Anavex Life Sciences Corp (AVXL)

[sokol]

The evolution of Anavex’s theory for treating Alzheimer’s and other CNS diseases.

I could be wrong about some of what I say below and still be correct in my overall belief that Anavex is on the correct path toward a treatment of CNS diseases.

AVXL 2-73 is a radical departure from mainstream science that believes that if we simply remove amyloid plaque all will be well with Alzheimer patients, except nothing is well as we all know. The Anavex approach is to correct the dysfunction within the body that causes the body to malfunction and prevents the body from clearing itself of waste, including amyloid plaque, and other offending matter resulting from a disconnect within the body’s central nervous system.

AVXL 2-73, a CNS drug, has evolved as something comparable to an immunotherapy drug in treating cancer. I think it is now postulated to be a small molecule drug that influences the central nervous system to heal itself.

Generally, over time (aging) the central nervous system, or parts thereof, become dysfunctional. Of course, some rare diseases involve genetic mutations that occur early in life as opposed to Alzheimer’s, Parkinson's and other CNS diseases that are prevalent or associated with aging.

Anavex is one of the first, if not the first, to adopt the ”immunotherapy” approach in the CNS area akin to that in the cancer area. Thus, the CNN article: Borrowing from the cancer playbook to find treatment for Alzheimer's disease.

Therefore, I suppose our Anavex drug does not directly treat CNS diseases, but it assists in restoring the central nervous system that becomes dysfunctional due to aging in the usual sense or because of a rare gene that causes a CNS disease early in life. In restoration of the central nervous system at an early stage, the body may in a natural way heal itself.

I have listed below some research references numbered 1-10 that I think support my thoughts. Therefore, please read my references, which are better than my thoughts.

CNS diseases may share the same genetic traits. See my number 1 below.

Anavex has identified gene variants and it seems the same the same variants will be used in all three upcoming trials. We may expect to receive some feed back for AVXL 2-73 trials near the end of this year or the first of 2019. Early reports from either the Parkinson’s trial or the Alzheimer’s trial may be applicable to any ANXL 2-73 trial as you may see, assuming you read everything below. Number 2 and more below.

Anavex has indeed borrowed from the cancer playbook and believes the drug "activates the body's own defense mechanism to restore cellular balance," Hampel said.” Number 3 below.

Lundbeck seems to confirm our approach as per 3 below.

Significantly, note this from 3 below: 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.

I have added 4-8 below in support what from the beginning about AVXl 2-73 influencing the body to heal itself.

See number 9 below. There is a definite connection between the central nervous system and the immune system.

Lastly see # 10. Restoration of that connection between the CNS and the immunne system seems to be relevant extending from the numerous mitochondria throughout the body to the brain.

The human body is incredibly complex, but I believe it was designed (or evolved) to work together in a way that we continuously struggle to understand. If we can nudge the body to regain and maintain homeostasis, it may be able to heal itself.

In any event, I believe that the recent genetic analysis announced at AAIC 2018 should give us some degree of confidence in the future of our clinical trials. Missling knows much more than we do, and he demonstrates confidence in where Anavex is headed. Perhaps his confidence is another reason why we too may be hopeful.

In the meantime, here is a partial list of research and references that provide support for my belief the Anavex approach to treating CNS diseases.

1. Many neurological diseases share some genetic architecture

https://www.illumina.com/science/customer-stories/icommunity-customer-interviews-case-studies/gleaning-genetic-insight-about-neurodegenerative-disorders.html

”It has been known for some time that neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS, better known as Lou Gehrig’s Disease) have strong genetic components.

The above Illuminia site mentions Alan Pittman, PhD, a Senior Research Associate in Molecular Neuroscience at the UCL Institute of Neurology. His research group is interested in finding the causes of neurodegenerative diseases. He says "If we can identify the genetics and how it influences the biology, we can begin unraveling the biological basis of these diseases.

”.... (Pittman) I believe that many neurological diseases share some genetic architecture. It may not always seem like certain diseases belong together. However, they do from a genetic standpoint. So, being able to look at individual diseases and groups of diseases at the same time will be very useful.”

2. Anavex has identified the gene variants, the same gene variants will apparently be used in the three upcoming trials, and we should hear something by the end of 2018 - first of 2019.

https://seekingalpha.com/article/4197432-anavex-life-sciences-avxl-ceo-christopher-missling-q3-2018-results-earnings-call-transcript?page=2

Missing:

”Out of the initial set of more than 33,000 genes KEM identified a gene panel of 102 genes linked to CNS, central nervous system. This is the magic, unbiased analysis of our data, identify genetic variance within the sigma-1 receptor and COMT genes as top ranking genes with a significant impact on response of patients exposed to Anavex2-73.

....all forth coming out of X2-73 clinical study designs, will incorporate the inclusion of genomic precision medicine biomarker identified in the Anavex2-73 Phase 2a study. We are very excited as we embark on this next phase clinical trials as this could be a unique differentiating factor for Anavex.”

”...The use of the biomarker which we identified will be done in the following way.

So we can stratify the patients which are coming into the study into those who have the gene variant. And those who have the wild-type variant and the wild-type variant is on average in a genetic biobank provided in the overall population to be in the range of 80%. And that population seems to indicate a response better to ANAVEX2-73, then the remaining 20% with a sigma-1 variant.

...it's important to appreciate that this approach is not limited to the Alzheimer’s study. This exact approach will be also incorporated in the Parkinson's dementia study as well as in the Rett syndrome study. So you have the ability basically to have two shots on goal if you say. So you will once find an outcome of all patients against the placebo arm in the study in all these three studies as well as then a pre-specified analysis of the outcome calculation of patients which are supposed to be more benefiting the drug without that gene variant against the control without the gene variant.

To compare apples with apples and oranges with our oranges, regarding the timing we said we would start the trial in the next couple of months. And we will update everybody at the same time with an announcement.

Jason Kolbert:

Thank you, Christopher. It sounds like we could see the Parkinson's dementia trial, the Rett syndrome trial and the Alzheimer’s disease trial, its possible we could see them all start by the end of this year, yes?

Christopher Missling:

We have announced prior that it will be within 2018 and we still stand by this.”


3. Borrowing from the cancer playbook to find treatment for Alzheimer's disease

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


”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.’

4. Anavex Mechanism of action.

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

"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."

5. Connection between mitochondria and endoplasmic reticulum

https://www.ncbi.nlm.nih.gov/pubmed/29309902

"The endoplasmic reticulum (ER) and the mitochondrial network are two highly interconnected cellular structures. By proteinaceous tethers, specialized membrane domains of the ER are tightly associated with the outer membrane of mitochondria, allowing the assembly of signaling platforms where different cell functions take place or are modulated, such as lipid biosynthesis, Ca2+ homeostasis, inflammation, autophagy and apoptosis. The ER-mitochondria coupling is highly dynamic and contacts between the two organelles can be modified in their number, extension and thickness by different stimuli. Importantly, several pathological conditions, such as cancer, neurodegenerative diseases and metabolic syndromes show alterations in this feature, underlining the key role of ER-mitochondria crosstalk in cell physiology. "

6. Endoplasmic function

Endoplasmic reticulum - Wikipedia

The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called cisternae and the transport of synthesized proteins in vesicles to the Golgi apparatus.
Endoplasmic reticulum - Wikipedia

7. Falconer's explanation of how AVXL 2-73 may work.

Falconer66a posted this on IHub.

"Unique, Effective Mechanism of Action. Anavex 2-73 addresses central nervous system diseases differently from any other drug currently or prospectively in use. It is a sigma-1 receptor agonist. There are a number of these, but none that work as effectively and safely as Anavex 2-73. The molecule causes dissembled rough endoplasmic reticula and mitochondria to re-connect and function collaboratively. It is well recognized that most CNS diseases involve mitochondrial dysfunction. Anavex 2-73 is able to re-establish the proper, healthful endoplasmic reticular/mitochondrial connection. With this, calcium ion exchange and adenosine triphosphate interchange (mitochondrion to the ER) can occur, restoring full, natural cellular functions, which result in clearance of the waste proteins (beta-amyloids, tau tangles) that cause Alzheimer's disease symptoms. "

8. http://nobleresearch.com/reports/AVXL_20170206_9669.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.”

9. The immune system and the CNS system connection.

The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and a-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.

https://www.nature.com/articles/ni1078#abstract

Several mechanisms by which the nervous and immune systems might interact have now been recognized. The nervous system may affect immune function via direct innervation of immune organs and by secretion of hormones from the pituitary and other endocrine organs. Conversely, cells of the immune system may influence nervous system function by secretion of a variety of chemical messengers, among which cytokines are the best recognized. Also, although classically the brain was considered ‘immunologically privileged’, it is now recognized that cells of the immune system may be active in the brain, and that this may be an important factor in many central nervous system (CNS) diseases.

http://www.els.net/WileyCDA/ElsArticle/refId-a0000195.html

Working primarily with mice, lead author and University of Virginia neuroscience professor Dr. Jonathan Kipnis and his group identified a previously undetected network of lymphatic vessels in the meninges — the membranes that surround the brain and spinal cord — that shuttle fluid and immune cells from the cerebrospinal fluid to a group of lymph nodes in the neck, the deep cervical lymph nodes.

The newly discovered vessels — which were also identified in human samples — could explain a variety of pathophysiological conundrums, namely how the immune system contributes to neurological and psychiatric disease. “It’s early to speculate,” says Kipnis, “but I think that alteration in these vessels may affect disease progression in those neurological disorders with a prominent immune component, such as multiple sclerosis, autism and Alzheimer’s disease."

Alzheimer’s is thought to be caused by the build up and transmission of a protein called amyloid in the brain. It could be that the amyloid isn't being cleared properly via these lymphatic vessels, and that somehow improving their patency might help rid the brain of the pathologic protein.

It’s been clear for decades that there is some kind of relationship between the brain and the immune system. Abnormal immune activity was reported in schizophrenia in the 1930s, and numerous mental and neurologic illnesses are known or thought to have an immune component. However that Kipnis’ group identified a tangible, anatomical structure facilitating this relationship suggests that the brain and body are intimately intertwined, and that the brain is not the citadel it was once thought to be.

https://www.scientificamerican.com/article/important-link-between-the-brain-and-immune-system-found/

The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603014/pdf/12929_2017_Article_380.pdf

Chaperones are proteins that assist the correct folding of other protein clients either when the clients are being synthesized or at their functional localities. Chaperones are responsible for certain diseases. The sigma-1 receptor is recently identified as a receptor chaperone whose activity can be activated/deactivated by specific ligands. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca2+ signaling from endoplasmic reticulum into mitochondrion. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca2+ homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. The sigma-1 receptor has been implicated in many diseases including addiction, pain, depression, stroke, and cancer. Whether the chaperone activity of the sigma-1 receptor attributes to those diseases awaits further investigation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150837/

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


10. Mitochondrial dysfunction.

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."