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More Than Anavex 2-73 In The Stable
One short but significant phrase in the announcement should be noted:
“...an increase in preclinical activities for ANAVEX®3-71 and ANAVEX®1066.”
I’ve contended for some time that back-lab work has most surely been progressing on both new indications for Anavex molecules and the working out of indications and applications for Anavex 3-71. Added here, now, is Anavex 1066.
According the company (http://www.anavex.com/pipeline/anavex-3-71/) it might be inferred that Anavex 3-71 has greater therapeutic potential for Alzheimer’s than even Anavex 2-73
Anavex 1066 (http://www.anavex.com/pipeline/anavex-1066/) targets various pains. The markets for such an application, including the very common neuropathic pains of diabetes, are very large.
Anavex 2-73 is just an early chapter of the ever-expanding Anavex story. Indications and applications will extend far beyond Rett, Alzheimer’s, and Parkinson’s.
Anavex Life Sciences Corp is not a one-trick pony. It’s an entire stable of powerful therapeutic steeds, requiring development. Such development has just been indicated for two new Anavex drugs.
The Anavex Sleep Health Factor
https://www.ted.com/talks/jeff_iliff_one_more_reason_to_get_a_good_night_s_sleep
Check the last three minutes of this Ted Talk, where the crucial role of sleep to clear beta-amyloid wastes is explained, preventing Alzheimer’s.
The fact that all of those Alzheimer’s patients with sleep problems in the Australian study got sound sleep while being dosed with Anavex 2-73 may, in the end, prove to be the most significant outcome.
As the presenter in the Ted Talk above mentioned, before many experience outright Alzheimer’s symptoms, sleep becomes ever more difficult and inadequate. Loss of sleep duration and quality is quite frequently the first indication of ensuing Alzheimer’s, as beta-amyloid wastes begin to accumulate from the loss of sleep.
So, what happens if Anavex 2-73 can be given prodromally, before outright symptoms appear? It is not unreasonable to envision (yet to be proved, of course) the following.
Anavex 2-73 proves itself and gets FDA approval as the new standard of care Alzheimer’s treatment. Several million American’s begin taking it in a year or two after approval. One of the first good outcomes is that sleep becomes normal and deep. Instead of getting up at night and fitfully wandering around and causing trouble, a major problem with Alzheimer’s patients, they all now sleep well.
It doesn’t take much of a brain to then think that, perhaps, it would be good to prescribe Anavex 2-73 to people who don’t yet have a full set of symptoms, just a few first hints of ensuing Alzheimer’s; forgot where the car keys were left, forgot why the person walked into the other rooms, and — no longer sleeping so well. Here, the general practitioner says, “Try a bit of this, Anavex 2-73. It should help you sleep better. Let’s see what happens.”
And, so it does. After a year or two of this, it is discovered that no one who was prescribed Anavex 2-73 just for good sleep went on to Alzheimer’s. Instead, their cognitive skills remained normal, with no ensuing dementia. Profound treatment success.
Profound benefits, too, to Anavex Life Sciences Corp, and to those of us who held our AVXL shares through those several years of little activity.
Here is another Ted Talk on the importance of sleep for health:
https://www.ted.com/talks/dan_gartenberg_the_brain_benefits_of_deep_sleep_and_how_to_get_more_of_it?utm_source=newsletter_weekly_2017-12-09&utm_campaign=newsletter_weekly&utm_medium=email&utm_content=talk_of_the_week_image#t-5139
[This author advises that his postings should not be used to prompt any AVXL buy or sell decision. Anavex Life Sciences Corp is presently a small, no-revenues, no-product start up pharmaceutical. It may have a great future, as its science is unique and effective. But, of course, never put at risk any non-discretionary funds.]
Well, Then, No "Achievement" Till Next Year
Anavex a Scam? Let the Selling Begin (Ha)
Eager for such. I’ll be catching a few hundred shares, then.
A Whimper or a Whopper?
The Future American Alzheimer’s Drug Market
Not Just the Common Cold
"The end for the common cold?"
Here's what that paper, in 2009, concluded:
HSP and Mitochondrial Dysfunction
This paper, Hereditary Spastic Paraplegia-Linked REEP1 Modulates ER Mitochondria Contacts, Ann Neurol. 2015 November ; 78(5): 679–696. doi:10.1002/ana.24488, tells of a protein, REEP1, that disrupts the endoplasmic reticulum-mitochondrial connection membranes, the MAMs in HSP.
This information fully supports the ability of Anavex 2-73 to restore those inter-organelle membrane connections, as it does in Alzheimer’s and other CNS diseases.
The paper tells of the causative involvement of MAMs disconnects in CNS diseases:
Thanks, Paper Was In English, Conducted in France
Have Hereditary Spastic Paraplegia — An Anavex Connection
I do have a hereditary neurological condition with a significant Anavex connection, I believe. I present the following, to allow readers to determine if I have a tainted or self-serving view of Anavex. That may have been inferred by some readers.
I have a mild case of hereditary spastic paraplegia, HSP. This, as with Rett syndrome and a good number of other central nervous system diseases, is genetic in origin. For me, with my form of the condition, the long motor nerves of my spine, controlling the adductor muscles of my legs, are hyperactive, causing chronic (on-going) tension or spasticity. My gait is inhibited. I have complete proprioception, an understanding of the location, extension, control and restricted movement of my legs. I can walk, but require a small walker in front of me, for support. I can drive with utter control and safety, able to perfectly control the throttle and braking functions.
Just before I retired from teaching, at the turn of the millennium, a neurologist did a complete work-up on me, as the spasticity had grown more debilitating. He said most likely one of the many forms of HSP. A few years later, I had to take up the walker.
Of course, I scrutinized all of the medical literature on the condition, and at the time there were about 30 identified phenotypes, or variations of the disease. It was clear, my particular set of symptoms (many lesser ones) pointed to an un-described version. Much later, a medical paper delineated 60 or so new variations. I was in one of those.
Now, here’s the Anavex connection. Last year or so, in my expansive scrutiny of journal articles involving Anavex 2-73 I came across a French paper where a researcher had treated transgenic rats who had been genetically manipulated with a human HSP gene with Anavex 2-73. At the start, these rats walked poorly, with spastic, locked back legs. As with me, their long motor neurons in the spine were constantly firing, tensing certain leg muscles.
Then, Anavex 2-73 was added to the water in their cages. In time, just a few weeks as I recall, the rats started ambulating normally. Leg spasticity and other symptoms were suppressed — just as we hope will happen with the little girls with Rett syndrome (as with HSP, a genetic disease).
Ineptly, I somehow mis-filed that French paper. I’ve spent a lot of time searching on the web for it, to no avail. It’s listed in my computer files, among the many dozens of others, but when I try to open it, I get some sort of file error message. The file is corrupted in some, irretrievable way. (If anyone discovers the URL, please post.)
No matter. I have the sound, evidence-based prospect of being able in a year or two to walk normally once again, without my standup walker.
This, of course, is but another isolated but noteworthy indication that the Anavex molecules can have a wide, diverse set of treatment and prevention applications beyond the few diseases presently being targeted.
Had it have been available when I was a kindergartner, I would have been spared the humiliation I endured from Miss Dillenschneider, my teacher. She castigated me for “refusing” to sit cross-legged on the floor while she read us stories. She thought I was being obnoxious. Instead, the spasticity was already occurring, to the degree that crossing my legs was physically impossible.
(None of that relates to the condition I mentioned in my previous post, where I devised a quite successful treatment regimen for another rare condition I had. That did not involve neurological dysfunction in any Anavex-applicable manner. Unrelated.)
Well, Just Who Am I?
Should anyone be concerned or interested, here are my credentials supporting my Anavex postings.
As it happens, I am a scientist, and a retired advanced placement biology teacher. Because of unique competencies and publications, I am an invited, unique consultant for a major federal science agency. Inappropriate to reveal the details of that here.
On another scientific matter, I work with a university research foundation in the creation and implementation of novel, unique and effective environmental solutions I’ve devised, affecting human health.
I was a major researcher and organizer for two statewide scientific projects of a professional science collaborative in my state.
I created and operated a premier secondary school science research program that won state and national awards. For their research competencies and published papers, my students won full academic scholarships in medicine, biology, engineering, and chemistry.
My peers designated me the best biology teacher in my state, for teaching college-level biology to high school students, where they gained early college admissions and credits (teaching, among other topics, detailed cellular biology, of all things).
I was invited by my state department of education to help construct scholastic achievement tests for biology, to, among other things, help select college scholarship recipients.
I have conducted medical research — on myself. Late in my teaching career I was afflicted with an uncommon but severe condition that threatened my professional position; for which existing medical texts claimed to be idiopathic, without known cause or effective treatment. After scrutinizing the medical data for the disease, I determined a unique probable cause, discovered several substances that would treat the disease, and over five years of self-experimentation both conquered the malady and then published the details of the treatment. Today, medical specialists use my treatment regimen for their patients. I’ve kept detailed documentation of safety and efficacy, with over 260 user accounts, with efficacy of over 90%. My user account data are used by specialists to determine treatment suitability for their patients.
I’m in the process of writing a retrospective, where all of this will be laid out. Publication should happen next year some time. Three-hundred+ pages now, another hundred to finish.
Beyond Just Neurons
For Approval, SOC Must Only Be Exceeded
Australians Must Be Stronger, Longer Thinkers
How It Can Be Known
But No Analgesic Placebo Effect in Alzheimer’s
https://medium.com/the-mission/the-worlds-most-essential-drug-f8f5eba8407b
Good article, telling the difficulties with the placebo effect. Placebo effect allows drug recipients, taking a sham placebo, to often have strong, detectable reductions in disease symptoms. A phenomenon well known today.
But, can the placebo effect work with all “drugs” and all human disease conditions? For Alzheimer’s, according to the article, no. “Painkillers don’t work as well for Alzheimer’s patients, as they are unable to formulate ideas about the future and don’t get the benefits of anticipating treatment.”
In these cases, the administered drugs are not placebos at all. They are approved drug analgesics. The Alzheimer’s patients’ reduced cognition keeps them from even understanding that the painkiller pill they just took is supposed to work. Because they don’t know about or understand the painkilling drug, it has reduced efficacy. A reverse placebo effect. Real drug, for a real medical condition, but reduced efficacy because of reduced cognitive abilities.
If a real drug, an FDA approved analgesic, can’t induce pain reduction in cognitively-deficient Alzheimer’s patient, how could that same patient turn around and start thinking normally in anticipation that the new pill that was taken was a new, highly-effective Alzheimer’s treatment?
Fact is, the placebo effect requires strong consideration in the design, conduct, and interpretation of new drug clinical trials. But to presume every sort of patient, of even markedly reduced cognition will be affected is not supported by experience. We all await the posting of data revealing a placebo effect for a new, in-trial Alzheimer’s drug. Many companies have conducted new Alzheimer’s drug trials for several decades. Any record of a placebo effect? If not, why would the placebo effect all of a sudden be in effect for the testing of a sigma-1receptor drug? Cognitively, the mid-stage Alzheimer’s patients wouldn’t be able read or pronounce acetylcholinesterase inhibitor or sigma-1 receptor agonist, let alone have any idea what good symptomatic outcomes they are supposed to evoke.
Clearly, the placebo effect is not universally applicable. If you think it is, next time you have a sore tooth from dental caries, take a spoonful of sugar and see how that works out in a few months. Sugar, from Saccharum officinarum, is a common placebo material, with “proven” effects.
Doctor, Some of Us Do Understand
Good, Rett Results Will Be Valid
Good to learn that the Rett trial will have proper experimental/control arms, of sufficient size and duration to confirm Anavex 2-73 efficacy.
Finally, an Anavex clinical trial investors can depend on. I think I'll hold my small position, awaiting official release of outcomes, whenever those might be. Finally, real science will be happening. So new to Anavex. Such good news. Can hardly wait.
Same, too, in the new Parkinson's study?
I think I'll risk and hold my entire AVXL investment and wait for results from both of the new 3-month studies. I might have some good things here to celebrate next July Fourth.
31 December A Fall-off, Crash-and-burn Cliff?
The entire Anavex world will crash and burn, will it not, should none of the three trials begin before then?
Clinical trial conduct must be really tricky, like the Anavex technologies themselves.
Not at all for the risk-averse. (Buy some government bonds. Safe, altogether.)
Tell Us, If Fits Subside Quickly, Does Anavex Work?
Please, render for us your cogent explanation should the following occur.
If in the upcoming Rett trial of little girls with this neurological condition, fraught with, among other symptoms, frequent epileptic fits and poor muscle control, Anavex 2-73 is administered blindly, in orange juice, apple sauce, or otherwise in a form the little girls cannot detect, and in say, in just three weeks of this, their mothers note that their frequent episodes of epileptic fits and poor muscle control markedly abate, would this be any indication the drug has authentic efficacy?
How should we unknowing AVXL shareholders react to some mother who might post here, "Hey, my little Susie has Rett, and after a month in that Anavex study no she longer has fits, and she's starting to walk normally!"
Without a proper two-armed study, real-drug and placebo, how could the upcoming Rett trial yield any scientifically valid results?
And, it's only for three months. Is that long enough to test a drug acting on a from-birth genetic anomaly?
Like yourself, we should be wary, should we not? Guide us. How should we interpret any interim results in any of the upcoming Anavex 2-73 clinical trials. We all messed up with the Australian study. We need guidance more so now. Most of us bought some AVXLs. Pretty risky, that was.
Nonetheless, Still Placebo Effect
No matter what happens in the Rett trial. The experts here have told us no double-blind, placebo-controlled trial can possibly yield "valid" results without a giant number of participants, for a lengthy test period, etc.
But, there will be no blinded placebo arm of the Rett trial. Therefore useless.
Nothing good or authentic ever happens because of Anavex 2-73. Always bad trial design, inadequate number of participants, no real placebo arm, or just plain placebo effect.
Lesson has been learned, has it not?
The Inability For Placebo to Change Alzheimer’s Remains
Yes, as the quoted text relates, analgesics (for pain reduction, as in migraine) and similar drugs are open to the placebo effect. No question about that.
The fact remains, however, there are no demonstrated or recorded cases of any “drug” (sham pill) ever causing the strong, persisting cognition stabilization or improvements that Anavex 2-73 did in the Australian trial. There is no conceivable mechanism by which the placebo effect, patient expectation (that’s the key factor), could possibly remove beta-amyloid plaques or tau tangles recognizably causing Alzheimer’s symptoms. The unique mechanisms of action of Anavex 2-73 could do this, however.
When will some drug be reported that it heals new broken bones after a 5-day course of treatment? Impossible. With broken bones, there can be no authentic placebo effect, where patient expectation “causes” the severed bones to quickly and spontaneously re-connect. Physically and chemically impossible.
The same is true with Alzheimer’s. No placebo-induced functioning of brain circuits (thinking) can possibly cause the disappearance Alzheimer’s toxins, the chemicals that actually induce all of the disease’s symptoms.
Were there existing, recognized cases of placebo effect outcomes in Alzheimer’s, the question would remain. But, for clearly obviating physiochemical reasons, mental expectations simply cannot suppress the lethal progression of Alzheimer’s disease.
One can’t wilfully believe away broken bones, hardened arteries, dental caries, urinary tract infections, cataracts, hernias, kidney stones, varicose veins, or a host of other humans diseases and conditions. Same with Alzheimer’s and Rett.
It is important to understand the placebo effect, and how it can distort or misrepresent clinical results. But it is a factor only in the conditions and diseases where it can operate. It simply can’t (and hasn’t) in Alzheimer’s or Rett.
The placebo effect is by no means operable in every human health condition.
The Placebo Effect
It is well known and understood.
https://www.medicinenet.com/script/main/art.asp?articlekey=31481
It occurs when an inactive substance such as sugar, distilled water, or saline solution is medically administered under the guise that it’s a real drug to treat a real disease, with supposed real benefits; whereupon the unknowing patient, because of expectation thinks its helpful.
Thereby (in some cases) the expectation causes the patient to thoroughly believe and act as if the “drug” made the condition better, with perceived reduction in symptom severity or duration.
All of this is psychologically-induced by belief or expectation, not by the “drug,” an utterly inactive substance. The actual nature of the “relief” is not an issue, whether or not actual pain perception, for example, was actually suppressed by the “drug.” The only consideration is patient's perception.
Concerning Anavex 2-73 and the patients that drug targets, the placebo effect has important considerations.
In the case of Alzheimer’s dementia and cognition decline, can there possibly be an authentic placebo effect, where mid- to mild-level Alzheimer’s patients a) cognitively understand what Anavex 2-73 is “supposed” to do for them, creating a placebo expectation, and b) are such patients capable of self-restoration of cognition by any sort of self-devised, internal psychological trickery?
Inasmuch as the dementia problems of Alzheimer’s are caused by cytological and histological dysfunctions in neurons and nerves directly involving several actual toxic chemicals and reaction cascades, there are simply no cases of any sort of placebo effects in Alzheimer's disease. Chemically difficult (well, impossible).
Very similar with Rett syndrome patients. First, these are neurologically compromised little girls. Their ability, at least in some cases, to understand that some new pill they will be taking should suppress their epileptic fits and motor neuron hyperactivities and poor muscle control is minimal, at best. Hard to conceive how they could formulate the expectations of improved health required for the placebo effect to actually happen.
Neurologically Compromised Little Girls Can Imagine Their Health
FDA Fast Track Designation
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf
Apparently (from a quick read-through), Anavex 2-73, as a treatment for Alzheimer’s might qualify for FDA Fast Track designation.
But first, it appears that the same, conventional safety and effectiveness standards required for non-Fast Track drugs must be met, including “well-controlled clinical investigations.”
Page 19 tells a bit of what’s required:
Where Might Anavex Fit?
Here’s the PDF’s listing of products regulated by the FDA Center for Biologics Evaluation and Research (CBER):
1. Blood Products
2. Vaccines (preventative and therapeutic)
3. Allergenics
4. Live Biotherapeutic Products
5. Devices Related to Biologics
6. Human Tissues and Cellular Products
7. Xenotransplantation Products
8. Gene Therapies
Which of these might accommodate any of the Anvex sigma-1 receptor agonists? Let’s see.
1. Blood Products
Nope. The Anavex molecules are not blood products; not produced with, by, or for blood.
2. Vaccines (preventative and therapeutic)
Nope. Anavex has nothing related to vaccines.
3. Allergenics
Nothing here, either. Nothing related to allergies.
4. Live Biotherapeutic Products
Again, nope. Anavex molecules are not “live.”
5. Devices Related to Biologics
Anavex molecules are not devices, physical structures.
6. Human Tissues and Cellular Products
Anavex does not produce anything from human tissues or cells. Anavex molecules are synthesized in biochemical labs, in vitro (“in glass”). Anavex molecules are not tissues or cells.
7. Xenotransplantation Products
“Xeno-“ means foreign or external. Anavex transplants nothing.
8. Gene Therapies
Lastly, Anavex molecules do not affect or target any genetic materials, DNA, chromosomes, nor any other.
Perhaps the company can petition the FDA for a unique, specific inclusion. But until that, the Anavex molecules don’t fit.
Probably, Yes.
No, Multiple Sclerosis Is Not At Synapses
In MS, Nerves Not "Broken," Simply No Insulation
If Myelin Remains, No Disease
By No Means
But Sigma-1 Receptor Agonists Are Not "Regenerative"
Thanks. Can Take Bigger Position, Then
When, Then? Now or Next Year?
Again, Rett Results Will Be Hard To Confine
Interesting the note in a posting below that girls being selected for the Rett trial have to display sufficient numbers of daily seizures to be enrolled.
That clearly reveals that seizure control or suppression is the target outcome of Anavex 2-73 in the upcoming 3-month trial.
Now, just how difficult will it be to quantify a reduction in seizure events in the girls in the study? Will blood have to be drawn and analyzed? Will electrodes have to be stuck on the girls and electromagnetic activity of the brain digitally charted and analyzed? Perhaps.
But, in fact, the mothers of every one of those little ladies will know in a day or two when, simply, their little girls lived a day or two without seizures. Useful assessment of Anavex 2-73 efficacy in seizure reduction in girls with Rett syndrome genomes will be rendered by motherly perceptions of the well-being status of their girls. Mothers know.
I'm not aware of the typical frequencies of seizures in Rett syndrome girls. But let's say it's once a day. How, then, will mothers react when they notice, say, in the fourth week of the trial, their girls went 7 days without a seizure? Will they think (as some here would), "Well, that's interesting. But who knows? Can't be that drug Little Susie is taking. Must be just chance. I'll keep quiet about this and won't say a thing until the trial is over. What could I know? I'm not a doctor."
No, Susie's mother will be telling all her friends that the drug is actually starting to work, that her girl now has the chance to live a normal life.
At that point, will anyone knowing of this post a message here, telling the whole world?
Let's see.
Market Populations Not Clinical Trials People
Picking, Using Only Favorable Clinical Participants
Do not presume the variable results of the Phase 1 / 2 Australian trial will be those of the big Phase 3 clinical study.
The two studies are not parallel, by any means. Offhand, it could be presumed (as many here do) that the new Alzheimer’s trial will be simply a bigger one, with a much larger n=, number of participants. With that (were it the only thing to consider), statistical significance of any of the measured outcomes will not be in question — as they are with the Australian study.
That study yielded a variety of results; most of which trended very favorably. Cognition was either maintained, or, for some, actually enhanced, improved.
So, were those data merely a result of happenstance, where by chance a good number of people were favorable responders to the drug; or were there just by chance people who would keep or improve their cognition regardless? Chance, or direct cause?
Did Anavex 2-73 cause any or all of the favorable outcomes; or, was it only by chance, with no real cause/effect connections? Since the number of participants was small (32?), many (here) will argue the by-chance causation, not an authentic, unique efficacy of Anavex 2-73 against mid- to mild-stage Alzheimer’s disease.
Now here’s the big thing; where the upcoming big n= Phase 3 will be utterly different. The difference will not be merely size, number of participants (200?). Rather, it’s not how many in the trail, but who.
Anavex Life Sciences Corp has engaged firms who have precisely and minutely detected any number of personal variables that affected favorability to positive Anavex 2-73 outcomes. This time, before any trial participant is administered her first Anavex 2-73 tablet, Anavex has a high-probability understanding how each individual will respond.
As per the new FDA drug testing protocols, (precision medicine), Anavex is going to be highly discriminatory. To participate, one must have more than diagnosed Alzheimer’s disease. The person must also have genetic, metabolic, or other detected traits that assure the highest, best response to Anavex 2-73.
In fact, it may be only 25% of the general Alzheimer’s population with high levels of Anavex 2-73 response. Those will be the people allowed to participate. People with traits negating or suppressing a strong response to our drug will not be allowed to participate. Again, profound discrimination; stacking the deck in Anavex’s favor.
And, creating the best chances for eventual FDA approval. Remember, again, to gain approval Anavex merely needs to show equivalent safety and better efficacy of any of the existing four Alzheimer’s drugs. The safety profile, from the Australian study, is exceptionally strong. It should be replicated in the new study. All four of the existing drugs merely slow symptomatic progression, and only for short to moderate periods. If only the best responders in the Australian study are the types allowed in the Phase 3 study, Anavex 2-73 approval is unquestioned. Poor responders won’t be in this trial. Strong responder data sets will greatly exceed those of the existing drugs.
Because of precise analysis of the Australian data, and because of new FDA drug testing rules allowing or encouraging precision medicine (matching specific drugs with particularly favorable populations) Anavex will have just the best patients to prove both the safety and profound efficacies of Anavex 2-73 against mid- to mild-level Alzheimer’s patients.
More Than Gut pH
It's the Thalidomide Regs, Not Thalidomide Itself
Of course, few women who might take Anavex 2-73 to treat Alzheimer's will be carrying a child. But some Alzheimer's patients exhibit early, prodromal indications in the forties --- when women do carry babies.
But that's not my contention. It's that the restrictive regulations that prevent some FDA official to simply call up Anavex and tell them to start selling the drug came about because of thalidomide.
Sorry, like it or not (in this case, because of all of what is positively known about our drug, I don't like it), NO WAY AROUND IT.
All the posts (including mine) telling how good and appropriate it would be for prompt FDA approval of Anavex 2-73 are folly. We are screaming into the distant wind. No one will hear us, or if they would (happen to see our postings), they'd just chuckle and click off.
Preliminary approval without trials comporting to new regs is ILLEGAL.
End of story. Laws still control the matter.