Mechanisms Behind Anavex 2-73’s Benefits Highlighted in Review

Activation of the sigma-1 receptor or SIGMAR1 — whose production is typically increased with age, but reduced in people with Alzheimer’s disease — drives a series of neuroprotective effects, including the clearance of unnecessary or damaged cellular components, a review study highlights.

This supports the therapeutic potential of Anavex 2-73 (blarcamesine), and Anavex 3-71 (AF710B), in slowing the progression of Alzheimer’s, the researchers noted.

The two orally administered SIGMAR1 activators, developed by Anavex Life Sciences, are designed to slow or prevent further neuronal damage in Alzheimer’s and other neurodegenerative diseases.

Notably, after showing promise in preclinical and early clinical studies, Anavex 2-73 is currently being evaluated against a placebo in treating people with early Alzheimer’s. That trial, a placebo-controlled Phase 2b/3 Anavex 2-73-AD-004 study (NCT03790709), was launched in 2018.

Anavex recently announced that the trial exceeded its target enrollment of 450 patients and that top-line results are expected by mid-2022.

“A significant unmet need exists currently for Alzheimer’s disease patients worldwide given the lack of available adequate therapeutic interventions, and we are excited to have exceeded enrollment of this study for Anavex 2-73,” said Christopher U. Missling, PhD, Anavex’s president and CEO.

“Given ANAVEX 2-73’s convenient oral route of administration we believe it has the potential to deliver broad clinical utility,” Missling added.

The review study, “The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s,” was published in the journal Expert Opinion on Therapeutic Targets.

In a separate press release, highlighting the mention of Anavex’s investigational therapies in the published study, Missling said that the “independent paper highlights the understanding of the relevance of utilizing sigma-1 receptor activation as compensatory mechanism to chronic [central nervous system] diseases.”

This type of approach, particularly in the form of Anavex 2-73, is being tested in Phase 2 or 3 trials not only for Alzheimer’s disease, but also for Parkinson’s disease dementia and Rett syndrome, Missling added.

Anavex 3-71 is initially being evaluated as a potential treatment for frontotemporal dementia, and is currently being given to healthy adults in a Phase 1 clinical trial (NCT04442945) taking place in Australia.

In the review study, researchers in Thailand focused on the current understanding of SIGMAR1 functions related to autophagy and their potential role in lessening Alzheimer’s disease.

Autophagy is a cellular process that helps clear damaged cellular components and misfolded proteins, which is essential for normal cellular and tissue function.

A protein receptor, SIGMAR1 is located at the surface of the endoplasmic reticulum — a cellular organelle involved in protein production, modification, and transport — and particularly at points of contact with mitochondria, the cells’ powerhouses.

SIGMAR1 and its ligands, or activators, are involved in several cellular functions, such as response to cellular stress, correction of protein misfolding, nerve cell survival, growth, and plasticity, which is the ability to adapt in order to compensate for injury. They also are associated with behaviors related to neurological and neuropsychiatric disorders.

These molecules also have been shown to suppress neuroinflammation and to reduce brain levels of amyloid-beta — one of the two main proteins, the other being tau, that form toxic clumps in Alzheimer’s.

Overall, SIGMAR1 and its ligands typically act to restore physiological or behavioral functions, according to researchers.

More recent studies have shown that SIGMAR1 activation also promotes autophagy, which plays a key role in the clearance of toxic protein clumps, including those of beta-amyloid and tau. This helped to better understand the underlying mechanisms of SIGMAR1’s neuroprotective effects.

Notably, in healthy aging, SIGMAR1 levels appear to increase, while those of receptors of brain messenger molecules and key autophagy proteins are reduced. This suggests that this age-related raise in SIGMAR1 levels may be a compensatory mechanism in an attempt to restore balance in the brain and prevent pronounced neurodegeneration.

However, people with Alzheimer’s have fewer of these receptors, when compared with age-matched healthy individuals, suggesting that they are more vulnerable to age-related neuronal damage and accumulation of toxic clumps.

As such, SIGMAR1 activation is a potential therapeutic approach for Alzheimer’s and other neurodegenerative diseases.

“Autophagy activation … along with other neuroprotective effects make it an interesting target for the treatment of Alzheimer’s disease,” the researchers wrote.

Anavex 2-73 and Anavex 3-71 are two small molecules that mimic SIGMAR1 ligands, thereby activating the receptor and promoting its neuroprotective effects. They have been shown to promote autophagy and suppress the toxic accumulation of beta-amyloid and tau, as well as neuroinflammation.

The team noted that the future of Alzheimer’s disease treatment may involve the combined activation of SIGMAR1 and autophagy, and that SIGMAR1 activators, or combination therapies, may be prescribed as a preventive approach, similar to the use of statins — cholesterol-suppression medications — for the prevention of heart disease.

“We suggest that future studies investigate the link between autophagy the [SIGMAR1] and [Alzheimer’s],” the researchers concluded.