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Any thoughts on what news Tuesday (8/15/23) will/may bring? BTW, today was a nice change.
Reminds me that some posts are non-value add .
Open wish to all for a trash free week of legitimate AVXL info exchange. We are due to have some solid-positive, clinical news any day now.
xodcode:
Our unwritten Goal, AF and his crew are road kill. No prisoners.
Anavex Life Sciences Corp. (AVXL)
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9.46+0.09 (+0.96%)
As of August 10 09:37AM EDT. Market open.
Maybe the FDA (Amyloid ) story will get the direct-balanced fact based truth now. They have been called out again ...https://bigthink.com/neuropsych/stave-off-alzheimers-protect-brain-mitochondria/.
It is a shame that so much time/money and energy has been spent , this kind of thing should never happen. Curious if the FDA will actually do an analysis-evaluation following their own (published-part 820) required corrective action process rules. What is reason (root cause) for decades of their ineffective corrective action process? This is basic ISO-cGMP management 101 stuff.
Throw another log on the fire.
Brilliant plan , by abew4me...thanks...it will also open the door as you point out...
bas2020
pain
The good doctor could not see simple errors in basic stats, you have very high expectations
Sub $7.75 expected by EOD for more reloading
Is this just another TEST? Well, save your breath, most of us do not need one.
Thx George;
Why is This Important? This problem affects the investing public. Whether invested directly in the stock market or in mutual funds, IRAs, retirement or pension plans that hold stock – it touches the majority of Americans. The participants in this fraud, which, when fully exposed, will make Enron look like child’s play, have been very successful in maintaining a veil of secrecy and impenetrability. Congress and the SEC have unknowingly (?) helped keep the closet door closed. The public rarely knows when its pocket is being picked as unexplained drops in stock price get chalked up to “market forces” when they are often market manipulations. The stocks most frequently targeted are those of emerging companies who went to the stock market to raise start-up capital. Small business brings the vast majority of innovative new ideas and products to market and creates the majority of new jobs in the United States. It is estimated that over 1000 of these emerging companies have been put into bankruptcy or had their stock driven to pennies by predatory short sellers.
We'll have to see how or if this develops. Of course, Anavex executives already know the answer, from closed-door murine (lab rodent) studies. This would be blarcamesine's yet unrevealed antiaging property. Might those be restricted only to aging neurons; or, for other body tissues, organs, and processes? Eventually, will everyone be taking a blarcamesine pill each day to maintain youthful health and function deep into life?
August 7th and 8th has a stacked schedule of events, not typical for AVXL. On Monday 8/7 we have the virtual gig and then on Tues 8/8 we have stock holders qtrly. rpt. Stay tuned I guess.
https://finance.yahoo.com/news/anavex-life-sciences-present-btig-113000382.html
So, all we must do is...PAY ATTENTION...THE SYSTEM (CNS) has a LOT TO SAY. We must stop thinking serially....
se·ri·al·ly
adverb
1.
in a series or sequence.
"his stories were published serially in periodicals"
2.
in a way that repeatedly follows a characteristic, predictable behavior pattern.
"a specialist who serially abused the trust of vulnerable patients"
Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a and recently a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson's disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You can also connect with the Company on Twitter, Facebook, Instagram, and LinkedIn.
Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a and recently a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson's disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You can also connect with the Company on Twitter, Facebook, Instagram, and LinkedIn.
Based on evidence from research on the receptors' function in the brain and the drugs that can activate or inhibit them, the authors propose possible mechanisms by which GABA-modulating treatments could help address the cognitive and affective symptoms associated with depression.
there is very real possibility that the good news brewing is almost at a boil.
Anyone care to speculate on what will happen w/NAS and AVXL SP in particular on 8/3/2003? IMO, we did OK today in-spite of the going NAS melt down.
boi568
Some lies can be considered free speech. You see it on this board every day.
tredenwater2
“When you see what we did you will understand why we did things the way we did them.”
Talon 38. Well done. Watch your 6.
Our competition with Biogen has been going on for years since the MS look.
8.45 +0.20 (+2.42%)
After hours: -...does this count?
TIA
Critical point here:
We are leaps and bounds ahead of them in “proving” our data and should know soon about approval status.
TempePhil...thx...excellent work.
AB-E-NORMAL...for AVXL...
8.20+0.28 (+3.47%)
As of 10:03AM EDT. Market open.
Plexrec.... "well done"...
-"Finally, ANAVEX2-73, a s1 receptor agonist, has been shown to provide significant and sustained improvement in cognitive function in mild-AD patients
"Nuff Said"...The s1 receptor participates in the regulation of intracellular Ca2+ migration and maintains homeostasis and protects cognitive function damage [119,120]. Research on the role of the s1 receptor in mediating mitochondrial function has found that the s1 receptor attenuates hippocampal dendrite formation through scavenging of free radicals, and protects cells from damage by mitochondria-derived reactive oxygen species (ROS) [121,122,123]. The ER stress sensor inositol-requiring enzyme 1 (IRE1) facilitates mitochondrion-ER-nucleus signaling for cellular survival via the s1 receptor chaperone [75,124].[/quote]
https://www.mdpi.com/1422-0067/24/15/12025
Now, we need to hear from the RSD crew...bless the kids and families...helping to support WW sick people and to resolve little kids and their families pain...does not get much better...LETS ALL HAVE A GOOD WEEK FOR ONCE.
Thanks hnbbadger1...Noted no contradictions with AVXL research published to date.
[quote]Increasing evidence has proved that the s1 receptor holds great potential as a biomarker for early AD diagnosis and progression and the monitoring of AD drug efficacy [49]. Hallmarks of human AD include progressive cognitive decline that follows chronic neuroinflammation and the emergence of hyperphosphorylated tau protein aggregates and Aß plaques [46], with all playing critical and perhaps interrelated roles in the progression of AD. In particular, Ca2+ plays a critical role in learning and memory processes [114,115,116,117,118], and Ca2+ dyshomeostasis is a pathological feature of AD and other neurodegenerative diseases [114,115,116,117,118]. The s1 receptor forms a Ca2+-sensitive chaperone complex with the binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78), and prolongs Ca2+-signaling from ER into mitochondria by stabilizing inositol 1,4,5-trisphosphate receptor (IP3R) at the MAM [74]. The s1 receptor participates in the regulation of intracellular Ca2+ migration and maintains homeostasis and protects cognitive function damage [119,120]. Research on the role of the s1 receptor in mediating mitochondrial function has found that the s1 receptor attenuates hippocampal dendrite formation through scavenging of free radicals, and protects cells from damage by mitochondria-derived reactive oxygen species (ROS) [121,122,123]. The ER stress sensor inositol-requiring enzyme 1 (IRE1) facilitates mitochondrion-ER-nucleus signaling for cellular survival via the s1 receptor chaperone [75,124].[/quote]
https://www.mdpi.com/1422-0067/24/15/12025
Anyone else get a sense of comfort (just this side of warm-fuzzy) from last trading session -EOD results?
I like the little bounce we experienced and read it is driven by good news out there waiting. I do also hold out a positive attitude about other credible large Pharma co. having researched AVXL work/results/trials/direction .. .but that is just how I see the way work has been done by Dr.M and team. The AVXL staff-team have been around long enough to recognize the REAL thing when they see it.
My other observations are less positive or certain. I have begun to recognize just how devious/misleading the BP-WS processes are, having previous lab time on my own but never paying attention to just how many types of liars there are around BP/WS. Relying on process results is typically a safe bet for me but that all changed when I tried to get a rational line of thinking in support of FDA Amyloid closed minded status. It looks to me like the entire BP world has wrapped itself around the wrong flag pole and AVXL is not on that path at all. WGT, but it is a tough uphill slough. Anyways, my sense is we will see a breakout soon including AVXL proof by trials of RWD -RSD.
IMO, the other good news I see includes the (certain) avalanche-awakening to the CNS upstream work done by AVXL and the S1R AHAA moments including RSD-PDD-AD trial findings . This black hole cannot last indefinitely...one small lite is all we need...then...BBOOOM.
longtermbeliever:
again i believe they don't show up at AAIC due to partnership deal.
hnbadger1: From MayoMobile’s interview on July 18 at AAIC-
“Dr. Grimmer thinks they're
being approached/in-convo with big pharma for
purchase/partnering which is why we have not
seen data yet.”
Makes sense, if true then some BP name gets in the photo-story when the biggest medical news ever is launched. An old Maine expression comes to mind..."Fish, or CUT BAIT". Doing nothing, is not an option.
tredenwater2...
I have a great feeling we will all sit back and say…..” ahhh, thats why they did things the way the did them.”
Recommended reading: from sokol .... .Nice work....we got this.
[CNS Drugs.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#) 2023; 37(5): 399--440.
Published online 2023 May 11. doi: [10.1007/s40263-023-01007-6](https://doi.org/10.1007%2Fs40263-023-01007-6)
PMCID: PMC10173947
PMID: [37166702](https://pubmed.ncbi.nlm.nih.gov/37166702)
# Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders
.....Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. ...
### ANAVEX2-73 (Blarcamesine)
Blarcamesine (ANAVEX2-73; Fig. [?Fig.2)2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/figure/Fig2/)) is a s1R receptor agonist with an affinity of 860 nM (IC50) [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)] developed for treating AD. Blarcamesine also has agonist activity at the muscarinic M1 receptor, and the NMDA receptor with affinities of 5 and 8 µM, respectively [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)].
#### Alzheimer's Disease
Pre-clinical studies have shown that blarcamesine can reverse scopolamine's long-term amnesic effects in mice [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)]. Furthermore, blarcamesine can reverse the effect of learning deficits in mice injected with Aß25--35 [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)--[224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR224)]. Blarcamesine given to mice injected with Aß25--35 restored respiration rates in hippocampal mitochondria and reduced lipid peroxidation levels. Blarcamesine could also prevent tau-hyperphosphorylation and amyloid-ß (1--42) generation in mouse models of AD [[223](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR223)]. Furthermore, indicators of increased toxicity, including Bax/Bcl-2 ratio and cytochrome C release into the cytosol, were reduced [[224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR224)]. Blarcamesine has protective effects in _Caenorhabditis elegans_ and cell culture models of AD by enhancing autophagic flux and increasing proteostasis [[65](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR65)].
A phase 1 clinical study in healthy male volunteers showed that doses up to 50 mg were well tolerated, with no serious adverse events reported in a poster at the CNS summit in 2014 [[225](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR225)]. At 60 mg, three out of four subjects presented dose-limiting CNS symptoms (dizziness and headache). The study concluded with pharmacokinetic analysis showing extensive biotransformation of blarcamesine to AV19-144 (the bioactive form of the drug) with assumed linear pharmacokinetics after single oral dosing of 1 to 60 mg blarcamesine [[225](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR225)].
A biomarker analysis, phase 2a study ([NCT02244541](https://clinicaltrials.gov/ct2/show/NCT02244541)), that include some exploratory study into the benefits of blarcamesine, where blarcamesine was administered over 57 weeks, showed a significant reduction in cognitive decline [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)]. When the study was extended to 265 weeks ([NCT02756858](https://clinicaltrials.gov/ct2/show/NCT02756858)), there was confirmation of this prevention of decline at 148 weeks with analysis of blood concentrations of blarcamesine and its metabolite AV19-144, showing that those with high concentrations of blarcamesine had improved therapeutic responses of 78% and 88% in adjusted MMSE and adjusted AD cooperative study--activities of daily living (ADCS--ADL), respectively, relative to the low/medium concentrations of blarcamesine.
Furthermore, genomic analysis also indicated the significant effects of biomarkers on clinical outcomes of blarcamesine. Two patients showed an exceptional therapeutic response at 148 weeks. Both subjects had s1R wild type and a high mean concentration of blarcamesine in plasma, with a baseline MMSE > 20 [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)].
The study of biomarkers that predict the potential therapeutic outcome of a drug is especially useful in a disease with such heterogeneity as AD [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)]. The ApoE e4 genotype alone lacks predictive power since only approximately 25% of people carry this genotype. The study discussed above identified that patients with a baseline MMSE greater than 20 who had the s1R wild type with a high mean blarcamesine serum concentration and _ApoE3_ alleles had significantly better outcomes in the ADCS--ADL. The _SIGMAR1_ Q2P variant, having a baseline MMSE score lower than 20 and a low mean serum concentration of blarcamesine were predictive of poor outcomes in the ADCS--ADL [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)].
Blarcamesine is undergoing further phase 2b/3 clinical trials (ongoing: [NCT04314934](https://clinicaltrials.gov/ct2/show/NCT04314934); completed with data yet to be published: [NCT03790709](https://clinicaltrials.gov/ct2/show/NCT03790709)). The results of these clinical trials will be interesting, given the promise blarcamesine has shown in the pre-clinical studies.
#### Multiple Sclerosis
Blarcamesine increased the proliferation of oligodendrocyte progenitor cells to myelin sheath-producing oligodendrocytes in a s1R-dependent manner and protected them from excitotoxic insults [[227](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR227)]. There are no currently listed clinical trials for blarcamesine in MS on [www.clinicaltrials.gov](http://www.clinicaltrials.gov/).
#### Rett Syndrome
Long-term administration of blarcamesine to mice deficient in MeCP2 restores physiological and neurological abnormalities that mimic the human Rett syndrome, including ameliorating motor and acoustic startle deficits and reversing expiratory apnoea [[228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR228)]. Several s1R-related mechanisms could benefit the neurological and motor symptoms seen in this and other models of Rett syndrome. Enhancement of calcium homeostasis via s1R shuttling of calcium to the mitochondria leads to improved mitochondrial function and the activation of autophagy via s1R activation, resulting in a reduction of misfolded proteins and fewer damaged organelles or the restoring/upregulation of BDNF [[65](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR65), [228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR228), [229](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR229)]. This leads to potential improvements in synaptic function in multiple brain regions.
Blarcamesine is currently in phase 2/3 clinical trials ([NCT03758924](https://clinicaltrials.gov/ct2/show/NCT03758924), [NCT03941444](https://clinicaltrials.gov/ct2/show/NCT03941444) and [NCT04304482](https://clinicaltrials.gov/ct2/show/NCT04304482)). Blarcamesine has shown positive results in a phase 2 clinical trial ([NCT03758924](https://clinicaltrials.gov/ct2/show/NCT03758924)) in female patients diagnosed with Rett syndrome (positive _MeCP2_ gene mutation), meeting both primary and secondary endpoints with no reported serious adverse events (press release) [[230](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR230)]. In another phase 3 ([NCT03941444](https://clinicaltrials.gov/ct2/show/NCT03941444)) clinical trial the primary and secondary endpoints were met with significant improvements versus placebo in the clinical global-impression of improvement scale (CGI-I); the anxiety, depression and mood scale (ADAMS); and drug exposure-dependent response of the Rett Syndrome Behaviour Questionnaire (RSBQ), all with a low incidence of adverse events (press release) [[230](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR230)]. It is important to note that the data available from these studies has not been peer reviewed and formally published. There are further ongoing phase 3 studies organized by Anavex Life Sciences ([NCT04304482](https://clinicaltrials.gov/ct2/show/NCT04304482)). However, while the data look promising, it will be important to see some independent studies with peer-reviewed results to fully assess the efficacy and safety of blarcamesine for Rett syndrome treatment.
### ANAVEX3-71
ANAVEX3-71 (AF710B) (Fig. [?(Fig.2)2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/figure/Fig2/)) is an agonist at the muscarinic M1 receptor and s1R, and the second drug developed by for AD treatment. ANAVEX3-71 has an affinity for the s1R of 1.3 nM and an affinity for the s2R of 10 µM [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62)]. The affinity for the M1 receptor is approximately 0.05 nM. ANAVEX3-71 also has affinities for the µ opioid receptor and serotonin receptor (approximately 10 µM for each) [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62)].
#### Alzheimer's Disease
Given the complex pathology of AD, it is of interest that a drug such as AF710B may interact with multiple target sites to have a beneficial effect in AD [[52](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR52)].
Pre-clinical studies have shown ANAVEX3-71 to be worthy of further study. AF710B has been shown to modify the disease-defining hallmarks of AD in transgenic (3×Tg-AD) mice, such as cognitive deficits, amyloid and tau pathologies, and beneficial effects on mitochondrial dysfunction and neuroinflammation [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62), [231](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR231)].
Phase 1 clinical trials ([NCT04442945](https://clinicaltrials.gov/ct2/show/NCT04442945)) in healthy individuals have been reported on Anavex Life Sciences' website, suggesting that in healthy volunteers, 5--200 mg daily had no serious adverse events. The pharmacokinetics of ANAVEX3-71 (serum concentration of AF710B) was also proportional to the dose for doses up to 160 mg. Furthermore, there were no clinically significant electrocardiogram (ECG) parameters throughout the study (press release) [[232](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR232)].
There are no further registered ([www.clinicaltrials.gov](http://www.clinicaltrials.gov/)) ongoing clinical trials with ANAVEX3-71. However, Anavex states on its website that they plan further phase 2 clinical trials. More independent studies are required. However, pre-clinical data on ANAVEX3-71 suggest it could be useful in treating dementia and AD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/
You have not replied to my recent post regarding titration.
Sokol,
Many thanks for this excellent compilation of AVXL trial data. Obviously the tools required to keep track of and analyze the findings for the CNS clinical world to deal with are badly needed.
All of this will make more sense some day, hopefully in our lifetimes.
If only the trials could get better synchronized then we could make better use of resources WW.
Danke.