Anavex Life Sciences Corp (AVXL)

[sokol]

What Falconer says MIGHT happen is backed by scientific studies some of which I reference below. However, as Investor points out and as most everyone here recognizes, the evidence is playing out in the clinical trials. The hypothesis for these clinical trials is shared by a number of scientists and studies. Granted many scientists disagree and have different theories for treating AD, PD and RS, but no one has any real success so far. However, the basis for these Anavex trials is sound. I believe what Falconer has published is reasonable based on the DD/research I have done, and based on what others on this board have found and shared. Therefore, my speculation is that OFP is dead wrong, and Anavex may likely prove some CNS benefit from AVXL 2-73 or from some of its other drugs. In any event, I hope this is how it plays out, and I am not at all deterred by anyone that attempts to rub my nose in the sand or dirt. Hope, I think is a good thing. Nothing can be accomplished without someone having some hope for what they are attempting to achieve. As Teddy Roosevelt said when he was restoring hope in America:

“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat.”

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.
Review article
Nguyen L, et al. Adv Exp Med Biol. 2017.
Show full citation
Abstract
Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.

PMID 28315269 [Indexed for MEDLINE] PMCID PMC5500918

https://www.ncbi.nlm.nih.gov/m/pubmed/28315269/

Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival
Summary
Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca2+ directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca2+-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca2+ depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca2+ signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca2+ concentrations, regulates ER-mitochondrial interorganellar Ca2+ signaling and cell survival.

https://www.sciencedirect.com/science/article/pii/S0092867407010999

Mitochondrial dysfunction has been consistently reported as an early cause of Alzheimer’s disease and the treatment and cure for Alzheimer’s disease may be very connected to the cure for mitochondrial disease.

In a scientific study conducted in France at the University of Montpellier and INSERM, ANAVEX 2-73 demonstrated disease-modifying effects, including the ability to repair normal mitochondrial functionality in the hippocampus, the part of the brain involved with learning, memory and emotions.

http://mitochondrialdiseases.org/anavex-2-73-linking-mitochondrial-functionality-to-alzheimers/

http://www.anavex.com/files/1303_ADPD_Valentine.pdfeenous Neuroprotection in Neurodegenerative Diseases', at the University of Montpellier and INSERM. "Mitochondrial dysfunction and resulting oxidative stress are critical hallmarks of Alzheimer's disease pathology and believed responsible for increased amyloid-beta production and Tau hyperphosphorylation."

"The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems.”
Cite
https://www.ncbi.nlm.nih.gov/m/pubmed/26869505/

Mitochondrial dysfunction has been consistently reported as an early cause of Alzheimer’s disease and the treatment and cure for Alzheimer’s disease may be very connected to the cure for mitochondrial disease.

In a scientific study conducted in France at the University of Montpellier and INSERM, ANAVEX 2-73 demonstrated disease-modifying effects, including the ability to repair normal mitochondrial functionality in the hippocampus, the part of the brain involved with learning, memory and emotions.

http://mitochondrialdiseases.org/anavex-2-73-linking-mitochondrial-functionality-to-alzheimers/

http://www.anavex.com/files/1303_ADPD_Valentine.pdf


”Anavex focuses on restoring cellular homeostasis: Alzheimer's is a complex disease potentially driven by amyloid beta, tau hyperphosphorylation, calcium ion imbalance, inflammation and mitochondrial dysfunction. Anavex is targeting treatment of Alzheimer's disease using a mixed muscarinic receptor and the sigma-1 agonist to restore cellular homeostasis by reducing chronic stress and protein misfolding. The sigma-1 receptor agonist activity is seen only under pathological condition and does not impact normal physiological activity reducing the potential for adverse effects.”

http://nobleresearch.com/reports/AVXL_20170206_9669.pdf


"Goguadze N et al presented preclinical data indicating that in addition to reducing oxidative stress, ANAVEX 2-73, ANAVEX 3-71 and ANAVEX 1-41 also demonstrated protective effects of the mitochondrial enzyme complexes I and IV during pathological conditions. The mitochondrial enzyme complex IV is directly involved in the synthesis of ATP, which provides energy within cells for metabolism. It is believed that energy production impairment and mitochondrial dysfunction play a role in the pathogenesis of neurodegenerative disorders and neurodevelopmental diseases."

https://www.anavex.com/anavex-life-sciences-reports-new-mechanism-action-data-related-anavex-compounds-targeting-sigma-1-receptor/


”Restoring 'cellular balance'
Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.

A worthy target for precision medicine, the Sigma-1 receptor "is involved in several important pathways related to Alzheimer's disease," Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer's patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients' brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.

The advantage of targeting the Sigma-1 receptor is that it "activates the body's own defense mechanism to restore cellular balance," Hampel said.”

Alzheimer's disease is a complex disease," he said. "The newest weapon in the fight against Alzheimer's disease might be your own body."

Lundbeck, a global pharmaceutical company focused on psychiatric and neurological disorders, also subscribes to this philosophy as it works to develop an immunotherapy for Alzheimer's patients.”

’...The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient's cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer's disease, Williamson said.

Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.

"An analogy to this would be cholesterol-lowering drugs and heart disease," Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. "You just needed to show you could reduce cholesterol.’

https://www.cnn.com/2018/07/30/health/alzheimers-treatment-precision-medicine-immunotherapy/index.html?no-st=1535202492