Anavex 2-73 (blarcamesine) is an experimental treatment that Anavex Life Sciences is developing to treat Rett syndrome. The U.S. Food and Drug Administration granted the treatment orphan drug status in January 2017 and fast track designation in 2020.
The therapy is also being investigated for its potential in Alzheimer’s disease, Parkinson’s disease, and infantile seizures.
How does Anavex 2-73 work?
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. This gene provides instructions for making a protein that acts as a switch and controls when other genes are active. Mutations in MECP2 cause the cells to make the protein incorrectly. This can cause other genes to turn on or off at the wrong times.
The mutations can also cause many persistent cellular problems in nerve cells. For example, there is an increase in the number of misfolded proteins because cells make them at the wrong time or in the wrong amounts. This leads to cellular stress, which, in turn, can cause problems with mitochondria, which provide energy to cells.
Problems can also arise with the biological processes that break down misfolded proteins because there are so many more proteins than usual. 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 caused by 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. This is a so-called chaperone, in that it guides newly synthesized proteins through a compartment in the cell called the endoplasmic reticulum, ensuring they fold correctly.
By binding and activating this receptor, Anavex 2-73 may be able to reduce protein misfolding. This, in turn, could decrease cellular stress and improve the function of the mitochondria. In this way, Anavex 2-73 may be able to treat a number of neurodegenerative and neurodevelopmental diseases, including Rett syndrome.
Anavex 2-73 in clinical trials
Results from a preclinical study, which researchers presented in November 2019 at a research symposium hosted by Rettsyndrome.org, 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) recruited 31 females, ages 18 to 45 with Rett syndrome in the U.S. to assess the safety, tolerability, and efficacy of Anavex 2-73. Patients received either Anavex 2-73 or a placebo once per day as an oral solution for seven weeks. At the end of the trial, all participants had the opportunity to continue treatment for a further 12 weeks in an open-label extension study.
The primary objective of the trial was to determine the number of side effects. Researchers collected blood samples to measure the amount of Anavex 2-73 that reached circulation. They also used the Rett syndrome behavior questionnaire (RSBQ) and the clinical global impression – improvement scale (CGI-I) to assess whether patients’ symptoms were alleviated over the course of the study.
Interim data on the first six patients showed significant improvements in RSBQ and CGI-I. The study has been completed, and top-line results are expected before the end of 2020.
Another Phase 2 trial called AVATAR (NCT03941444) will investigate different dose levels of Anavex 2-73 in female patients, ages 18 to 45. The trial is currently enrolling an estimated 30 participants at two locations in Australia and potentially two sites in the U.K.
Similar to the U.S.-based trial, patients will receive either an oral solution of Anavex 2-73 or a matching placebo once a day for seven weeks. Afterward, all patients will have the option of continuing for 12 weeks in an open-label expansion.
The trial will investigate the side effects and pharmacokinetics (movement in the body) of the treatment. It will also compare scores on the RSBQ and the CGI-I scale. The trial is expected to be completed in December 2020.
A Phase 2/3 randomized, double-blind, placebo-controlled trial called EXCELLENCE (NCT04304482) is investigating Anavex 2-73 in children and adolescents, ages 5 to 18. The trial aims to enroll an estimated 69 patients in Australia who will receive either Anavex 2-73 or a placebo for 12 weeks. Patients will then have the option to participate in a 48-week open-label extension.
The primary outcomes of this study are scores on the RSBQ and the CGI-I scales. Secondary outcomes will investigate changes in several metrics related to anxiety, depression, and mood, sleeping habits, seizure frequency, and motor behaviors. They will also report adverse events. Researchers anticipate completing the trial in July 2021.
Last updated: Oct. 12, 2020
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