Anavex-2-73 is an experimental therapy being developed by Anavex Life Sciences to treat Rett syndrome. It was granted orphan drug status by the U.S. Food and Drug Administration in January 2017.

Anavex is also evaluating Anavex-2-73 as a potential therapy for Alzheimer’s diseaseParkinson’s disease, and infantile seizures.

How Anavex-2-73 works

Rett syndrome is a rare neurodevelopment disorder that primarily affects girls. The disease impairs brain function including cognition, emotional development, and movement. Most cases of Rett syndrome are caused by mutations in a gene called MECP2, which encodes for a protein that acts as a switch and controls when other genes are turned on or off. Mutations in MECP2 lead to the protein being made incorrectly, which can cause other genes to turn on or off at the wrong times.

These mutations can cause many persistent cellular problems in nerve cells. For example, there is an increase in the number of misfolded proteins because they are made at the wrong time or in the wrong amounts. This leads to cellular stress, which in turn can cause problems with mitochondria, the “powerhouse” of the cell.

Problems can arise with the biological processes that break down misfolded proteins because there are so many more proteins than usual that need to be broken down. These problems can cause the immune system to respond inappropriately in the brain, leading to inflammation. All of these factors are thought to contribute to the neurological problems seen in Rett syndrome where nerve cells fail to develop properly and make the appropriate connections with each other.

Anavex-2-73 is a small molecule that targets a protein receptor called the sigma-1 receptor, which is a so-called chaperone that guides newly synthesized proteins through a compartment in the cell called the endoplasmic reticulum, ensuring that proteins fold correctly as they are made. By binding and activating this receptor, Anavex-2-73 may be able to reduce protein misfolding, which can reduce cellular stress and improve the function of the mitochondria. In this way, according to researchers, Anavex-2-73 may be able to treat a number of neurodegenerative and neurodevelopmental diseases, including Rett syndrome.

Anavex-2-73 in clinical trials

A preclinical study, presented at a research symposium hosted by the International Rett Syndrome Foundation, demonstrated that Anavex-2-73 could significantly improve motor and reflex responses to stimuli compared with a placebo in a mouse model of Rett syndrome. Treated mice also demonstrated improved balance and gait patterns.

A Phase 2 clinical trial (NCT03758924) is recruiting an estimated 15 adult females with Rett syndrome to assess the safety, tolerability, and efficacy of Anavex-2-73. The study is being carried out in Alabama, Illinois, and Ohio. Patients will receive either Anavex-2-73 or a placebo once per day as an oral solution for seven weeks. At the end of the study, all participants will be offered the opportunity to continue treatment for a further 12 weeks in an open-label extension study.

The primary objective of the trial will be to determine the number of side effects. Blood samples will also be used to measure the amount of Anavex-2-73 that reaches circulation. The Rett syndrome behavior questionnaire and the clinical global impression improvement scale will be used to assess whether patients’ symptoms improve over the course of the study.


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