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Yes, if you read the Anavex tweet Bio posted in response to a Nidan post, it implies that we are likely to receive an announcement Thursday morning followed by a CC at 11 EST, I think.
It is difficult to conclude why the 11:00 E.T. was selected, but it might be for international participation. There is an international call in number included. As others point out, there should be an announcement outside market hours either tomorrow evening or early Thursday morning. Perhaps we will hear something directly from someone with first hand knowledge that was involved in conducting the PDD trial? This way, details about the results will come from a third party that was in a position to observe events, gather information, and data as the trial progressed. Otherwise, if it’s just a Missling presentation, there will be those that doubt the veracity of whatever is said about the trial unless Missling relates news that is all bad. I certainly do not expect the news to be all bad, but I do not know if it is going to be all good either. I am tempering my expectations. I will only be surprised and disappointed if the PDD trial is a total failure, and I say that because I am interested in advancing treatments for CNS disease as well as for personal gain. I can afford to lose the money I have invested, but people that need to be treated for CNS diseases cannot afford continuing failure of attempts to obtain treatments for PDD, AD, Rett, etc.
I like it. Thank you, Bio.
Yes, I think that is likely what will happen.
Well, Missling is not waiting for the market to close to make the announcement.
AVXL AD DOSAGE CONCENTRATION P VALUES BIOMARKERS RESPONSE SUMMARY FROM SLIDE PRESENTATIONS:
1.ANAVEX DOSAGE OVER TIME:
ANAVEX®2-73 Phase 2a Study in Alzheimer’s Disease
Efficacy (MMSE & ADCS-ADL) has been evaluated long-term
Part A (5 weeks)
Period 1 Period 2
IV (3mg or 5mg)
&
Oral (30mg or 50mg)
Part B (52 weeks)
Daily Oral Dose:
10mg, 20mg, 30mg, or 50mg
Part A and B – 57 weeks total
Extension (208 weeks) (57 & 208 weeks extension – 265 weeks)
Daily Oral Dose:
10mg, 20mg, 30mg, or 50mg
Note: This is from slide 5 of this slide presentation: https://www.anavex.com/wp-content/uploads/2019/03/Anavex-ASENT-March-2019.pdf
See also slide 7: Concentration is key as Investor says. This slide also states:
• High Concentration of ANAVEX®2-73 => High Delta ADCS-ADL (improved response)
• # Plasma concentration of ANAVEX®2-73 is correlated with the administered dose
2.AVXL 2-73 - GENOMIC BIOMARKERS - CONCENTRATION - P VALUES – AT 148 WEEKS:
• Systematic analysis using KEM® identifies actionable parameters enabling a precision medicine approach to include best responders in follow-up Phase 2b/3 study
• Patients with a wild-type SIGMAR1 gene were found to have an improved benefit from ANAVEX®2-73. Patients with a variant of the SIGMAR1 gene (rs1800866) were found to have a limited benefit from ANAVEX®2-73. Same for COMT variant (rs113895332/rs61143203)
• Including patients with milder disease stage (baseline MMSE ≥20) and the exclusion of AD patients carrying SIGMAR1 variants results in a score improvement of +1.7 MMSE and +3.9 ADCS-ADL, respectively at week 57. The additional exclusion of the COMT variant results in a score improvement of +2 MMSE and +4.9 ADCS-ADL, respectively for the same period. Both effects would be clinically meaningful
• The minority of the population (about 20%) has the variant SIGMAR1 gene, hence the majority of patients (about 80%) is expected to benefit from ANAVEX®2-73
• Gut microbiota has been collected and will be incorporated in future analysis
https://www.anavex.com/wp-content/uploads/2019/03/AAIC_Anavex_Gene_poster_2018_Final.pdf
High Concentration cohort shows 88 % difference to low concentration cohort
In addition to Concentration, the significant covariates identified in MMRM-LME model are: SIGMAR1 (p<0.0080),COMT (p<0.0014) andAPOE e4 status (p<0.0001)
SLIDE 16
Patients treated with higher ANAVEX®2-73 Concentration show higher cognitive MMSE1 Performance over 148 Weeks, compared to the lower Concentration (p-value < 0.0008) SLIDE 17
http://www.arianapharma.com/wp-content/uploads/2019/03/ANAVEX2-73_CTAD_2018_Presentation_v2.pdf
Yes, thank you. Frrol also pointed that out to me - lack of knowledge on my part about that stock and the stock split.
I see that now. Thanks
Yep! Unbelievable.
Investor: That is a good guess. I had the same thought - just not as quick as you. There’s science behind SR1 activation combatting the cytokine storm, inflammation, etc. However, Anavex does not have the resources to immediately pursue this. Anavex needs to remain focused on its pending clinical trials and its other day to day business. I imagine all of the available time of all of its employees is stretched as it is. Lastly, the material from this bio website does not have all of the typical securities language.
Sigma-1 activation may blunt the Covid “Cytokines Storm” according to some research I did some weeks ago after reading the below mentioned article in the WSJ. However, I did not post this research because I felt we have a long way to go before we get to this. In any event, here is a bit of my research (numbered 1-4):
1. Inflammation is the major problem causing deaths in Covid -19 patients. It is sometimes referred to as the "cytokine storm". WSJ article "Haywire Immune Response Eyed in Coronavirus Deaths, Treatment - Researchers are looking at treatments to suppress ‘cytokine storm,’ increasingly linked to the most severe Covid-19 cases"
This virus adversely impacts the central nervous system and organs throughout the body. See for example: The Surprising Neuroscience of COVID-19 Effects on the central nervous system might contribute to respiratory failure.
2. Sigma Receptor 1 activation attenuates release of inflammatory cytokines MIP1?, MIP2, MIP3a and IL12 (p40/p70) by retinal Müller glial cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451448/
3. Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection
SIGNIFICANCE
Cytokine storm plays an essential and commanding role in the clinical outcome and pathogenesis of influenza virus infection. We previously documented that a small molecule that activates sphingosine-1-phosphate-1 receptor (S1P1R) signaling is primarily responsible for blunting cytokine storm to protect the infected host from the consequences of influenza infection. In the present study, we map host innate signaling pathways of cytokine storm and chart where along those pathways the drug is effective. We find that the efficacy of S1P1R agonist in blunting cytokine storm is through global inhibition downstream of myeloid differentiation primary response gene 88 and IFN-ß promoter stimulator-1 signaling.
Keywords: pathology, pulmonary
ABSTRACT
During pathogenic influenza virus infection, robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. .....Here, we show that S1P1R agonist treatment suppresses global cytokine amplification. Importantly, S1P1R agonist treatment was able to blunt cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P1R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-ß promoter stimulator-1 signaling, indicating a common pathway inhibition of cytokine storm. ....
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956176/
4. These slides were used at the Anavex presentations in 2019:
http://www.arianapharma.com/wp-content/uploads/2019/07/Anavex-Microbiota-Presentation-AAIC-July-2019-FINAL-1.pdf
See specifically the slide entitled: SIGMAR1 Restores Homeostasis Caused by Neuro-inflammation
“Pending mid-2020 Releases:”. The article list 16 biotech companies with pending “mid-2020 Releases”. So, Anavex is one of the 16 biotech’s this article mentions with pending mid-2020 releases. Now that we are about exhausted in bludgeoning Anavex and Missling, let’s expend any left over anguish in lambasting these other 15 biotechs that also have not reported data.
https://www.benzinga.com/general/biotech/20/07/16778963/the-week-ahead-in-biotech-spotlight-on-gw-pharma-ultragenyx-fda-decisions-pfizer-earnings
This is what Trump said tonight: “I think we can knock it out before it disappears," Trump said. "That's what I want. And if I had my choice between vaccines or therapeutics, give me therapeutics every time because I'd love to walk into a hospital and give everybody something and they start walking out in two days. That's what I'd like."
https://www.newsweek.com/president-trump-says-give-me-therapeutics-over-covid-19-vaccine-1519852
Boi:
Thank you for your post. I agree that not all sigma-1 agonists are the same. I add this in support:
Donepezil is a nonselective sigma-1 agonist as opposed to a sigma-1 receptor selective medication such as AVXL 2-73. Selective sigma-1 agonists show promise for treating dementia and other conditions.
"Although no sigma-1 receptor–selective medications are currently approved by the FDA, several currently marketed agents and other substances interact with sigma-1 receptors in a nonselective manner, such as fluvoxamine, donepezil, haloperidol, and pentazocine.".....
ANAVEX2-73: The leading sigma-1 agonist under development is ANAVEX2-73, an amino-tetrahydrofuran derivative and mixed muscarinic/sigma-1 receptor agonist.16 At present, 3 active clinical trials involve ANAVEX2-73: one for Parkinson disease with dementia and 2 for Alzheimer disease.17 Another clinical trial for Rett syndrome is planned, announced in October 2018 by manufacturer Anavex Life Sciences."...
https://www.neurologylive.com/journals/neurologylive/2019/april-2019/sigma1-agonists-offer-combination-approach-to-dementia-symptoms
"ANAVEX 2-73 (AV2-73) is a novel cholinergic and selective sigma-1 receptor agonist under development as potential agent for Alzheimer’s disease or dementia with neuroprotective properties. "
https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/2321147
It seems to me, very much a non-expert, that comparing selective sigma-1 agonists with non-selective sigma-1 agonists is an apples/oranges comparison.
Furthermore, AVXL 2-73 “... it is a mixed ligand for sigma1/muscarinic receptors...”, and that needs to be kept in mind in making comparisons.
Anders: Sound analytical analysis. Thank you.
Anders: Than you.
Anavex has good patent counsel.
Steffen Thomas, PhD, is a member of Anavex’s Board of Directors. He had 15 years of experience in intellectual property as of 2015, patent law and proprietary technology rights as well as significant expertise in small molecule pharmaceuticals.
See this for more about Thomas’ pharmaceutical and patent background: https://www.anavex.com/anavex-strengthens-board-of-directors/
Anders:
The International Patent System; It does not protect you everywhere, but see this:
https://www.wipo.int/pct/en/?_ga=2.6780978.1078528252.1594847172-1017747583.1594847172
PCT – The International Patent System
COVID-19 update – IB interprets COVID-19 as falling under PCT excuse of delays provision | Important information for PCT Users
The Patent Cooperation Treaty (PCT) assists applicants in seeking patent protection internationally for their inventions, helps patent offices with their patent granting decisions, and facilitates public access to a wealth of technical information relating to those inventions.
By filing one international patent application under the PCT, applicants can simultaneously seek protection for an invention in a large number of countries.
Double click here to see the countries:
https://www.wipo.int/pct/en/pct_contracting_states.html
Supposition, but perhaps change the gut microbiome is associated with increased mitochondrial complex I activity. According to the recent Seeking Alpha article, "A2-73 ... increased mitochondrial complex I activity, which is dysfunctional in PD neurons."
https://seekingalpha.com/article/4357368-anavex-is-likely-to-report-positive-parkinsons-disease-trial-results-for-a2minus-73
A new study found that exercise -- and in particular high-intensity interval training in aerobic exercises such as biking and walking -- caused cells to make more proteins for their energy-producing mitochondria and their protein-building ribosomes, effectively stopping aging at the cellular level.
https://www.sciencedaily.com/releases/2017/03/170307155214.htm
Recent studies suggest that exercise has a number of benefits for the gut microbiota. It is linked to increases in the number of beneficial microbial species and enriching microbial diversity as well as enhanced short-chain fatty acid synthesis and carbohydrate metabolism.
https://atlasbiomed.com/blog/how-does-exercise-affect-gut-microbiome/
I have not found much more about this and it may not be very helpful, but see this:
Host mitochondria influence gut microbiome diversity: A role for ROS
https://stke.sciencemag.org/content/12/588/eaaw3159
Seriously, Missling impresses me as a strategic planner. We are not speaking about the stock market or biotechs in general. We are speaking about Anavex and Missling, and the manner in which he runs his company.
Bio:
Thank you. Excellent perspective and strategic thinking. Anavex has multiple drugs, all with various uses. Anavex has several plans for accessing capital. There is no pressure to act hastily to stay afloat. We have the time, the money, and the drugs for many indications with blockbuster potential. All together, Anavex has many options for achieving great success in the long run.
In the meantime, if AVXL 2-73 obtains approval for one indication, it will be available to help some patients suffering from the dreaded diseases for which there is little or no treatment. Rett will not make us rich, but I read the recent N.Y. times article Gina Kolata wrote about three different families with rare diseases entitled "It will consume your Life": Families take on rare diseases." One is about a Rett Syndrome family. It will give us a great deal of satisfaction if some of these families and patients may benefit. Off label use will not make us much money either, but it may help some like those on this board who have expressed a desperate need for treatment for themselves or a loved one.
How may AVXL 2-73 benefit motor impairment of Parkinson's Disease?
Levodopa is a drug to treat Parkinson's disease, but a side effect of long-term use of levodopa is dyskinesia.
"The features of dyskinesia include rapid, involuntary, and uncontrollable movements other than the tremors typical of Parkinson’s. Dyskinesia can present as body swaying, writhing, twisting, squirming, arm flailing, fidgeting, or head bobbing. Dyskinesia initially appears on the side of the body most affected by Parkinson’s. Although it can be localized to one part of the body such as the legs and arms, it can also spread to the torso, head, and neck. In rare circumstances, dyskinesia can also affect speech and respiratory and eye muscles.....
In Parkinson’s, there is a loss of brain cells called dopaminergic neurons that make dopamine; therefore, the level of dopamine in the brain starts to decrease. The purpose of taking levodopa is to temporarily restore the dopamine that is lost. However, since levodopa is intermittently taken over the course of a day, the level of dopamine will rise and fall. These dopamine level fluctuations, in combination with the loss of dopaminergic neurons, are thought to cause dyskinesia. Dyskinesia can occur when the level of levodopa in the body is at a maximum, referred to as peak dose dyskinesia, or when the levels of levodopa are rising or falling, referred to as diphasic dyskinesia."
https://www.apdaparkinson.org/what-is-parkinsons/treatment-medication/medication/dyskinesia/
"Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time. Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy. "
https://parkinsonsnewstoday.com/2019/07/23/imbalance-in-neurotransmitters-dopamine-acetylcholine-tied-to-parkinsons-progression/
"ANAVEX 2-73 is a sigma-1 receptor agonist, which also has micromolar affinities for muscarinic M1–M4 receptors...'' https://drugs.ncats.io/substance/9T210MMZ3F ...ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.[2] "....https://newdrugapprovals.org/tag/%E3%83%96%E3%83%A9%E3%83%AB%E3%82%AB%E3%83%A1%E3%82%B7%E3%83%B3/
"M4 muscarinic receptors function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.........
Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease." https://en.m.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4
Note: Apparently, Anavex is one of the key players in the Muscarinic Acetylcholine Receptor M4 Market
Major Key players covered in this report:– Anavex Life Sciences Corp, AstraZeneca Plc, Heptares Therapeutics Ltd, Karuna Pharmaceuticals Inc, NeuroHealing Pharmaceuticals Inc, Sumitomo Dainippon Pharma Co Ltd.
Muscarinic Acetylcholine Receptor M4 Market Potential
Premium Insights on Muscarinic Acetylcholine Receptor M4 Market 2020 with Market Players Positioning;
Download Free Sample Copy:
https://inforgrowth.com/sample-request/6301780/muscarinic-acetylcholine-receptor-m4-market
https://coleofduty.com/military-news/2020/05/27/latest-update-2020-muscarinic-acetylcholine-receptor-m4-market-by-covid19-impact-analysis-and-top-manufacturers-anavex-life-sciences-corp-astrazeneca-plc-heptares-therapeutics-ltd-karuna-pharmace/
The M4 market reports are costly, and I have no access to those reports.
ANAVEX 2-73 is a sigma-1 receptor agonist, which also has micromolar affinities for muscarinic M1–M4 receptors...''
https://drugs.ncats.io/substance/9T210MMZ3F
...ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.[2] ....
https://newdrugapprovals.org/tag/%E3%83%96%E3%83%A9%E3%83%AB%E3%82%AB%E3%83%A1%E3%82%B7%E3%83%B3/
M4 muscarinic receptors - Dopamine and Acetylcholine - Cognition - Dyskinesia (uncontrolled, involuntary movements).
Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine.
In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control.
Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time.
Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy.
Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum.
To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death.
This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance.
“While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote.
Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters.
Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded.
Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.
https://parkinsonsnewstoday.com/2019/07/23/imbalance-in-neurotransmitters-dopamine-acetylcholine-tied-to-parkinsons-progression/
M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[6]
They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.........
Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease. https://en.m.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4
In anatomy, the extrapyramidal system is a part of the motor system network causing involuntary actions. https://en.m.wikipedia.org/wiki/Extrapyramidal_system
The striatum is one of the principal components of the basal ganglia, a group of nuclei that have a variety of functions but are best known for their role in facilitating voluntary movement. https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum
M4 muscarinic receptors - Dopamine and Acetylcholine - Cognition - Dyskinesia (uncontrolled, involuntary movements).
Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine.
In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control.
Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time.
Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy.
Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum.
To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death.
This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance.
“While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote.
Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters.
Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded.
Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.
https://parkinsonsnewstoday.com/2019/07/23/imbalance-in-neurotransmitters-dopamine-acetylcholine-tied-to-parkinsons-progression/
M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[6]
They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.........
Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease. https://en.m.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4
In anatomy, the extrapyramidal system is a part of the motor system network causing involuntary actions. https://en.m.wikipedia.org/wiki/Extrapyramidal_system
The striatum is one of the principal components of the basal ganglia, a group of nuclei that have a variety of functions but are best known for their role in facilitating voluntary movement. https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum
........
The muscarinic acetylcholine M4 receptor is primarily found in the CNS [15, 16, 17], its distribution largely overlapping with that of M1 and M3 subtypes. M4 receptors function as inhibitory autoreceptors for acetylcholine [18, 19], activation of which inhibits acetylcholine release in the striatum.....
Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission and activation of M4 receptors in the striatum inhibits dopamine-induced locomotor stimulation in mice [20]. M4 receptor-deficient mice exhibit increased locomotor simulation in response to dopamine agonists, such as amphetamine and cocaine [21, 22, 23, 2]. Neurotransmission in the striatum influences extrapyramidal motor control. Therefore, alterations in M4 receptor activity may contribute to conditions such as Parkinson's Disease [24, 25, 26].
https://www.ebi.ac.uk/interpro/entry/InterPro/IPR001432/
Intermittent dosing is interesting. I thought about intermittent dosing when I did research for my first post about the recent Seeking Alpha article, which mentions mTOR. Overwhelming evidence shows a primary role for TOR signaling in aging and CNS diseases are diseases of the aging. The SA article mentions this:
"...AD and PD are both associated with impaired autophagy, so stimulating autophagy flux is desirable. A2-73 activates autophagy by somehow increasing phosphorylation of the protein ULK1 at a serine amino acid located at position 555 (pS555). This is exciting because S555 phosphorylation of ULK1 can block age-related enhanced mTORC1-mediated ULK1 phosphorylation at S757 and subsequent autophagy downregulation."
The reason why I thought about the use of intermittent for AVXL 2-73 is because either the SA article and research mentioned mTORC1 as a target for the drug rapamycin. I did research on rapamycin. That drug is used to suppress the immune system so that organs transplanted will not be rejected by the body. Rapamycin has adverse side effects. Interestingly, intermittent dosing of rapamycin is used off label for anti-aging purposes. Some profess that if used intermittently rapamycin's side effects are minimal, and that "knocking down" the adverse consequences of mTor once a week results in the prevention of many problems that come about with aging. (My non-professional wording from reading quite a number of articles.)
I will write more about this later when I have time. I think intermittent dosing is interesting because some companies have been trying to produce a drug that has the same effect as rapamcyin on age related problems, but not the same side effects. Rapamycin, I think, will never be widely used for anti-aging or aging problems.
Of course, it seems that AVXL 2-73 is safe. If turning off mTor activity that creates many problems for us folks that are aging, it may be used safely - especially if it is used intermittently. If used intermittently, it too is less expensive even if the initial price of AVXL 2-73, if approved, is high.
Please excuse any typos, etc. I wrote this without checking it.
The Fox Foundation and the Seeking Alpha article written by Michelle Cutler-Strom believe that Sigma1 agonist may improve motor deficits in PD patients. The Fox Foundation and the Seeking Alpha article written by Michelle Cutler-Strom
1. This is from the recent Seeking Alpha article: Anavex Is Likely To Report Positive Parkinson's Disease Trial Results For A2-73, Increasing Share Value https://seekingalpha.com/article/4357368
"PD is characterized by abnormal dopamine signaling due to the loss of dopamine producing neurons....cocaine, and perhaps A2-73 ... enhance D1R and D2R signaling.
PD patients have sworn that cocaine relieves their dyskinesia during "off" episodes." (Dyskinesia is abnormality or impairment of voluntary movement.)
"Sig1R agonists increase Sig1R monomer binding to DAT, stabilizing DAT, and increasing extracellular dopamine. In several different mouse models of PD, treatment with the SigR1 agonist PRE084 significantly attenuated motor impairment. Increased dopamine signaling relieves PD motor symptoms, but there is also evidence that patients with higher Levodopa dosages (dopamine) maintain their cognitive ability."
2. This is from the Fox Foundation: https://www.michaeljfox.org/grant/neurorestorative-effects-sigma-1-receptor-agonist-model-parkinsons-disease:
"In a previous MJFF-sponsored project, we evaluated PRE-084 (an experimental compound binding to the sigma-1 receptor) in pre-clinical models of Parkinson’s disease. Chronic treatment with PRE-084 produced a gradual improvement of motor deficits and activated molecules involved in brain repair. In this project, we will evaluate a sigma-1 receptor agonist (ANAVEX2-73) produced by Anavex, which is now being evaluated in patients with Alzheimer’s disease. In our experimental study, the efficacy of ANAVEX2-73 on Parkinson’s biology will be compared to that of PRE-084 and other Sig-1R ligands. "
3. This from: Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases (Under the heading "Role of S1R in Parkinson's Disease (PD). https://www.frontiersin.org/articles/10.3389/fnins.2019.00862/full
Role of S1R in Parkinson’s Disease (PD)
Dopamine receptors play important roles in learning and memory, motivation and movement and S1R agonists modulate dopaminergic signaling through multiple mechanisms. This has primarily been studied in the context of psychostimulant research, but these results may be important for understanding regulation of dopamine neurotransmission and its dysregulation in HD and PD. S1R appears to differentially regulate dopamine D1 and D2 receptors, as S1R activation by cocaine inhibits D2R (Navarro et al., 2013) and prevents histamine H3 receptor-dependent inhibition of the dopamine D1 receptor, stimulating Gs, recruitment of ß-arrestin and phosphorylation of ERK1/2 (Moreno et al., 2014). Although S1R activation does not affect basal dopamine neurotransmission, it attenuates methamphetamine-induced and DAT-dependent increases in firing of dopamine neurons (Sambo et al., 2017). It also interacts directly with the DAT and attenuates calcium signals evoked by methamphetamine (Sambo et al., 2017). As a result, S1R limits hyperactivity, motivated behavior and reinforcement from methamphetamine (Sambo et al., 2017).
Abnormalities in movement and cognition in PD result from degeneration of dopaminergic neurons projecting from the substantia nigra to the striatum. S1R is expressed in these neurons (Hong W.C. et al., 2017) and it can bidirectionally modulate NMDAR-dependent release of dopamine in striatal brain slice experiments (Gonzalez-Alvear and Werling, 1994). S1R may be decreased in striatal regions that are preferentially affected in PD (Mishina et al., 2005), which could contribute to neuropathology as indicated by studies with S1R KO mice. Similar to PD patients, S1R KO mice have age-related deficits in motor behavior and degeneration of dopaminergic neurons (Hong W.C. et al., 2017). This appears to be related to aggregation and phosphorylation of a-synuclein which may be driven by phosphorylation of eIF2a from ER stress and proteasomal dysfunction (Hong W.C. et al., 2017). Pharmacological inhibition of ER stress prevented oligomerization of a-synuclein, dopaminergic neuron loss and motor impairments in S1R KO mice (Hong W.C. et al., 2017).
Recent studies found that S1R agonists are protective in PD models. For example, chronic treatment with PRE-084 gradually improves PD-like motor deficits from unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesions (hemiparkinsonian model) when treatment onset was prompt (Francardo et al., 2014). This treatment suppressed neuroinflammation while increasing levels of neurotrophic factors, monoamines (e.g., dopamine and serotonin), dopaminergic innervation of the striatum, and nigral neuron survival (Francardo et al., 2014). Low dose pridopidine treatment (0.3 mg/kg) of unilaterally 6-OHDA-lesioned mice partially protected nigral dopaminergic cell bodies and increased dopaminergic fiber density in the motor striatum (Francardo et al., 2019). This was associated with a gradual restoration of forelimb use (cylinder test, stepping test) and prevention of rotational bias toward the ipsilateral side (Francardo et al., 2019). The delayed recovery of motor function corresponds roughly with the expected timeline of pridopidine-dependent dopaminergic axon sprouting (Francardo et al., 2019). Treatment efficacy was absent in S1R KO mice, which had reduced loss of dopaminergic neurons in the substantia nigra pars compacta, but a greater loss of dopaminergic fibers in the striatum compared to wild-type mice (Francardo et al., 2019). The increased vulnerability of S1R knockout mice to axonal degeneration in the nigrostriatal pathway could relate S1R’s ability to promote growth and repair of neurites (Francardo et al., 2019). The neuroresorative effects of pridopidine were associated with upregulation of neurotrophic factors (BDNF, GDNF, pERK1/2) and associated signaling in the striatum and substantia nigra as well as reduced microglial activation (Francardo et al., 2019).
One reason why AVXL 2-73 may be beneficial for PD and AD is this: Sigma 1 agonist, like Cocaine, MAY decrease mTORC1. The author of Anavex Is Likely To Report Positive Parkinson's Disease Trial Results For A2-73, Increasing Share Value https://seekingalpha.com/article/4357368 says this:
"mTORC1 is hyperactive in AD an PD, and hyperactive mTORC1 decreases transcription factor TEFB activity to downregulate autophagy and lysosomal gene expression. And here is the clincher... Cocaine, a sig1R agonist, decreases mTORC1 activity and increases autophagy.
I think it is safe to extrapolate that A2-73 will have the same effect as cocaine since it explains how ULK1 was phosphorylated by A2-73 treatment. In absence of sig1R, autophagosome clearance is impaired, which is exactly what happens in AD and PD. Thus, A2-73 should increase autophagy in AD and PD and this is huge!"
I did a bit of research to better understand and verify the above quote from the Seeking Alpha article. Below are a few of these research references that may help others, like me, that struggle to understand what the author has concluded and whether this one point is valid. I hope to research other points later when time permits. This research may be too basic for some, but helpful for others.
1. ULK1 is an enzyme that in humans is encoded by the ULK1 gene.[5][6]
Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ULK1/2 genes.[5][6] It is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded.[7......Ulk1/2 is an important protein in autophagy for mammalian cells....ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy......Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals.[11]. https://en.wikipedia.org/wiki/ULK1
2.Phosphorylation is important in the fields of biochemistry and molecular biology because it's a key reaction in protein and enzyme function, sugar metabolism, and energy storage and release.....Phosphorylation plays critical roles in the regulation of many cellular processes including cell cycle, growth, apoptosis and signal transduction pathways. Phosphorylation is the most common mechanism of regulating protein function and transmitting signals throughout the cell. https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/phosphorylation.html
3.The mammalian target of rapamycin mTOR complex 1 (mTORC1) negatively regulates autophagic activity via inhibitory phosphorylation of ULK1, and is the key initial regulator of canonical autophagy. More downstream membrane expansion is modulated by two ubiquitin-like conjugation systems (ATG12-ATG5 and ATG8/LC3) and the ATG18 protein family members of WD repeat domain phosphoinositide interacting 1-4 (WIPI1-4), as recently excellently reviewed [10]....it was demonstrated that cocaine-mediated autophagy in astrocytes involves Sig-1R [36].... Sig-1R Activation Induces ULK1 Phosphorylation and Affects Expression Levels of Distinct Autophagy Network Factors Activation of the serine/threonine protein kinase ULK1 (unc-51-like kinase 1) via phosphorylation at serine 555 indicates stimulation of the canonical autophagy pathway. ANAVEX2-73 significantly induced ULK1 serine 555 phosphorylation (up to 2-fold at 1 µM; Figure 2A). Again, we analyzed also PRE-084 as Sig-1R agonist and found that it promotes ULK1 serine 555 phosphorylation to a similar extend (up to 1.5-fold at 1 µM; Figure 2B). It has to be mentioned that this activating ULK1 phosphorylation can be inhibited by mTOR as well as stimulated via AMPK kinase [46], both are basal physiological sensors of nutritional conditions and key signal transducers of canonical autophagy stimulation. ULK1 is actually the signal mediating the induction of the formation of the phagophore during the autophagy process and therefore, a central promoter of autophagy. ULK1 itself functions in a complex with at least three protein partners: FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG13, and ATG101. Since a complex pattern of upstream pathways (including mTOR and AMPK) converge on ULK1, it suggests this complex acts as a node converting multiple signals into autophagosome formation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468724/)
CONCLUDING COMMENT: OF COURSE, WE MUST WAIT AND SEE THE RESULTS OF ANAVEX TRIALS. IT’S ALL VERY COMPLICATED, AND THE RESEARCH TO BE VALIDATED.
Richelle Cutler-Strom
Long/short equity, Growth, growth at reasonable price, short-term horizon
Member Since 2019
Company: Battle biotech
I am a research scientist and a registered patent agent, with a wide range of biotechnology expertise. I have high accuracy in predicting clinical success of compounds in development. My success is attributed to studying a compound's mechanism of action and possible side-effects using research publications and clinical trial data. In addition, I evaluate risk by identifying the competition, intellectual property status, and financial security. Altogether, my in-depth analysis provides a reliable appraisal of market potential to ensure investment success.
INVESTING IN SCIENCE ----87% return this year. 156% time weighted return.
Offering investment consultation for developing biotech companies at $51/hr.
Note: I will do more research about Richelle later when I have time, but it sounds to me like she is an excellent and dedicated researcher judging from her work.
Today's Share Price Action: It depends on your perspective, but for me, today's share price movement is meaningless. Anyone else thinking longer-term may agree. Those involved in this stock for the short term may either beat themselves on the chest or bang their heads against the wall. The stock price may move lower or rally in the coming days, but that is not my concern. It is success in the long run that matters. I saw nothing today that changes my mind about my investment.
Yes, I did not mean for my comments to be an attack of what you said, Doc. I think that investor interpreted it that way. You may have as well. I suppose that was due to my comment “However, see this.” What I meant was for this to be a reply to Anders, and to provide some papers for him to consider. Sorry about that.
UniProtKB/Swiss-Prot Summary for SIGMAR1 Gene
....Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria.....
https://www.genecards.org/cgi-bin/carddisp.pl?gene=SIGMAR1
But, AVXL 2-73 is a mixed ligand for sigma1/muscarinic receptors. Doc's concern is this: "M4 agonism may worsen tremor (see link below where I discussed in more detail). Clinically, muscarinic antagonists help motor function in PD so agonists would not be expected to help. However, there is potential for the dementia to improve with A273 in PDD via M1 agonism (and maybe S1R), similar to possibility in AD.
An ideal medication for PDD may be an M1 agonist and M4 antagonists.".
However, see this:
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286317/
Roles of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson's Disease
Abstract
Antagonists of the muscarinic acetylcholine receptors (mAChRs) were among the first treatments for Parkinson's disease. ...Understanding the roles of specific mAChR subtypes in regulating basal ganglia and motor function could lead to the development of novel agents that have antiparkinsonian activity with fewer adverse effects. .... ...M1-selective antagonists may have weak antiparkinsonian activity but would not have the full efficacy observed in nonselective mAChR antagonists. Consistent with this, the M1-selective antagonist VU0255035 partially reversed reserpine-induced akinesia and decreased haloperidol-induced catalepsy in rats but did not have the full efficacy observed with the nonselective mAChR antagonist scopolamine. These results suggest that the M1 receptor participates in the overall regulation of basal ganglia function and antiparkinsonian effects of mAChR antagonists but that other mAChR subtype(s) also play important roles at multiple levels of the basal ganglia motor circuit.
2. https://www.michaeljfox.org/grant/highly-selective-m1-muscarinic-receptor-positive-allosteric-modulators-treatment-parkinsons
Hypothesis:
We believe that small molecules that affect the function of the M1 mAChR in a highly selective manner have the potential to deliver novel, well-tolerated and efficacious drugs to treat learning and memory deficits in individuals with PDD.
Study Design:
We have generated small molecules of novel chemical classes that are positive allosteric modulators of the M1 mAChR and have a good understanding of the structure-activity relationship of these molecules. Based on this knowledge, we will synthesize these molecules and optimize them for target engagement in the brain and safety.
Nidan: I think you just said all we can say about the financing announcement. Good judgment well stated!
Assuming the science behind Anavex's drug development is legitimate and worthy of exploring, as many do. Access to capital to do that is critical, and “access to reasonably priced capital” is better as I think Froll understands better than I. Access to capital supposedly has been a problem for emerging biotechs all along. See this:
Emerging Biotechs’ Greatest Challenge: Acquiring Capital
"Biotechnology companies heard a clear message at the 12th annual Biotech Investment Conference, in Millbrae, Calif.: To get cash, you need a good management team to get a product to market. Acquiring capital is the major challenge emerging biotechs face. And, without products to sell, there are limited ways to obtain capital, making the task daunting."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564327/
So, I am open to trying to understand what, if any, well-meaning concerns there may be to the steps that Anavex has taken to obtain the capital necessary to the development of its drug or drugs that may be of great benefit to society. Moreover, if well-founded worry or unease exists, I think it should be in terms that are meaningful and understandable. After all, we discuss a drug or drugs that may affect the lives of human beings with dreaded and fatal consequences—their lives matter.
I am a novice at this, but I attempt to learn the best I can. How unusual was the put option activity for July $5 puts on the day before the financing amendment was announced? In looking at the volume for AVXL July $5.00 put option contracts for that day, I see where the volume reported via Yahoo finance was 200 and the open interest 2.3k. Assuming those numbers are correct, it does not seem like the July $5.00 put option activity was unusual or that it is indicative of where the AVXL stock price should go? But, you may have some better information or insight than I do.
In researching stock options, I do see where various stock option spread strategies exist where one sells one higher strike price put option contract and then buys another lower strike priced put option contract.
The maximum profit for a bull put spread is equal to the difference between the amount received from the sold put and the amount paid for the purchased put. In other words, the net credit received initially is the maximum profit, which only happens if the stock's price closes above the higher strike price at expiry.
The goal of the bull put spread strategy is realized when the price of the underlying moves or stays above the higher strike price. The result is the sold option expires worthless. The reason it expires worthless is that no one would want to exercise it should the stock price move higher.
Using the July 17 $5 and $7.5 put options as an example, if one were bullish on Anavex, you could buy a $5 put contract for $.50 and sell a $7.5 put contract at a price of $2.60 and pocket $2.10 x 100 = $210 per contract as a credit. If the stock price moved above $7.50, the $7.5 put contract would expire worthless, and you keep the $210 without having to purchase Anavex stock at a price of $7.50. If you were wrong about being that bullish, you would of course have to purchase Anavex stock at $7.50, but you still keep the $2.10 per share so your net in that stock would be $7.50 - $2.10 = $5.40. So, wouldn't you have to analyze the stock option spreads to get a clear picture of whether to be bullish or bearish on a stock? Just asking.
So, what Anavex announced yesterday may send the message to big pharma on this July 4th that, “You are not going to rain on my parade”
Yes, that answers Turner’s question.
With this agreement, Missling is not under any “pressure” as he put it to, for example: (1) to make a deal with big pharma, (2) to worry about whether the pandemic may get worse and cause unexpected problems, (3) to not be able to raise capital if economic conditions worsen for any reason and lead to some sort of liquidity crises, or (4) to worry about market conditions that affect a clinical stage pharmaceutical company.
The agreement gives Anavex a great deal of time and flexibility without having to worry about market conditions. When someone says wait and sell for a higher price, I ask what higher price? It is not that simple to do - sell at that higher price. For example, INO (developing among other things a Covid vaccine) was at a high of $33.39 Friday a week ago. Wednesday of this week it reached a low of $18.35 after Pfizer’s announcement of some slight degree of success in its limited vaccine trial. Biogen or another big pharma could announce just about anything regarding AD, and everyone would fall all over themselves to buy that big pharma stock leaving Anavex in the dust. If you remember, we have seen that happen. My point is that market conditions - especially for clinical stage pharmaceutical companies in normal conditions are subject to wide fluctuations. We are not experiencing normal times with the pandemic, this presidential election (remember the remarks about drug prices in the last election?), protests and the like we are experiencing. Even if Anavex shoots up to $14 per share Monday morning on positive news, no one knows where the price may be 3 days later. Anavex’s stock shot up to over $14 per share Friday, November 6, 2015, and Friday, November 20, 2015, it reached a low of $3.16 per share.
While on the subject of market conditions, I am not so sure that we are past the stage of experiencing lock limit down days in the markets like we saw this past March. In times of a crises, with lock limit down days, investors are sometimes forced to sell everything. Anavex’s desire should be to keep the company on track without any interruptions from unexpected shocks that may hit the markets. The LPC agreement helps to assure that will be the case.
After thinking more about the amendment to the agreement between Anavex and LPC, both parties are thinking long term. Anavex needs to raise capital if its drug development outlast its cash position, which is presently enough to last for one year assuming its current clinical trial situation is all that Anavex has planned for now. Anavex may also have something else in mind in making this deal. Either way, Anavex will need more capital, and LPC is willing to risk capital, just like some of us on this board, because it thinks there will be a payoff that is worth the risk.
Either way, it's a good deal for Anavex.
If the trials are positive, Anavex may not need to sell much, if any, stock to LPC. Anavex could sell stock to others at a higher price, and/or Anavex may find some other favorable option such as a partnership.
If Anavex's current trials are not so positive (as some here think), Anavex can sell stock to LPC, use the capital to seek to salvage what it can from current drug trials, and conduct new trials for AVXL 2-73 and for its other drugs down the road.
Any way you look at it, Anavex is planning to remain in business, and will need more capital beyond its current one year capital position. Additionally, LPC is willing to risk a large amount of its capital because it thinks the payoff may be huge enough to take that risk.
Another way of stating this is that:
(1) Anavex is willing to give up some ownership if its future capital needs for drug development or its future situation demands it, and
(2) LPC thinks the award is worth the risk of providing a substantial amount of that future capital to Anavex.
Therefore, on balance, this agreement is positive for Anavex and its shareholders.
Typo. Thanks
It takes a meeting of the minds to make an agreement or to amend an existing agreement. Both parties must be willing. It is not a unilateral transaction on the part of Missling as some may imply. Moreover, this is not LPC’s first rodeo. To view this as a Missling ploy to take advantage of LPC, an experienced party, is a significant stretch. Everyone knows clinical trials and results are pending. No experienced party enters a $250,000,000 agreement like this without doing its due diligence.
Why would either of the parties to such a purchase agreement be interested in continuing with and amending this agreement if either of the parties expected (1) negative clinical trial results, (2) positive clinical trial results, or (3) had no idea about what clinical trials may demonstrate?
Nidan: I agree, and I do not see how it can be interpreted negatively. On the contrary, I view it is positive as expressed in previous posts.