Neuroprotective Mechanisms of Anavex 2-73 Revealed in Preclinical Study

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by Alice Melão |

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New preclinical data have shown for the first time the underlying mechanisms mediating the therapeutic activity of Anavex 2-73, an investigational therapy being evaluated for the treatment of neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS).

Anavex Life Sciences’ investigational activator of the sigma-1 receptor was found to exert its neuroprotective effect by re-establishing the normal functioning of cells’ “recycling system,” preventing the accumulation of toxic protein clumps.

The therapy is currently being evaluated in a Phase 2 clinical trial (NCT03774459) as a treatment for Parkinson’s dementia. The study, being conducted in Spain, is still recruiting participants.

The study, “Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo,” was published in the journal Cells.

Anavex 2-73 is an orally available small molecule that activates the sigma-1 receptor located in a cellular structure called the endoplasmic reticulum, which is critical for several cellular regulatory mechanisms. Activation of the sigma-1 receptor can help reduce neuroinflammation, as well as the accumulation of beta-amyloid and tau proteins, and oxidative stress, all features known to contribute to the progression of neurodegenerative disorders.

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Studies in mouse models of Parkinson’s have shown that Anavex 2-73 may represent a potential strategy to treat this disease, as the compound was able to restore the function of damaged nerve cells and significantly improve motor function in these mice.

Now, using cells and worm experimental models, researchers at the medical center of the Johannes Gutenberg University in Germany have explored the underlying mechanisms involved in these therapeutic effects.

“The ability to identify key molecular functions in age-related disease is central to developing new therapeutic strategies that target these mechanisms and ultimately provide clinical impact by preventing or treating disease,” Christopher U. Missling, PhD, president and CEO of Anavex, said in a press release.

The team found that activation of the sigma-1 receptor through treatment with Anavex 2-73 could significantly improve cells’ natural recycling system called autophagy. The treatment not only enhanced the autophagic flux, it also triggered several signals involved in this process. These findings demonstrated that sigma-1 receptor activation “has a positive modulatory effect on autophagy,” according to the researchers.

Experiments with worms that had enhanced accumulation of amyloid proteins confirmed that treatment with Anavex 2-73 could effectively increase the autophagic flux by 2.5 times. Interestingly, this effect in autophagy was accompanied by a significant reduction in protein aggregates.

Deposition of amyloid proteins over time in worm’s muscle cells is known to cause paralysis. Treatment with Anavex 2-73 was able to not only prevent the accumulation of amyloid protein aggregates, but also significantly reduce the paralysis rate.

Supported by these findings, the researchers believe that induction of autophagy through Anavex 2-73 can promote proteostasis (protein rebalance) and support the clearance of toxic protein aggregates.

These results “[suggest] a possible role of sigma-1 receptor activation in the prevention (and treatment) of neurodegeneration associated with an imbalanced protein homeostasis,” the researchers wrote.

Anavex is also exploring the safety and therapeutic activity of Anavex 2-73 in a Phase 2/3 study (NCT03790709) in patients with early Alzheimer’s disease, and is preparing to launch a Phase 2 trial (NCT03758924) of Anavex 2-73 in patients with Rett syndrome.