-73. (Of course, that's not what happened. Each participant had favorable results; the actual range bars remained close the mean, with no poorly-treated outliers)
Well, the range bands DO indicate universal symptomatic stabiliazation or improvement.
How you can interpret them differently, with no low range bars markdely below the mean data points reveals an ignorance of common statistical data presentation. Should anyone wish to continue to believe otherwise, he is welcome to that view. Those of us who have had elementary statistics know better.
In fact, that's exactly why range bars are included, to indicate the diversity of scores that were averaged to attain the mean (average) data points. With a long vertical range bar line, the reader knows scores were highly divergent, not centrally clustered, as they are with the Anavex2-73 cognition data.
If even one of the trial participants had typical symptomatic worsening during the course of the trial, each range bar would have gotten longer, descending ever farther beneath mean data plot, indicating that person's worsening condition. Didn't happen. Every participant had a favorable result (stabilization or symptomatic reduction).
There is no plainer way to present the plotted data. Just gotta know the rudiments of statistics.
SEC "Safe Harbor" statement rules restrict what companies can say or project about their share's present or future value.
Here's the Anavex Safe Harbor Statement:
Safe Harbor
This presentation contains forward-looking statements made within the meaning of the
Private Securities Litigation Reform Act of 1995 by Anavex™ Life Sciences Corp. and its
representatives. These statements can be identified by introductory words such as
"expects," "plans," "intends," "believes," "will," "estimates," "forecasts," '"projects" or
words of similar meaning, and by the fact that they do not relate strictly to historical or
current facts. Forward-looking statements frequently are used in discussing potential
product applications, potential collaborations, product development activities, clinical
studies, regulatory submissions and approvals, and similar operating matters. Many factors
may cause actual results to differ from forward-looking statements, including inaccurate
assumptions and a broad variety of risks and uncertainties, some of which are known and
others of which are not. Known risks and uncertainties include those identified from time to
time in the reports filed by Anavex Life Sciences Corp. with the Securities and Exchange
Commission, which should be considered together with any forward-looking statement. No
forward-looking statement is a guarantee of future results or events, and one should avoid
placing undue reliance on such statements. Anavex Life Sciences Corp. undertakes no
obligation to update publicly any forward-looking statements, whether as a result of new
information, future events or otherwise. Anavex Life Sciences Corp. cannot be sure when or
if it will be permitted by regulatory agencies to undertake clinical trials or to commence any
particular phase of clinical trials. Because of this, statements regarding the expected timing
of clinical trials cannot be regarded as actual predictions of when Anavex Life Sciences Corp.
will obtain regulatory approval for any "phase" of clinical trials. We also cannot be sure of
the clinical outcome for efficacy or safety of our compounds. Potential investors should refer
to the risk factors in our reports filed on Edgar.
Consequently, astute retail investors must determine for themselves the validity and applicability of company-provided information and data.
Anavex had to use the phrase "seem to" when stating their clinical results. Truthfully (prohibited by the Safe Harbor law) the phrase should have been "do indicate."
Lawyers and legal lanquage "protect" us. Aren't we thankful?
The arcane and inscrutable investment machinations of hedge funds, “financial advisors” and the like are far beyond anything I know.
How come far more astute investment advisors fail to see what I see in the Anavex data? Well, they aren’t ignorant. Most of them had an elementary statistics course in their MBA or other training. The precise Anavex data are not a mystery to them — the data, perhaps, are a threat, jeopardizing self-serving positions they have or wish to take regarding Big Pharma investments.
I’ll let others speculate on all of that. That’s why I indicated “retail Anavex investors.” We common citizen owners of Anavex shares, with long positions, have parsed the available data and are very comfortable with our positions. We won’t be selling anytime soon. We can see that the Anavex story will develop over years, not months; and has the potential to change 21st-century medicine even more than antibiotics did in the last century.
Efficacious treatment of Central Nervous System diseases, as with (soon enough) Alzheimer’s and Rett Syndrome, alone will be transformative. I take a longer view, where Anavex technologies will be used for geriatric disease prophylaxis. That’s a big, long story too detailed to describe here. Later.
Could it have been bad clinical design, or cherry-picked data?
Kid2 intelligently asked, “Could it possibly be due to a flawed trial design? Could it possibly be due to biased data collection? Could it possibly be due to ambiguous data presentation?”
A understanding of the answers to these cogent questions should bring clarity as to why I and so many other retail AVXL shareholders are certain of Anavex’s successful future.
Were the profoundly successful clinical results of the trial because of bad clinical trial design? Did Anavex construct the trial so that only positive results might emerge, making the drug “look good,” when, in fact, actual patient experiences were not as presented?
This would be an allegation of profound fraud, for which the Securities and Exchange Commission would take great offense. It’s both academic and fiducial fraud.
And, it did not occur. The presented trial results are true and accurate.
Examine the upper plot on p 29 of the CTAD presentation (http://www.anavex.com/wp-content/uploads/CTAD-Anavex-December-2016-2.pdf).
This a plot of the MMSE (Mini–Mental State Examination) scores. The MMSE score is a widely-used, professionally-accepted determination of cognitive impairment in neurodegenertive diseases, particularly Alzheimer’s. The questionnaire (not generated by Anavex) is here: http://www.heartinstitutehd.com/Misc/Forms/MMSE.1276128605.pdf
The instrument to determine the state and progression of cognitive impairment during the Anavex2-73 clinical trial was as accurate and precise as possible in modern psychology.
The trial was conducted by PhDs and MDs whose professional careers rest upon use of accepted and replicable clinical methodologies. The presentation was vetted and pre-accepted for presentation at the 10th Clinical Trials on Alzheimer's Disease (CTAD) conference, conducted by world-class Alzheimer’s researchers and clinicians. As in similar scientific conferences, statistically or methodologically questionable data are simply not allowed to appear. The accuracy and applicability of the Anavex data were thoroughly vetted. CTAD is no eighth-grade science fair with sketched data on some cardboard displays.
Were the data “ambiguous?” No. They were very precise, within very narrow range bands. Someone asked how I could be certain that every single trial participant demonstrated symptomatic stabilization or improvement. Again, look at the plots on p 29. Notice the black vertical lines and bars at each data point. They indicate the range of all of the assessed scores at that timepoint. Had there been a few whose symptoms did not stabilize, whose cognition scores continued to worsen (the case in all other Alzheimer’s drug studies longer than three months), the range bars toward the end of the study, on the right would have been long, descending sharply downward, away from the yellow mean score line.
For those who know how clinical trials are conducted, and how to interpret plotted clinical results, the CTAD Anavex data couldn’t have been more positive. Anavex2-73, when administered over a year to those with mid to mild stage Alzheimer’s, will either terminate symptomatic worsening, or even reduce it. This happened in all clinical trial patients, without exception. As presented before (post 86140) the chances of these results occurring by fortuitous happenstance, not actual drug efficacy, are nil.
Thank you for asking.
I have no particular knowledge of the neuropathic chemistry of Rett Syndrome, nor how the Anavex drug might be theraputic. The Anavex researchers clearly have investigated this and have very good reasons to believe efficacy can occur.
As in virtually every other human disease Anavex drugs will be tested for, the legitimacy of murine (mouse and rat) models to determine putative human efficacy comes into question. Mice are not men (well, people); but their nerve genetics and chemistries can be almost identical. Transgenic murines may be used, where the actual human genes of the relevant pathologies have been inserted into the genomes of the rats or mice being tested. Clinical results from these animals are extremely likely to be replicated in equivalent human trials, in people with the same genetic pathologies.
I made no "assertion" of a non-Gaussian distribution of clinic results. There was none, whether I putatively asserted such or not.
The results were not bell-shaped, where a few did well, a few did poorly, and the majority responded moderately. That's a bell-shaped curve, expected when variability is random.
In the Anavex2-73 trial, there was 100% stabilization or improvement of symptoms. Nothing could be plainer: Anavex2-73 either stablizes symptoms (no Standard of Care drug today does that), or it acually improves symptoms. There were no exceptions. Not a single trail participant experienced typical symptomatic worsening.
Your perspectives on the probabilities of 100% symptomatic stabilization or improvement in all (n=25) trial participants is invited. (See my post 86140.)
How could those profound efficacy results, albeit from a small number (n=25) have occurred unless Anavex 2-73 actually did cause them? The probabilities of this occurring by chance are impossibly small, as I've described in the post.
The results were not an expected Gaussian (bell-shaped) curve. There were no "non-responders" among the 25. Every single participant received a benefit that exceeded the current Standard of Care, where Aricept is able, for a short period, to merely slow the otherwise universal decline in function.
Anavex 2-73 either stabilized or actually improved mental function for every single trail participant. No exceptions.
Should a trial of a larger cohort be conducted, the same results are statistically certain to occur.
Can’t imagine a better new drug approval, under Trump and the Cures Act.
Perfect sort of thing for Trump to Twitter about: “My FDA just approved a cure for Alzheimer’s. It’s safe, and it works. First new drug from Cures Act. I'm gonna make it work for us!”
[I know, A2-73 is a successful chronic treatment, not a “cure.”)
Will watch (with a bit of glee) for an announcement-generated short squeeze (should it ever happen).
The abstract Conclusion says it all --- but in a rather timid manner (required for publication; accepted scientific understandings must be delicately and incrementally assailed).
Here's the truth of the study, with a precisely accurate version of the Conclusion (where I've deleted the timid words and inserted the precise ones, in caps):
The safety of ANAVEX2-73 was assessed and MTD was determined. Despite not optimal dosing, both cognitive and functional performance is sustained over at least 12 months, INDICATING that the effect of the compound does not worsen AD symptoms with repeated dosing. In a progressive degenerative disease this is a PREVIOUSLY UN-DEMONSTRATED, positive outcome. The data support further clinical development of ANAVEX2-73 and preparation for a larger confirmatory study is underway.
As with the data and plots presented at the CTAD event, the Anavex2-73 human clinical data are revolutionary. Nothing like itever before. Just how (or why) so few want to neglect or dismiss the fact that simply no other drug has ever, to any degree, however minor, ever demonstrated even a fraction of the favorable outcomes A2-73 did in Alzheimer's sufferers is beyond me.
The statistical validity of the findings are unassailable. You can't get a year-long placebo effect in every 25 Alzheimer's participant.
Post a link to the abstract, please (so we are all reading the same material).
Many Zeros
Several topics in the air here. All appropriate, to be considered by all.
There are continuing questions (by some) that the very positive symptom stabilizations or improvements during the recent clinical study can not be used because of the small trial participant numbers (n=25). It is stated that proper clinical trials require much larger populations (say n=300), in both a placebo or control arm, and a parallel experimental arm. Half of the participants, say, 150, in the control arm take a daily pill visually and palatably identical to the Anavex-containing pills the 150 in the experimental arm are taking. Neither the patients nor the doctors or nurses know who’s getting what; only a locked computer recording pill lot numbers. At the end of the trial, the blinded computer data are unlocked and matched against symptoms assessed during the trial. Appropriate statistical procedures are used to crunch and connect the data, which are then plotted (as in the CTAD presentation).
As a biologist, I know this well. The study must be double-blinded (neither patients or doctors know) so only authentic drug-caused results appear. Minimization of placebo effects.
If I were a reviewer of an Anavex clinical trial on humans, to be published in a peer-reviewed journal, all of the above (and more) would be required. Journals don’t like data appearing that were by chance or poor trial design showing unrelated or complicating drug-related phenomena. Bad numbers reveal bad science.
But, when I made my several AVXL purchases (last one just after parsing the CTAD data plots), I did not act upon my knowledge of strict clinical conduct rules, used to obviate erroneous by-chance or bad-influences results. I was (and am) confident in my equity purchases for the following arithmetical reasons.
Although the final trial cohort number was very small (n=25) — normally too small to offer a high-probability rendering of data accuracy — I was convinced otherwise.
Simply stated, all of the participants had one of two things transpire during the clinical period: they either remained symptomatically static or stable, or, actually had symptoms improve. Not a single instance of normal symptomatic decline. How could that be?
Only two explanations. Perhaps by remarkable happenstance, against all odds, 25 trial participants (the entire cohort in contention) just happened to be Alzheimer’s patients who so rarely show no decline over the many months of the trial.
Or, the cohort included typical Alzheimer’s patients, for which symptoms would normally get worse, but they didn’t because of Anavex 2-73 efficacy.
Which was it? An exceptionally atypical sampling of Alzheimer’s patients, all of which either held their symptom progression at bay or even suppressed them, regardless of any putative inefficacy of A2-73; or, do the simple sampling stochastics (probabilities) make the former explanation improbable?
It’s the latter. For those questioning the validity of the trial’s results, attributing them to pure happenstance, where an atypical number of Alzheimer’s patients got included who had rare abilities to innately stop or reverse symptomatic progress, let’s do simplest statistical probabilities for such an outcome.
First, we have to know the fraction of Alzheimer’s patients who (at the mid to mild stages of the disease, as per trial participants) can innately remain symptomatically stable for 52 weeks (or whatever the actual trial period in question was). Frankly, I’ve never read or learned of any spontaneous remission of Alzheimer’s symptoms. Once they appear, they continue to progress undiminished and in ever greater magnitudes.
But, I’ll presume that one percent of Alzheimer’s patients DO have this capability; that’s one out of a hundred, from time to time, who experience year-long remissions in symptom severity increase. For a year, they stay stable, as show on the CTAD plots.
What, then, are the chances of including everyone (n=25) in the trial cohort with such a trait? If the cohort had but one person, the chances of such results would be four percent, one out of 25. But we had 25. What are the chances of stochastic (pure chance selection) inclusion of 25 such symptom-controlling people? Multiply each individual’s chances with all the others.
The chance of this happening — if one out of a hundred Alzheimer’s patients have the rare ability to spontaneously yield flat or ascending favorable symptom data points — is 1E-50. To get 25 of these patients, it’s the number 1 with 50 xeros after it.
But, maybe in the unique population of Alzheimer’s patients the clinical cohort was drawn from, one out of ten had the unique symptom-controlling traits. Much better chance of Anavex inefficacy, then. How much? Just 1E-25. The number one followed by 25 zeros.
I forked over my few hundred dollars to my online brokerage and made my AVXL purchase with the greatest confidence that Anavex 2-73 actually does suppress or reverse symptomatic progression in Alzheimer’s. The many zeros tell it all.
The use of Anavex molecules for diseases beyond the three currently in consideration (Alzheimer’s, Parkinson’s, and Rett) is a fuzzy proposition — but one that should be investigated.
The multiple ways Anavex molecules restore (or create) cellular homeostasis, proper, normalized function, are still being parsed out. The re-connection of disconnected rough endoplasmic reticula to mitochondria, which is the primary mechanism (but not the only one) that allows A2-73 to suppress Alzheimer’s symptoms, is now well understood and characterized. Mitochondrial dysfunction is almost universally common among Central Nervous System diseases, and many others.
In reading the many obscure technical reports on Anavex molecules, so far pretty much just in diseased rats and mice, it’s clear the molecules do restorative things heretofore never imagined or envisioned; far beyond just the ER-mitochondrial phenomena. The preliminary murine data showing efficacies against other CNS diseases (such as the one I have, hereditary spastic paraplegia), including cancers, cardiovascular conditions, and psychiatric anomalies are just stunning. The data look too good to be true. Anavex molecules appear to be “cure alls,” dare I say (well, “treat alls”).
Now some real, hard clinical data, both murine and human, will need to be generated to determine with some precision just what Anavex pipeline drugs (or their emerging analogues) can effectively treat what diseases at what stages at what dosages at what durations. The stuff is safe, with virtually no side effects. Throw Anavex molecules at diseased animals and see what happens. Based upon the unique, facilitating, restorative biology of Anavex drugs, I will not be surprised to learn in the coming year of all sorts of potential, new treatment applications.
Lastly, as I’ve so rather frequently mentioned, the best and most rewarding use of Anavex technologies may prove to be age-related disease prophylaxis. Pop 500mg of Anavex 3-71 everyday with breakfast, and chances of age-related disease plummets. For genetically defective infants, use the drug to epigenetically suppress bad genes.
Gonna be exciting to watch how this plays out.
I didn't copy the report. As I recall, it was a brief mention of Anavex and its new drug candidates.
From that, I went to the Anavex website and learned the technical details of their molecules.
Sorry, haven't taken the time or effort to parse out that company's molecular pathways to treat Parkinson's. Right off, there's a lot of stuff there I don't understand; have no experience with.
I cannot give any useful advice on the company or its molecules; other than that they are clearly very different from those of Anavex (whose molecules and cellular functions I do understand with useful sufficiency).
As a biologist, I scrutinize a large number of daily techincal science reports on the Web.
Saw a report of Anavex's transformative technology last summer.
Checked it all out, and it was revolutionary; brand new neuron treatment stuff.
Molecularly Very Different
From the company's website:
vTv has identified novel non-electrophilic Nrf2/Bach1 modulators that can activate nuclear factor-E2 related factor (“Nrf2”) and inhibit Bach1 (the Antioxidant Response Element (“ARE”) transcriptional repressor) leading to potent activation of the Nrf2 pathway. The results from the laboratory of Dr. Thomas suggest (1) Bach1 may be a promising novel target for drug development against Parkinson's disease, and (2) vTv's compound, HPPE, may protect against nigrostriatal dopaminergic neurodegeneration by virtue of its ability to activate neuroprotective Nrf2/ARE genetic response in a preclinical mouse model of Parkinson's disease.
************
Not at all related to or similar to Anavex molecules. It might well be a useful Parkinson's treatment. If so, well and good.
I'll stay with Anavex, however.
Out of curiosity, what other equities are you invested in?
No Other Equities of Significance
I am not a practiced equity investor. I do own a few other companies' shares; none of which presently are yielding any useful returns. Must be honest about that.
No one, I hope, regards my postings as financial advice; merely the presentation of (mostly) scientific information — which I hope can help more financially astute or gifted parties make useful, rewarding decisions about Anavex.
"...with your strong conviction why you're not backing up the truck."
I have no truck.
As a retired teacher, I'm living on an adequate but not excessive pension. I keep precise financial records, and allocate a small fraction of my non-discretionary funds for "speculation."
Am I speculating on Anavex by buying and holding some AVXL shares? Of course. Every equity is a speculation. None are assured of growth or even survival. One must make informed decisions about such investments. I've done that with Anavex.
I'm not a trader of AVXL or sny other equity. All of the "buy low, sell high" stuff is a financial sport I'm in no position to engage in. I don't read or trade on charts. I don't trade all, actually. Anavex for me is a classic "buy and hold."
With Anavex (and the few other equities I own), I take a long-term perspective; looking for rewarding dividends in some years in the future, with associated high share values --- which most likely will pass on to my heirs.
“...why have no others been approved to treat CNS, or few other diseases?”
Simple. Getting a new class of drugs to market is extremely difficult. Takes years, with multiple big clinical tests, in multiple stages. FDA approval rules are extremely complex and exhaustive.
And, there are intellectual property rights concerns. Who’s going to spend several years of ones lab life experimenting with a molecule protectively owned by a commercial entity? Doesn’t happen.
Things got this way, pretty much, because of the thalidomide difficulty. Thalidomide was marketed, over the counter, in Germany in the 1950s. Wonderful stuff. Suppressed all sorts of psychological problems. But because it had never been tested for teratogenicity, disruption of fetal development, thousands of European babies died or were born without limbs. Be assured, FDA requires teratogenicity tests of all drugs (tested on animals, which have the same fetal development mechanisms as humans).
Fortunately, at the time, there was an FDA official, Frances Oldham Kelsey, who did not rely on information from the company. She single-handedly prevented thalidomide use in the US, even though FDA regulations were not as strict then.
Everyone is free to conduct thought experiments. Ideas cannot be patented or protected. But the testing and use of patented molecules is legally protected and restricted.
Not Just Yet.
In fact, most of my postings, particularly the ones anticipating marvelous futures for Anavex and the users of its to-be-approved drugs are open conjectures. Yes, should things resolve as I hope — with eventual FDA approval of either A2-73, or better, A3-71— I have solid-science reasons to believe my conjectures will eventually come to pass.
Presently, however, things Anavex are still rather nebulous, with no certain, clearly visible outcomes. Lots of postings here on executive remunerations, potential buy-outs or collaborations, patent validities and periods, and even (perplexingly) questions regarding the validity and applications of the clinical results posted at the CTAD conference.
For me, presently, all of the above (except for the CTAD presentation) is irrelevant. I’ve purchased my few AVXL shares, and will now just sit on them. Frankly, I don’t anticipate that anything substantive will happen until sometime into the next quarter, in Jan or Feb, at the earliest.
Yes, some official indication that one of the Anavex molecules will be released for use under “compassionate care” provisions, or an announcement of a favorable Big Pharma collaboration involving larger clinical trials and subsequent marketing and revenues projections will generate broader retail and institutional investment interest. Perhaps the share price might ascend toward $10 or so.
Nice, when that happens. Were I to sell at ten bucks, nice little profit for me, having gotten in under five bucks.
But instead of the daily or weekly perspectives that predominate here, I continue to look to the distant horizons for Anavex. As I’ve noted, I have a moderate neurodegenerative condition (hereditary spastic paraplegia, HSP) for which an Anavex drug has been shown in a transgenic rat study in France to eliminate symptoms. Some would claim my support of Anavex is overly based upon a personally hopeful application. Not really. I’m a biologist. I taught human physiology and know a reasonable amount about neurons, their organelles, and intrinsic chemistries.
More than most who post here, I comprehend the unique, revolutionary molecular biology of the Anavex molecules. I marvel how so many wish to compare (and degrade) Anavex technology with the dozens of previous Alzheimer’s clinical results; all failures. That’s easy (but ignorant). Billions have been spent by others, and not a one a success. Therefore (when lacking a knowledge of neuron chemistry and physiology), Anavex simply can’t and won’t be any different.
I (and the Anavex and Biogen and other Big Pharma insiders) know better. The Anavex stuff is entirely different. Nothing like it before. It requires new, open perspectives on nerve science. Until Anavex, what the Anavex molecules do inside neurons (and other cells, too); the restoration of “homeostasis,” the restoration of normalized cell functions; was pretty much thought to be impossible. Not even envisioned. But the murine lab data (rat and mouse studies) and the recent human results (as incomplete as they might be — I think they are entirely adequate) simply show that the Anavex molecules do work, with virtually no side effects.
Again, however, nothing useful is going to happen just yet. I await Anavex developments. It will take longer than I’d prefer; but the science is too good. It’ll happen.
The Prospect of Anavex Prophylaxis
The CTAD symptoms response plots clearly showed that A2-73 did one of two things: either stabilized, maintained symptomatic progression, holding things at a stable, at-the-start level; or, even more significantly, it actually reversed mental and functional declines. Toward the end of the trial, participants scored higher than at the start.
Nothing on the shelves of pharmacies, nor anything reported from the labs and clinical trials of any other drug company has ever shown such favorable plots of clinical data.
Right now, all of us with an interest in both Anavex perspectives: relief for victims, and financial rewards for AVXL investors; are understandably focusing on what A2-73 has been shown to do for Alzheimer’s patients: hold them steady, or even improve their conditions. Alone, those results should prompt eventual FDA approval.
But as good as we can imagine those outcomes to be, I’m certain they will be eclipsed when, eventually, it is determined that the best and most effective use of A2-73 and A3-71 will be for prophylaxis, used to PREVENT the onset of Alzheimer’s, Parkinson’s, ALS, and other neurodegenerative central nervous system diseases.
If Anavex drugs can stop disease progression, or even reverse it to any degree after symptoms appear, there is every good reason to believe administration before symptoms appear could keep them chronically and sub-clinically suppressed at length. Take the stuff to keep any of the CNS diseases from ever starting. The cost savings and health benefits will be, without exaggeration, the best of any medical development since antibiotics changed things in the late 40s and early 50s.
Experts at the Vitamin D Council:
“Vitamin D toxicity, where vitamin D can be harmful, usually happens if you take 40,000 IU [yes, 40,000 IU, not 4000] per day for a couple of months or longer, or take a very large one-time dose.”
https://www.vitamindcouncil.org/about-vitamin-d/am-i-getting-too-much-vitamin-d/
Anavex as a New Aspirin
My posting here of this personal perspective diminishes (for some, anyway) my more evidence-based, substantive postings. Nonetheless, I’ll set it out.
I would so much wish to see a murine (rats) study of chronic administration of Anavex 3-71, to determine its effects on the onset and severity of aging. (A3-71 appears to be better than A2-73.)
Inasmuch as disrupted cellular homeostasis (normal cell functioning) is involved with virtually all neurodegenerative diseases (Alzheimer’s, Parkinson’s, ALS, et al. ), chronic administration of A3-71 has the potential of preventing or retarding the onset of any of these, if administered before any symptoms appear. Similar cellular dysfunctions amenable to Anavex therapies may be revealed in other major disease complexes, including diabetes, cardiovascular conditions, and psychiatric debilities (there already is preliminary lab animal evidence for efficacies in each of these).
So infrequently mentioned in discussions of Anavex drugs is their profound tolerability, the absence of any severe adverse effects. Simply put, Anavex 2-73 in the recent human trial simply had no disqualifying severe adverse effects; just a few, very minor side effects; which may well have been coincidental with other conditions, or normal disease state variabilities. For drugs affecting nerves and the nervous system, this is virtually unheard of.
The safety of Anavex 2-73 (and equally, A3-71, to be demonstrated more completely in new murine and human studies) is profound. Game-changing.
What if (as I expect) expanded human trials of either of these drugs reveals no adverse effects, in the manner of, say, aspirin? Yes, aspirin can cause intestinal bleeding and minor blood loss. But its benefits far out weigh those minor (well, sometimes more considerable) side effects.
As I’ve mentioned before, the prospect of every 40- or 50-year old popping a prophylactic (disease preventing) Anavex pill each morning at breakfast is not at all eventually out of the question — with profound chronic health benefits. An anti-aging therapy, as it were.
Try it first on 100 rats, fifty getting glucose in their water drips, and 50 getting some Anavex 3-71. Simply record the course of their diseases as they age, along with a quantification of any side effects. As with humans, the frequency and incidence of geriatric conditions in aging rats is well-known. They get old and diseased and mentally reduced as do we with age. I’m betting that one or two of the Anavex molecules will prevent or retard the onset of old-age symptoms in rats — then, in humans.
Ponder the social and fiscal implications, should this be so.
Implications of the Anavex Pipeline
This is by no means any sort of exhaustive discourse on the other molecules (beyond Anavex 2-73) in the company’s pipeline; merely a short presentation on my perceptions of such.
By now there is a rather extensive availability of papers and presentations on the science of Anavex 2-73. Needless to say, this molecule holds the strong promise of being able to effectively stop, or even reverse, the course of Alzheimer’s disease progression. It will be able to do this because it a) has virtually no side effects, and b) uniquely, unlike any other drug in any company’s pipeline, restores normalized neuron chemical functions, reverting neurons to normal pre-disease states, the so-called “homeostasis.”
How Anavex 2-73 does this has been previously explained. It should be known by new Anavex equity investors; as it is by Big Pharma executives and researchers. The cellular and chemical methods involved with Anavex 2-73 safety and efficacies are unique, and will prove, I believe, to be utterly revolutionary.
Now, after spending some time scrutinizing the available documentation on the other molecules in the Anavex pipeline, particularly Anavex 3-71, which appears to be everything and much more than A2-73, it appears to me that Anavex Life Sciences Corp. will be able, in time, to simply solve a massive number of modern health problems, not just Alzheimer’s.
In fact, most of the symptoms of these diseases occur because normal cell functions, whether in neurons, heart cells, or many others, come about because intracellular communications and organelle connections have been disrupted. Simply, Anavex molecules put cellular things back together again, allowing normal, non-disease functioning. Sounds too simple and too good to be true. But the mechanisms by which homeostasis is restored by each of the Anavex pipeline drug candidates have been rather precisely determined, or at least, observed, by substantiating testing in lab rats and mice.
Frankly, were I a corporate research director for a Big Pharma (I’m not; I’m a field biologist and former biology instructor) I’d do every thing I could to get access to all of the Anavex molecules, for development into remarkable new drugs, which have gigantic market sizes
The implications, then, of all of this? Be assured, any discussions between Anavex principals and those of other drug firms involve all of this. The game will not be played with only Anavex 2-73 in the lineup. Sitting on the Anavex bench, ready for substitution, is Anavex 3-71, which has even better preclinical stats than A2-73.
Anavex has a strong A2-73 first-team, about to start playing real games — which it will win hands down.
But on the Anavex bench is A3-71, getting ready to enter a starting lineup. Once in play (meaning, human trials results), it will score and win even better than A2-73.
It’s easy to disregard the many other players Anavex has still suiting up back in the lab locker rooms; chemicals that will play games against many diseases beyond Alzheimer’s and Parkinson’s, and win handily, I believe.
So, any buy-out or collaboration discussions between Anavex and any Big Pharma must take into account all of what Anavex possesses, the entire team, revolutionary new drugs that will have massive target clienteles and be uniquely successful. It’s not just Anavex 2-73 and Alzheimer’s, by any means.
And the Anavex principals, more than any, know all of this. They will be driving some very hard deals, should any be needed or transpire.
The presumption that AVXL is a $4 to $5 stock, based on the available science, is ludicrous.
Anavex 2-73 is created purely by in vitro (in labware) processes, not in vivo (in microbes or other living organims).
Not a problem. I'm an educator.
Getting perceptions right in the public mind is what I do. Spent 30 years in the classroom teaching biology, producing students who had functional and correct understandings of the subject.
Biology, on the surface, appears simple and easy. DNA codes for genetics, and genetics controls organisms.
But superficial understandings obscure important details, the stuff that at the core makes cells and organisms really work.
Such is the case with the Anavex molecules. Pretty complicated stuff even on the surface (simple ER/mitochondrial connections). But the stuff is far more complicated --- for which I will admit I'm not competent to comment on (and won't). The involved cellular chemistries are exceptionally complex; the structures, binding sites, and molecular pathways. Real brain chemistry, as it were.
Nonetheless, the rudiments of the science affirming the validity of Anevex molecules can be presented and usefully understood. That's what I attempt to do. The Anavex stuff works; I try to tell how, in understandable messages.
That's crucial for all parties; for potential Anavex investors, collaborators, product prescribers, and users.
I speak for myself, not the company or anyone else. I welcome other perspectives and presentations of the developing Anavex story. It's real, and it's big.
Old Data, New Results
'To date, no single animal model has exhibited both neuropathological and behavioral symptoms characterizing human AD.'
The rats used the study were new, transgenic rats, with human Alzheimer's genes inserted and being expressed, as shown by cognitive deficits and the amalyoid deposits.
Yes, the transgenic McGill rats are a perfect animal model upon which to test the human validity of A2-73.
(If they were not, none of the researchers or funders of the study would have published it. It would have been invalid. Neurology researchers know the subject well. Transgenic rats are perfect test specimens. Extrapolated data from them will apply accurately to humans.)
Long-term A3-71 Results
Yes, I saw that, too. Stunning, that symptomatic resolution would endure following A3-71 dosing durations (without the drug).
First, we dare not use the word “cure.” Ever. Just too loaded with unprovable traits or difficult substantiation. Would be nice; take A3-71 for six months, go off it, and live many, many more happy years without any Alzheimer’s symptoms.
Doubt that would be the case, however. Whatever first caused the loss of neuron homeostasis; bad foods, other drugs, normal aging, whatever; would still be present and the symptoms would return.
I hold the view that Alzheimer’s and the other CNS diseases Anavex will treat with their new drugs are chronic diseases, similar to type 2 diabetes. Something causes insufficient production or function of insulin, and serum glucose levels elevate, with untoward symptomatic consequences. Administer sufficient insulin, and systematic glucose homeostasis is restored. Stop the insulin, and things go bad again. Gotta take the insulin chronically and persistently to control the diabetes (in most cases).
I see the same with Alzheimer’s, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), Parkinson’s, and any number of similar CNS diseases. Once symptoms appear, A2-73 (or, probably better, A3-71) will be prescribed. “Take one of these once every morning after getting out of bed. Forever.”
Of course, contemplate the continuing revenue streams to Anavex should their drugs be so administered. How many Americans are entering or are in old age ranges where CNS diseases proliferate? In a few years, how many daily Anavex dosages will be consumed by aging people in the world — not only to treat emerging symptoms, but as prophylaxis, taken before symptoms appear, to prevent disease onset?
Because of the absence of side effects, either of the new Anavex drugs could be taken chronically, as in the manner of low-dose aspirin.
Imagine the social, financial, and medical outcomes should Anavex drugs both treat and prevent a multitude of geriatric diseases, including cardiovasuclar conditions, cancers, or psychiatric conditions. There are preliminary reports of all of these in murine (rat) lab studies.
Thanks for re-posting these data — phenomenal, indeed! A3-71
I was not aware of the first poster. Albeit from murine-derived data (from a rat species, not humans), the data are, from my perspective, even more prognostic for favorable treatments in humans than the CTAD data were. Those data showed profound stabilization or improvement of Alzheimer’s symptoms, along with a remarkable safety profile. Those two factors, alone, should move Anavex 2-73 closely toward FDA approval.
But none of the people in the trial had their brains assessed for A2-73's removal of amyloid beta deposits (if it even occurred). Here, after dosing with Anavex 3-71, Alzheimer's rats’ brains were sectioned and stained, showing conclusive proof of A-beta clearance with Anavex 3-71.
So, in both this murine study and the human CTAD report there’s solid evidence of enduring symptomatic stabilization or improvement. But the rat study, with A-3-71, also shows A-beta clearance.
Ain’t that something? The Big Pharmas have been trying to do that for years, with consecutive failures. But little Anavex gets it done, without side effects.
Clearly, now, Anavex 3-71 profoundly treats Alzheimer’s by two mechanisms. The first, is the drug’s re-connection of endoplasmic reticula with associated mitochondria, allowing restored, normalized enzyme production and function.
The second is by beta amyloid clearance, the target mechanism no other drug company has yet (or is likely to) attain. Their drugs simply have too many side effects, or don’t work sufficiently.
The question arises, how, perhaps, might A3-71 be able to clear the waste proteins, when other drugs have such difficulty? I think it’s rather clear. A3-71, itself, does not clear the waste proteins. But when enzyme homeostasis is restored by it within the neuron, normal waste-clearing enzymes can function once again.
Out, damned amyloid!
Most likely 3-71 will be very beneficial.
But I have no useful knowledge of the molecule, or its potential applications, other than the posted material on the Anavex pipelines page.
Of this we can be certain, of, however. The brilliant molecular biologists and neuro researchers in the Anavex labs simply wouldn't post a thing about a new drug or molecule unless they were certain it had some sort of in vitro (in labware) or even in vivo (in living cells or organsims) outcomes pointing in favorable directions.
Ask, why might they persist in working with a new molecule that merely matches the efficacies of Anavex 2-73? Research and clinical dollars are at a premium, and must be directed only toward the most promissing outcomes.
The far greater (but related) question is this: Are Anavex technologies new, revolutionary medical game-changers, with far greater treatment and prevention applications beyond just Alzheimer's and Parkinson's disease?
My perception, awaiting future results, is that Anavex's unique ability to restore cellular "homeostasis," normalized cell function, will extend far beyond those two diseases. It appears that most, if not all, geriatric neurodegenerative (and other geriatric) diseases commonly involve the sorts of mitochondrial disfunctions A2-73 rectifies.
I await announcements on all of this; PRs that tell how Anavex molecules prevent, stop, or improve all sorts of dieseases. The central nervous system diseases are in the spotlight right now. But diabetes, cardiovascular disease, psychiatric conditions, and who knows which others cannot be removed from Anavex inclusion.
Put poorly functioning cells back to their functional youth, allowing mitochondria to effectively make and transfer ATPs to connected endoplasmic reticula; who could then resume making properly-folded proteins, enzymes, that mediate normal cellular reactions. Cells functioning properly means they are healthy, as will be the organism they constitute.
Again, I don't think it's going to be just A2-73 and Alzheimer's. Much, much more, I think this for clear cellular chemistry reasons, not mere hope. Anavex has the right molecules. No one else does.
The question of Aducanumab (Biogen) and A2-73 synergism is interesting.
Aducanumab is a monoclonal antibody; chemically unrelated to Anavex 2-73. It binds to or helps clear beta amyloid aggregations.
I can see no chemical reason either of these molecules would favorably enhance the efficacy of the other. They work so differently, with differing cellular structures and chemistries.
My bets are that A2-73 will work very effectively by itself; that concomitant dosings with Aducanumab might improve clinical outcomes by only the smallest of fractions, if at all.
Key is this. A2-73 has caused no severe adverse outcomes; Aducanumab has caused, among other things, brain swelling, which by no means is minor or inconsequential. The threat of such adverse events over rides, I believe, whatever minor improvements it might provide.
Clinical trials will determine all of this, of course.
Penicillin and Anavex
I contend that Anavex 2-73, and its in-the-pipeline analogues are a 21st-century penicillin, the antibiotic that revolutionized medical care in the last century. Before penicillin, an infection from a merely-scratched zit could (and often did) lead to systemic infection, sepsis, with ensuing death.
Propitiously, penicillin was discovered in 1928 by Scottish scientist Alexander Fleming. But it was not used clinically until 1942. It took many years for two crucial things to work out: a) acceptance by the medical community that penicillin actually worked and was safe, notions abjectly rejected by many for many years (“That can’t be. Fleming is nuts. No chemical can exist that kills bacteria in the body without bad side effects. We all know that!”). And b) the devising of methods to mass produce the molecule. That latter obstacle was finally overcome by American pharmaceutical firms, using innovative new production methods.
By 1942, penicillin was in full production and was a factor in Allied military successes. Our solders didn’t die of minor wound infections.
How does any of that relate to Anavex? Very much.
First, as we know so well, the medical community — researchers, physicians, and medical journalists — as they did with Fleming’s early penicillin contentions, utterly dismiss the Anavex science. “Hey, we’ve been working on Alzheimer’s now for 30 years, and we know full well it’s an amyloid and tau proteins problem. Anavex people are nuts for thinking it somehow involves rough ERs and mitochondria. We know better. We’ve been doing this for a long time.”
Secondly, as with penicillin, use of A2-73 will take a bit of time to get into the clinic (but not 14 years — let’s hope for, say, just 14 months).
And, as with penicillin, the medical community, impelled by client populations (insurance companies, patients, and caregivers), will rather quickly embrace Anavex’s new drugs; once they are available. I look forward to the media’s response to people getting up out of their nursing home beds and returning to their own beds back home.
Let’s watch the two crucial moves, the clinical testing of A2-73, FDA approval, and clinical availability; followed by what we are all really waiting for, widespread effective treatment of CNS diseases that Anavex products will work for.
Right now, we are pretty much just at the early Fleming stage of development. The science has been observed in both the lab and a few humans. 2017 should take the story into new, bigger chapters, ultimately with the successes, clinical and financial, we expect.
Purposes of This Board
My continued participation here becomes questionable.
Anavex will proceed forward, disregarding the comments of anyone here; me, or any one else. The science is now demonstrated and thoroughly understood by those with biological training. The unique and proprietary molecular mechanisms by which Anavex's molecules reduce or suppress Ahzheimer's symptoms will, in time, propel Anavex to a significant place in modern pharmacology.
A professed ability to read technical plots of share prices and volumes, so as to putatively predict either near-term or future financial outcomes of Anavex, along with vague postings of previous other "pumps and dumps," lends for me (and I'm sure, many other readers) no useful information on the core issues with Anavex: Does the company have unique, proprietary, clinically-proven technologies that will effectively treat and/or prevent CNS diseases?
Board postings could be accurately placed within just three generalized categories:
1. Discuss how to profitably day-trade AVXL shares.
2. Discuss how to profitably invest, long-term in Anavex.
3. Discuss the validity and applications of Anavex technologies.
Professed competencies in No. 1 have no relevance whatsoever to No. 3; and only minutely to No. 2.
The validity of Anavex technologies, No. 3, will necessarily control everything else.
I’ve made my several postings elucidating the truths and profundities of Anavex science. When appropriate (probably seldom), I’ll continue to contribute useful Anavex biology information, in Discussion Topic No. 3.
I’ve taken my long-term investment position in AVXL, and have no reason to modify it for many years. So, I wish the best of luck to those focused on Topics 1 and 2. My perspectives are decadal, derived from Topic 3 — so I retreat, comfortably.
Best wishes to all.
George,
Thanks.
Whatever dextromethorphan's chemical mechanisms in the brain or nerves might have been shown to be, experience with thousands of Alzheimer's patients have failed to show any persisting outcomes riveling or approaching those of Anavex 2-73.
The "orders of magnitude" factor explains the matter. Too weak to be of any clinical competition for A2-73, regardless of whatever chemistry the molecule might possess.
No, dextromethorphan and donepezil are chemically and physiologically unrelated to Anavex’s molecules. Utterly different, with profoundly different and better outcomes for Anavex.
Dextromethorphan is a sedative, calming the overactive states of some Alzheimer’s patients. Incidental usage, failing to slow or stop symptomatic progression.
Donepezil, trade name Aricept, is a commonly used Alzheimer’s drug. It is an acetylcholinesterase inhibitor, promoting elevated levels of acetylcholine in nerves. This facilitates normalized nerve impulse transmission, so, for a period, mental activity is improved or stabilized — but only for a period, a few weeks or months only.
You ask, “Why will Anavex succeed where they have not?” Simple. Anavex will succeed because it successfully and chronically treats the real cause of Alzheimer’s, which is the presence of mis-folded, purely- or non-functioning enzyme proteins. Dextromethorphan is merely a sedative, with no useful chronic outcomes. Donepizil (Aricept) also fails to correct in any way protein misfolding. Anavex 2-73 does this, allowing normalized enzyme production, restoring normal nerve function.
Good questions — for which answers aren’t so clear.
If, as I’ve contended, all Big Pharma insiders see the profound implications of the Anavex story, why isn’t Anavex then being favorably approached by each and every one of these firms. They know the story, and they have drug synthesizing, packaging, and marketing structures to take Anavex 2-73 right to the market, once FDA approval is attained. They’ve all conducted big clinical trials, so they know how to do those, too. And they have the funds to make all of this happen.
They’d just want some sort of mutually-favorable deal with Anavex, to be certain.
Now here, my reasoning and conjectures are entirely speculative, not based upon any personal knowledge or expertise whatsoever.
I would be surprised to learn that Anavex hasn’t been approached, very quietly and privately, by any number of Big Pharma execs, each with a differing set of proposed collaborations or deals.
Certainly, were this to happen (I have every reason to believe it is happening), no Big Pharma is going to let a word of this out to the public, nor to any competitor. Each wants to make the best collaboration or buy-out offer to Anavex. Letting competitors know one’s requirements for such discloses advantages to them. Keep it all quiet, behind closed doors, with cabs waiting in back alley doorways.
What do Big Pharma execs do? Try to work out collaborations with Anavex, sharing developmental costs and sales revenues? Would one Pharma determine that for them, they’d make out best by doing most of the marketing and distribution; another company might want to do everything, as quickly as possible, with favorable licensing and franchising revenues off to Anavex? The multitude of variations on any of these arrangements are the semester paper assignments for MBA students. Beyond my ken, for sure.
At the same time, there must be buy-out offers. Anavex’s proprietary molecules get bought out in their entirety, at giant prices and continuing franchise fees. Share buy-out and concomitant share-for-share trade ratios would be negotiated. (I’ve pondered this: knowing what I perceive to be the company’s future exponential worth — counting the many zeros — at what price would I be satisfied in selling all of my shares to a new buy-out company. More likely, on my part, a duel deal; at what price do I sell my shares, along with what number of new-company shares do I also get for participating in the deal?)
That last scenario is one all AVXL shareholders may have to act upon, if there would be shareholders’ vote on a buy-out. At the right price, with the right number of new company shares in return, I’d vote for such a measure — but right now I have no idea what would be acceptable terms for me. They’d be very favorable for me, of course.
One important point. It is not the goal or purpose of any pharmaceutical company to cure any disease. It is solely to financially reward the company’s owners, the shareholders.
I perceive that Anavex principals are savvy and attentive to all of this. Better than anyone, they can see the Big Anavex Picture. The officers have substantial share holdings, which would be devalued by any bad deals with Big Pharma. Their self-interest then works for mine. Maximize the value of Anavex and its future products. All AVXL shareholders will benefit.
And, so will Alzheimer’s patients, so wonderfully.
(Would love to learn about the back-room, closed door, private online discussions going on right now. Will be big chapters, probably a book, in future corporate studies manuals.)