Anavex Life Sciences Corp (AVXL)

[sokol]

One approach (among others) Anavex will seek to use in its discussions with regulators is that Anavex 2-73 restores Protein Homeostasis and reduces Aß (Abeta) induced deficits, which is all connected to the unproven amyloid beta plaque theory. I think Anavex may do this in conjunction achievement of endpoints and other outcome measures such as MRI, blood assessment, and CSF assessment.

Leqembi, which may be less effective, more expensive, and not as safe as AVXL 2-73, was given emergency approval based solely on its Phase 2 data, not phase 3 clinical trial results. Leqembi was approved because it removes amyloid beta plaque which is believed (not proven) to be a critical factor in the disease. Keep in mind that the FDA has allowed accelerated approval of Alzheimer’s drugs although nothing has been clinically proven. It did so based on what it thought was reasonably likely to result in clinical decline of Alzheimer’s disease.

Therefore, it would strike me that it would be ironic for regulators to dismiss any evidence of protein homeostasis and reduction of Aß (Abeta) induced deficits with the administration of Blarcamesine. Below is some of my research references that forms a basis for my thinking.

However, the FDA disapproved Lily's donanemab this past week because Lily did not provide data from at least 100 patients who received a minimum of 12 months of continued treatment. Therefore, Anavex may need to provide data from at least 100 patients who received Blarcamesine for 12 months. One question Lane Simonian raised in a comment on Seeking Alpha is whether 48 weeks is close enough to satisfy the FDA. In any event, Blarcamesine may obtain accelerated approval in Europe, the UK, or Asia without data from 100 patients that received AVXL 2-73 for 12 months.

References:

1. Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell.[1][2] Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes,[3] as well as aggregation-associated degenerative disorders.[4]Therapeutic restoration of proteostasis may treat or resolve these pathologies.[5] Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostatic perturbations from pathogens such as viruses.[2] Cellular mechanisms for maintaining proteostasis include regulated protein translation, chaperone assisted protein folding, and protein degradation pathways. Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded proteome.

Proteostasis
en.wikipedia.org
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2. Proteostasis.
Protein homeostasis or ‘proteostasis’ is the process that regulates proteins within the cell in order to maintain the health of both the cellular proteome and the organism itself. …..
Proteostasis involves a highly complex interconnection of pathways that influence the fate of a protein from synthesis to degradation. As individual components are affected, the others adjust accordingly to maintain normal function. Disruption of one or more of these proteostasis influencers can manifest in pathologies such as Alzheimer’s disease, cancer, and diabetes.
https://www.enzolifesciences.com/platforms/proteostasis/

2a. The loss of proteostasis is one of the reasons we age. The Hallmarks of Aging [1] describes the loss of proteostasis as the failure of the protein building machinery of the cell and the accumulation of misfolded proteins, which is one of the root causes of age-related diseases, including Alzheimer’s disease.
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Why we Age: Loss of Proteostasis
lifespan.io

3. Protein Homeostasis, Aging and Alzheimer’s Disease

Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis….
…..
Cells permanently encounter the problem to maintain the integrity and functionality of the proteome. Within the crowded cellular environment, the correct conformation of proteins must be controlled and misfolded and irreversibly damaged proteins must be efficiently refolded or removed. Central players of the protein homeostasis system are molecular chaperones that sense misfolded proteins and, when refolding fails, direct them to the protein-degradation pathways. Molecular chaperones are specified as proteins that interact with and participate in folding or refolding of non-native proteins. Therefore, chaperones help unfolded proteins to achieve their functional conformation without being present in the final structure. They exert a multitude of activities, including de novo folding, refolding of denatured proteins, transport to subcellular compartments, oligomeric assembly and disposal by proteolytic degradation…

nlm.nih.gov

3a. Protein Homeostasis, Aging and Alzheimer’s Disease

Alzheimer’s disease (AD) is one key medical challenge of the aging society and despite a great amount of effort and a huge collection of acquired data on molecular mechanisms that are associated with the onset and progression of this devastating disorder, no causal therapy is in sight. The two main hypotheses of AD, the amyloid cascade hypothesis and the Tau hypothesis, are still in the focus of AD research. With aging as the accepted main risk factor of the most important non familial and late onset sporadic forms of AD, it is now mandatory to discuss more intensively aspects of cellular aging and aging biochemistry and its impact on neurodegeneration. Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis

4. ANAVEX®2-73 activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and increased inflammation.
https://www.anavex.com/press-releases/anavex-life-sciences-receives-approval-to-initiate-phase-2b%2F3-clinical-trial-of-anavex%C2%AE2-73-for-the-treatment-of-early-alzheimer%E2%80%99s-disease

5. ANAVEX®2-73 (blarcamesine) activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring cellular homeostasis. https://www.anavex.com/post/anavex-life-sciences-announces-completion-of-anavex-2-73-u-s-phase-2-rett-syndrome-clinical-trial

6. Sigma-1 receptor: The novel intracellular target of neuropsychotherapeutic drugs

Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival.

sciencedirect.com


7. The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy

Neurodegenerative diseases are linked to dysfunctional proteostasis and disturbed autophagy.

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The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy - PubMed
nlm.nih.gov

8. Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo
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Sigma-1-Receptor-Activation-Induces-Autophagy-and-Increases-Proteostasis-Capacity-In-Vitro-and-In-Vivo
PDF Document · 2.6 MB
ANAVEX2-72 Positively Regulates Autophagy, Increases Proteostasis Capacity, and Improves Protein Aggregation

9. Protein Homeostasis
Protein homeostasis (proteostasis) refers to an extensive network of components that acts to maintain proteins in the correct concentration, conformation, and subcellular location, to cooperatively achieve the stability and functional features of the proteome…..
… Proteostasis, or protein homeostasis, is essential for all physiological processes of the organism. Cell stress, due either to accumulation of misfolded or aggregated proteins, or exposure to some environmental stimuli, triggers activation of stress sensors and specific response pathways within the cell, leading to transcriptional activation and synthesis of factors that promote proper folding or clearance of defective proteins to restore proteostasis

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-homeostasis achieve the stability and functional features of the proteome.

10. Anavex Life Sciences Announces ANAVEX®2-73 Significantly Prevented Aß (Abeta)-induced Deficits

ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.[1] SIGMAR1 also promotes autophagy and results in the degradation of amyloid-beta precursor protein (APP) thereby inhibiting Aß production

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Anavex Life Sciences Announces ANAVEX®2-73 Significantly Prevented Aß (Abeta)-induced Deficits
anavex.com


Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468724/