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Frontline Professionals Confirm
It's the FDA, so approval time inscrutable.
The Blarcamesine/Rett drama progresses. Will be approved.
Not an iota of negative or disqualifying information of any sort was produced by this trial; just the opposite.
The drug will be approved by the FDA (for Rett). It is safe; has no side effects of any concern. It is also efficacious; provides symptomatic improvements for adults with Rett syndrome.
Strong indications that titrating to higher doses (beyond the weak 5mg doses in the trial) will yield even greater therapeutic outcomes.
Anyone betting against Anavex Life Sciences and/or blarcamesine will lose. Girls with Rett syndrome will win (as will multitudes of others with other neurodevelopmental diseases for which blarcamesine will prove, in trials, to be efficacious).
Would muscarinic M1 agonism complicate prophylactic use?
Chronic blarcamesine dosing needs to be checked.
Probably not necessary.
Would be the very best.
And, others, too.
Actually, for some time I've had just the slightest knowledge of ALS, encountered when I dug for information on the CNS disease that affects me, a form of Hereditary Spastic Paraplegia (HSP).
Fortunately, my HSP is "uncomplicated," meaning it's not severe. There are a multitude of HSP genotypes, and I've never had a genome assay to determine which form causes my HSP. For me (and most with HSP), the primary symptom is spasticity, particularly in my legs. They are continually stiff. To ambulate I require a wheeled walker, which I control with ease. Can no longer walk up a staircase, as I can only shuffle my legs along the ground. The spasticity (for me) causes no pain; just the ambulation difficulty and frustration.
But HSP has caused urinary retention. I've consequently had to have a suprapubic catheter surgically installed.
A treatment for HSP, expensive, often with complications, and not always so successful, is the implanting in the spinal column of a rubber bladder-like reservoir that mechanically expresses into the spinal column gamma-aminobutyric acid, GABA, which is able to turn down the chronic (always-acting) excitability of the long motor nerves that control muscles in my legs. For some, this brings certain levels of relief, but the bladder must be re-filled with a GABA solution by injection. Metering out precise amounts of GABA can be problematic. Because of all of that, I've learned to live with my HSP as it otherwise presents itself.
A number of years ago I discovered an obscure paper, I believe from France (written in English) where a researcher put blarcamesine in the drinking water of rats that had HSP genes. As in humans with HSP, the rats had poor control of their rear or lower appendages. The back legs were typically spastic.
But after drinking water with included blarcamesine, the rats in a short period of time gained full, normalized control of their legs; could spin themselves normally on a rat-cage wheel. Blarcamesine (then with a different name) was able to restore normalized GABA levels in the spinal column and motor-control (muscle controlling) nerves functioned normally.
Most unfortunately, three years ago the hard drive holding this file went out; I was not able to retrieve the document. I've searched hither and yon on the Internet, but have been unable to find it. For the HSP community, this report was extremely important; one of the only real hopes for successful treatment.
My personal goal is this. When blarcamesine is approved for Rett or some other however obscure CNS disease, my AVXL shares will have appreciated wonderfully. I'll sell a few so I can buy a prescription of blarcamesine for my off-label use, for my HSP. I'm confident that my neurologist will agree with this ploy. Of course, my health insurance company would not, so I'll have to pay, out of pocket, full price for the blarcamesine.
The significance of all of this, beyond HSP? Simple. Eventually, blarcamesine may be therapeutic, either by itself, or as an adjunct drug for the treatment of any number of CNS diseases. Right now, the foci are on just Rett syndrome, Parkinson's disease dementia, and Alzheimer's. Soon FTD, frontotemporal dementia, will be tested with Anavex 3-71 (as I understand it). Presently, we've discussed Anavex drug treatments or prevention of autism spectrum disorder.
Simply, Anavex has the potential of treating or preventing a large number of CNS and other diseases. I've refrained from projecting any of this (until here) for some time. Just as some readers will with this posting, many would have regarded my laying out the several (well many) other diseases that Anavex Life Sciences Corp might potentially treat as only "magic bean" thinking.
For the present, each reader will discern and decide for himself or herself. Later, clinical trials will decide the matter. There is a great deal of supporting, guiding evidence that will prompt new trials with other CNS diseases.
Blarcamesine to Treat ALS
Amyotrophic Lateral Sclerosis (ALS, "Lou Gehrig's disease") is a severe CNS disease, with all sorts of progressing, lethal symptoms. Most or all involve hyperexcitability of nerves. And a primary agent of those over-excited nerves is glutamate. In animal models of ALS, when glutamate can be suppressed, ALS symptoms are reduced. Clearly, profound suppression of glutamate in nerves would be a major therapeutic step for ALS.
For detailed information on the subject, look at any of the links that appear after entering "Glutamate and ALS" in an online search engine. Here's a bunch:
https://duckduckgo.com/?q=Glutamate+and+ALS&ia=web
As those who scrutinize the clinical results of blarcamesine in humans know, from the six girls in the early Rett syndrome study of blarcamesine for safety and tolerability, two significant outcomes, in a very short period, occurred: a) glutamate levels significantly declined, and b) gamma-aminobutyric acid (GABA) levels increased.
For ALS, this would be a treatment double-whammy. First, sufficiently suppressing glutamate levels would turn off the core, rood-cause factor for ALS nerve hyperexcitability. This would be helpfully facilitated by elevation of GABA, which turns down pathogenic hyperexcitability in nerves.
There is no reason whatsoever that blarcamesine shouldn't be tried in humans with ALS, in a new clinical trial. First, as shown in all the other trials with real humans, blarcamesine produces no untoward, disqualifying adverse events ("side effects"). The drug, uncommon for those acting in the central nervous system (CNS), does not disrupt or adversely affect either the CNS itself, nor other body systems, organs, or tissues. Profoundly safe.
So, let's get some blarcamesine into ALS patients, to see if it can, as it does in Rett, suppress glutamate levels.
There is every reason to believe this would happen. Of even greater significance might be the very early administration of blarcamesine to ALS patients, when the disease is first detected; before it progresses to the various nerve and organ debilities that prove lethal. Again, prophylaxis, therapeutic "prevention" is likely to be profound.
Correct, regarding the new dollars.
And, I just checked. There are mouse models of autism disorder:
https://pubmed.ncbi.nlm.nih.gov/25181011/
Early, preclinical tests of the Anavex molecules against autism can be conducted in those mice. Let's learn how they work (both the mice and the drugs).
Anavex Sigma-1 Receptor Agonists Against Autism
I, too, would like to see if either blarcamesine (Anavex 2-73) or Anavex 3-71 might be able to direct normalized thought patterns, etc. in kids with any of the autism spectrum disorders.
For the current CNS targets, there are murine models, lab rodents with those diseases, in which the Anavex drugs can be tested. But I don't know if there are murine models of autism. If so, Anavex would have most likely have already done tests with their molecules.
But because blarcamesine in every human trial has shown to be safe, a Phase I study for children with autism would be interesting. What would be the implications, social and economic, if any of the Anavex molecules could solve the gigantic autism problem?
Effects of early and optimized dosings.
The PDD data will speak for themselves.
As expected.
The close alignment of the Anavex science and the actual, not conceptual or theoretical effects of blarcamesine in humans with various central nervous system (CNS) diseases continues. The new clinical results, from a very low dose (5mg) of blarcamesine for older girls with Rett syndrome, were exactly as I expected.
First, and for drugs treating CNS diseases, safety is so important. Blarcamesine once again, in real humans, yielded a very, very favorable safety profile. No report of severe or disqualifying adverse events ("side effects"). Drugs that mess with the endocrine system, disrupt brain chemistries, or affect genes or DNA have poor prognoses for clinical approval. In neither murines (lab rodents) nor humans have any of these appeared. Profound therapeutic safety, as shown in the new Rett data. So rare for drugs working in the CNS.
But most importantly, for older girls with Rett syndrome, blarcamesine works. Simply, in the trial every desired clinical endpoint was achieved. Alone, those data will mandate FDA approval. But approval is further prompted by the fact that no other drug comes close to providing the favorable clinical results of blarcamesine for non-pediatric Rett. Three conditions must be met for the FDA to approve a new drug:
1) It must be safe. Adverse events can't outweigh therapeutic results. With Rett, blarcamesine meets this criterion.
2) It must be effective, provide demonstrated, significant therapeutic outcomes. This criterion is met (as the new clinical results reveal).
3) It must match or exceed both the safety profiles and therapeutic efficacies of existing drugs. For non-pediatric Rett, there are none.
Let the reader determine, then, the regulatory fate of blarcamesine for the treatment of Rett syndrome in girls with this debilitating CNS disease.
Once again, I note that whenever blarcamesine has been administered to human beings with a targeted CNS disease, a) there have been no safety issues, and b) there have been measured, useful symptomatic improvements.
Biochemists focusing on the theoretical aspects of the new results must attempt to explain them, at the base molecular level. Once again, the unique mechanism(s) of action (MOA) of blarcamesine, facilitating optimal sigma-1 receptor protein function, is further substantiated. Becomes ever more difficult to negate this MOA as it would favorably apply to other CNS diseases (such as Parkinson's disease dementia, Alzheimer's disease, etc.) — all of the ones listed in the Anavex pipeline. To see them, scroll down on this: https://www.anavex.com/
Very small amount.
The single-factor, pure response perspective.
In science research, it's called "reductionism." It's complex, but in full play with Anavex:
https://en.wikipedia.org/wiki/Reductionism
Study complex phenomena by reduction, reducing them to simplified, single-factor perspectives.
It's the "only a cure works" thing.
Will blarcamesine be needed for human spaceflight?
A new study shows that humans in space have, among other chronic health problems, significant mitochondrial disfunction. Simply, in long-term low-gravity conditions, mitochondria fail to function properly. With that, all sorts of downstream health problems can ensue.
https://www.cell.com/cell/fulltext/S0092-8674(20)31461-6
So, a new Anavex study needs to send some mice to the International Space Station, where half will drink plain water; the other half water amended with an appropriate concentration of blarcamesine --- to see if the Anavex drug might prevent mitochondrial disfunction in space.
The drug's activation of the sigma-1 receptor protein, on earth, restores mitochondrial function. It might do that for humans, in space.
Thoughts on earlier Anavex success, before 2023?
Until revenues and/or sales approval, doubts control.
Prophylaxis, again.
"Murines" you mean.
Yes, I believe I recall some results of increased or accelerated nerve growth or repair with blarcamesine in murines, lab rodents. But don't have the studies at hand.
What, then, in seven months, or seven years?
Yes, wonderful therapeutic results appeared in the data from the six girls participating in the early, very short Rett syndrome clinical trial of blarcamesine; as noted, here, in the posting from which this refers:
RSBQ Total from 59 to 14 in just 7 weeks
RSBQ Hand Behaviours Subscale from 5 to zero in just 7 weeks
RSBQ Breathing Problems Subscale from 9 to 4 in just 7 weeks
% Change in Glutamate 66% reduction from baseline in just 7 week
CSHQ (Sleep) Total 20 in just 7 weeks
Glutamate µmol/L 11 µmol/L of Glutamate in just 7 weeks
% Change CSHQ Waking 1% decrease during the Night in just 7 weeks
% Change in RSBQ Total 76% reduction in just 7 weeks
% Change in GABA 80% increase in just 7 weeks
Seven weeks, about 49 days, of blarcamesine treatment caused these favorable metrics.
What would happen, however, if these girls continued their blarcamesine treatments on out chronically (in long-term continuation), first for seven months, than on out to seven years? Only three trends would be likely:
Trend A. Treatments are optimized, fully achieved after just seven weeks; but no further symptomatic improvements after that period. Continuing dosings yield no subsequent improvements. Blarcamesine reaches its full therapeutic potential in dosing periods no longer than seven weeks. No improvements after that.
Trend B. After the initial seven weeks of dosing (as shown in the trial), symptoms continue to be even more strongly suppressed on through lengthy, extended treatment periods, from seven months to seven years. Longer, time-dependent treatment periods produce stronger therapeutic results. Longer is better.
Trend C. After about seven weeks of blarcamesine dosing, after clinical metrics have improved, symptoms reverse and continue to get worse with extended blarcamesine dosings beyond seven weeks. Blarcamesine works only for short, initial dosing periods; after that things revert back to the pre-dosed pathologies.
No evidence for either A or C. The trial was too short to determine the effects, if any, of much longer, even chronic (continuing) dosing periods.
The key, for Trend B (continuing long-term symptomatic improvements) would be the drug's ability to restore debilitated organelles and cellular functions. That might well involve a period longer than seven weeks. Nerves (when they do), don't grow very fast at all. It may take many months, even several years, for blarcamesine to induce cytological "healing," with new, fully-functioning organelles and biochemical reaction sequences.
If blarcamesine can produce only Trend A, bring about favorable outcomes within short dosing periods, because of its attendant safety it will be a useful Rett syndrome therapeutic in older females with the condition. Good enough.
But, very likely, with continued, longer dosing periods, Trend B will occur. After several months, on out to several years, neurons debilitated by Rett cytological anomalies might be even more fully "repaired" by blarcamesine.
Or, at length, the drug may only prevent the worsening of Rett syndromes, as the girls age. Either way, every girl with the disease would benefit.
Of course, all of this needs to be considered for each of the other central nervous system diseases blarcamesine is being tested against. At length, might blarcamesine continue to reduce CNS disease symptoms, in time approaching normalcy?
All of this points to another potential blarcamesine process; prophylaxis, prevention, of either worsening disease symptoms or their complete prevention. For Rett, what is the likelihood that very young girls, administered blarcamesine when first discovered in them, might avoid progression to severe (and ultimately lethal) outcomes? Same for Alzheimer's and Parkinson's; prevention or progress suppression.
Given blarcamesine's unique mechanisms of action within neurons, these are all very possible.
(And, I bet that Anavex has checked all of this in murines. If blarcamesine can prevent the onset or progression of CNS diseases in murines, lab rodents, it can do that in humans.)
What for?
Whoa. Anavex is going to spend a lot of dollars for some new person, unrelated to the company, to come in and take on new responsibilities? Just what can the company be thinking?
https://www.indeed.com/viewjob?cmp=Anavex-Life-Sciences&t=Medical+Monitor+Req&jk=a524e4df220c6ced&sjdu=QwrRXKrqZ3CNX5W-O9jEvbIz9WNS0a2CaZUdGYDNxfuLLoE8LJGIFphcsISdgfBwBR4Nf3kE4fKaLGRDz5g3NN6YyneYV5oNWWn5ZTmnD0c&tk=1en6bmb0tp7gj800&adid=344415837&ad=-6NYlbfkN0CD6Hi3EC6N-so3X8uf3ODGhx-5B54hqjHiBGKdFb4qM4u3FOKVH-t8zdFGBevFm2UYmLfaMGUVJi6O2aYr_MaDyG5-Iu_OSSrq8Bb3IZs20LLC4NWliZMOOBXuw7xG_LT2_v4kQlw8MEEQ3bV9fTNKRh8kEV5daWb2xtNrE9hdhxcJkbjv74KmcUvR0ao_RmjeZf-H8_YPyAT9FN1xiJMZybaXAF1Ln2Whf0BcK7DomIwGnIvVbbfOzUaCeygY1Bp-pBTkgMnRiOzvP9KbpYF5Qm_zQx-brVpO-zfeg_SSTgG9WcAlIAXa7j9nyTHcYgk%3D&pub=4a1b367933fd867b19b072952f68dceb&vjs=3
Decide for yourself. Here's a list of the new person's responsibilities, duties:
– Establishing procedures and standards for medical monitoring with the sponsor CMO
– Being the primary contact for sites on questions regarding subject participation in the study(ies): eligibility, titration, tolerability, assessment of subject discontinuation, and other protocol implementation issues.
– Performing ongoing review of clinical laboratory results.
– Performing ongoing review of Adverse Events (AEs), with emphasis on Serious AEs (SAEs).
– Reviewing protocol deviations.
– 24-hour medic "on call".
– Handling other study-related medical issues, such as emergency unblinding.
– Identifying the need for and provide ongoing protocol and Investigational Product (IP) specific medical education and support to the sites via the CRAs or directly with the investigators.
– Answering medical questions from CRAs and study team.
– Documenting communications with investigators and study teams.
– Communicating with internal team and sponsor.
– Reviewing data listing and related material for safety reports, including DSMB reports.
– Reviewing the Clinical Study Report.
– Reviewing Pharmacovigilance Project Plan
– Reviewing protocol, when needed.
– Attending Kick-off meeting, meetings/calls with investigators, and Pharmacovigilance team meetings when needed
– Support DSMB Meetings and attend if needed
– Transitioning of MM activities.
– Preparing Medical Monitoring Plan
– Make Medical Study Decisions in discussion with the Sponsor
– Maintaining a Q&A Log
In the real-world.
Might blarcamesine stop COVID-19 cytokine storms?
Someone else, I believe, already posted this interesting science report:
Title: Antidepressant may prevent severe COVID-19, trial suggests
https://www.eurekalert.org/pub_releases/2020-11/uovh-amp111320.php
It is reported that fluvoxamine, "sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class which is used primarily for the treatment of obsessive–compulsive disorder (OCD)," "appears to prevent COVID-19 infections from worsening and may help keep patients out of the hospital, a trial based on research from the University of Virginia School of Medicine suggests."
https://en.wikipedia.org/wiki/Fluvoxamine
One of the major lethal problems with COVID-19 is the storm of cytokine activity that causes all sort of severe inflammation in advanced cases, often lethal. Stop the inflammation associated with COVID-19 and it may become less severe, with far fewer lethal results.
How could this psychoactive drug work to suppress COVID-19 inflammation? ""There are several ways this drug might work to help COVID-19 patients, but we think it most likely may be interacting with the sigma-1 receptor to reduce the production of inflammatory molecules," said Washington University's Angela M Reiersen, MD."
Whoa? "Interacting with the sigma-1 receptor..." can reduce the production of inflammatory molecules? Who'd a thought?
Only one question now: Which works better to prevent lethal COVID-19 cytokine storms, fluvoxamine, or blarcamesine?
Fluvoxamine does have a few (well, many) side effects:
Common (1–10% incidence) adverse effects
Nausea
Vomiting
Weight loss
Yawning
Loss of appetite
Agitation
Nervousness
Anxiety
Insomnia
Somnolence
Tremor
Restlessness
Headache
Dizziness
Palpitations
Tachycardia (high heart rate)
Abdominal pain
Dyspepsia (indigestion)
Diarrhea
Constipation
Hyperhidrosis (excess sweating)
Asthenia (weakness)
Malaise
Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.)
Xerostomia (dry mouth)
https://en.wikipedia.org/wiki/Fluvoxamine#Adverse_effects
How many of the above does blarcamesine have?
Come on, Anavex, tell us, soon, how your lab ferrets dosed with the SARS-CoV2 virus fared with some blarcamesine in their drinking water, compared to the dosed, infected ferrets across the room that lapped up just plain water?
Final Rett Readout To Be Positive
Updated, Complete Anavex Posting
Anyone curious about Anavex Life Sciences Corp's future needs to scrutinize every datum and fact now laid out in a new, updated product information posting on the company's website:
http://www.anavex.com/wp-content/uploads/2020/11/Anavex-Presentation-November-2020.pdf
It's all there, for everyone.
Updated, Complete Anavex Posting
Anyone curious about Anavex Life Sciences Corp's future needs to scrutinize every datum and fact now laid out in a new, updated product information posting on the company's website:
http://www.anavex.com/wp-content/uploads/2020/11/Anavex-Presentation-November-2020.pdf
It's all there, for those who can comprehend.
Does it mean anything? AVXL closed at the high of the day.
Yes, "Rhett" was some guy in an old movie. Nothing to do with Anavex or girls with a sex-linked genetic disease.
10 won't be good enough. Nothing will.
And is still the case.
Just as before. But, but stronger.
Once again, in humans, blarcamesine safe, effective.
It will take a while for the significance (statistical, and beyond) of these new human clinical trial results to be understood by the general public. Very likely, they will be reported in some news reports, which will have the usual disclaimer, "...but further studies will be required to fully assess both the safety and efficacy of this new drug."
Legacy medicine and conventional investors, corporate and retail, simply don't want anything to change; and don't believe it can or should. Blarcamesine is too good to be true, or believed. Check 'em out; the side effects of any new prescription drug treating CNS diseases. Not a one has only a bit of infrequent dizziness, resolved with time or reduced dosages.
For CNS disease skateholders of every kind (including Anavex shareholders), blarcamesine is unique. Nothing else like it; nothing to compare it to. Therefore, somehow, anything clinically positive being reported about it, even with the profoundly 'significant' statistics, just has to be questioned and is wrong. The "needs more study" notion.
For me, as a biologist who has scrutinized the blarcamesine data and studies, in both murines (lab rodents) and humans, I understand the continuing accumulation of thoroughly positive results of the drug. Not a single safety or efficacy failure in any study, human or murine.
It's now but a matter of time before some country's drug regulatory agency authorizes the sale and therapeutic use of blarcamesine for a central nervous system disease. The US Food and Drug Administration, the Australian Therapeutic Goods Administration; or elsewhere?.
In the case of Parkinson's disease dementia, the drug has now been proven (yes, that's the word — if you think not, tell of any other drug that matches or exceeds its safety and efficacy) to beat any existing SOC (standard of care drug) as to both safety and efficacy.
New buyers after Friday CTAD?
After public media reports.
Just as significant is blarcamesine safety.
But, will anything happen in Australia?
Everyone following Anavex, pro or con, has been pondering what might result from Anavex's 15 minutes of mic-time at the CTAD conference. Very well; appropriate.
But, how will the Aussies respond; if at all? How might they handle very positive reports in the media of "New American drug successfully treats Parkinson's disease dementia?"
If results are positive (they will be), both the American Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) will be questioned by both media reporters and the general public about blarcamesine. Of course, at least with the FDA, the standard "...data are incomplete; further studies are required" dictum will be the first, and probably only thing stated.
But with solid data, with people actually being known to be safely, successfully treated for their dementia, public conversation about the drug and its results will be prominent. The words "Anavex" and "blarcamesine" will be more widely known and encountered; just as happened with "penicillin."
The Anavex snowball is now at the top of the hill.
I hope so; but maybe not.