Replies to post #317158 on Anavex Life Sciences Corp (AVXL)

[Biostockclub]

I agree Steady.

Was just pointing out that we are in fact associated with the Holy Grail preferred dogma of anti-amyloid - just upstream.

The FDA could sell that or buy that if needed to save it’s ass.

But, in effect, it would be riding 2 horses at once for awhile as we would still be acknowledging the amyloid plaque theory as the root until a crossover can be published extensively discussing that people walk around with plaque and have no dementia and the clearing doesn’t restore cognitive function on its own so - zero correlation.

Thanks for adding to the discussions always /
Bio

[HMB2010]

Excellent point and a way for FDA to save face!

Anavex Now

[bas2020]

I believe it was stated by Macfarlane a couple of years ago that 2-73 naturally clears A-beta plaque. I remember that because I thought it didn't fit the basic MoA. But perhaps he's correct.

[Investor2014]

The Cells Autophagy Paper.

We may well have the now established amyloid plaque biomarker for AD, assuming that PET scans are used both before and after dosing in the P2b/3 AD study. Can't recall and haven't yet searched to very if that is the case.

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

The pathogenesis of neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease (AD, PD) as well as amyotrophic lateral sclerosis (ALS), has been linked to a disturbed protein homeostasis [1,2,3]. Therefore, the control and maintenance of proteome integrity and proteostasis is of utmost importance. Cellular proteostasis includes protein folding, protein assembly, refolding of damaged proteins, as well as protein degradation, and is under the control of a fine-tuned network of factors, including chaperones, such as heat shock protein 70 (HSP70), and distinct co-chaperones [4]. For intact function and long-term survival of the cell it is crucial to remove misfolded proteins via specialized processes; the two major cellular degradation pathways are the ubiquitin proteasome system (UPS) and autophagy [5,6,7]. The UPS is of particular importance for the physiological protein turnover, but is limited in the degradation substrates, and the autophagic-lysosomal pathway is responsible for the clearance of aggregated and disease-associated proteins, especially under pathogenic and aging conditions.

Take that together with this Anavex PR: Anavex Life Sciences Reports New Publication in Medical Journal Elucidating the Mechanism of ANAVEX®2-73 (blarcamesine) and ANAVEX®3-71 (AF710B) related to the Treatment of Alzheimer's Disease

Scientific Paper Highlights:

Sigma-1 receptor (SIGMAR1)’s expression increases with age, however in Alzheimer’s disease (AD) it decreases
The decrease in SIGMAR1 expression during AD coincides with an age-related decrease in autophagy
The SIGMAR1 may compensate for loss of receptors and autophagic machinery during healthy aging
SIGMAR1 is activated by ANAVEX-compounds
ANAVEX®2-73 has been shown to induce autophagy
Activation of the SIGMAR1 can induce cytoprotective autophagic pathways
The authors of the paper point out that studies using positron emission tomography (PET) have shown that in healthy aging, there is no loss of the SIGMAR1; in fact, there is a possible increase in SIGMAR1 expression2 that coincides with the age-related loss of the M1/M4 muscarinic receptors3, D1/D2 dopamine receptors4, and serotonin (5HT2A) receptors5. The increase in SIGMAR1 expression may be a compensatory mechanism for the loss of the other receptors6.

However, PET scans of patients with a recent AD diagnosis show a reduction of SIGMAR1 expression7. SIGMAR1 also promotes autophagy and results in the degradation of amyloid-beta precursor protein (APP) thereby inhibiting Aß production8.

The publication explains that AD is a multifactorial disease, where several pathways interlink with each other and cause cognitive impairments. The available drugs only tend to target a single pathway and mitigate the symptoms of AD without slowing the disease progression. Combinatorial therapy has been suggested as a treatment strategy; however, the existence of drug-drug interaction is a concern. Hence, there is a need for the development of drug molecules that can target multiple pathways to halt disease progression and improve the memory function.

SIGMAR1 has emerged as one of the prominent targets in treating neurodegeneration. It is involved in the modulation of glutamate levels, maintaining endoplasmic reticulum (ER) function, and calcium regulation, promoting neurogenesis, reducing reactive oxygen species (ROS) formation, suppressing neuroinflammation and ameliorating Aß toxicity9. Recent studies with ANAVEX®2-73 show that SIGMAR1 activation is also involved in autophagy, an intricate phenomenon that clears damaged cellular organelles and misfolded proteins10. SIGMAR1 agonists, including ANAVEX®2-73 and ANAVEX®3-71 have been reported to block toxic Aß, tau and neuroinflammation11.

Autophagy and the cellular machinery involved are essential to homeostasis and cell survival. Autophagy has been shown to be important for axonal health and homeostasis as autophagy inhibition leads to axonal wasting12.

During the early stages of AD, it has been noted that there is an accumulation of Aß and tau protein in the dystrophic or swollen neurites of AD patients’ brains. Furthermore, it is well known that autophagy plays a key role in the management of Aß and tau protein levels, and that some of the key proteins involved in the autophagy mechanism disappear with age, resulting in decreased autophagy in older brains13. At the same time the SIGMAR1 is upregulated, possibly compensating for the reduction in autophagy, and reduction in other receptors, such as muscarinic receptors14, dopamine receptors15, and serotonin receptors16, in an attempt to protect the neuron cells.

Since it has been observed that a number of SIGMAR1 agonists, including ANAVEX®2-73, is able to upregulate SIGMAR1 expression in the brain, it is possible that these drugs could help the cells to compensate for the loss of other receptors and autophagy machinery.

The authors conclude, that in the future it may be the case that SIGMAR1 ligands (or drug combinations) targeting the activation of autophagy, and other SIGMAR1 related neuroprotective pathways, are prescribed prophylactically, in much the same way as with statins for the prevention of heart disease today in an effort to prevent the loss of the SIGMAR1 receptor seen during AD.

“This independent paper highlights the understanding of the relevance of utilizing sigma-1 receptor activation as compensatory mechanism to chronic CNS diseases, currently tested in late-stage placebo-controlled ANAVEX®2-73 Phase 2b/3 clinical Alzheimer's disease study, which recently completed enrollment, as well as in Parkinson’s disease dementia (ANAVEX2-73-PDD-001) and ongoing Rett syndrome program (ANAVEX2-73-RS-001/002/003)”, said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.

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.17