Preliminary clinical data from a Phase 2 trial testing Anavex-2-73 suggest the investigational therapy is effective and safe for the treatment of Rett syndrome.
Detailed results will be presented at the 6th European Rett Syndrome Conference, to be held in Tampere, Finland, Sept. 27-28, according to a press release from Anavex Life Sciences, the company developing the therapy.
Anavex-2-73 (blarcamesine) is a synthetic small molecule that works by activating a protein receptor known as the sigma-1 receptor (S1R). The S1R is involved in making sure other proteins fold correctly as they are produced.
Through the activation of S1R, Anavex-2-73 will decrease protein misfolding. That, in turn, will result in less cellular stress and better functioning of the mitochondria, known as the “powerhouses” of cells, which could improve the survival of neurons (brain cells). This is a unique strategy for treating neurological diseases like Rett syndrome.
The new data come from the first six participants with Rett syndrome — ages 18-36 — in the Phase 2 clinical trial (NCT03758924) of Anavex-2-73. The trial is exploring the therapy’s safety, tolerability, and efficacy. It is still recruiting participants, and is expected to enroll about 15 adults with the disease, ages 18 and older, across five sites in the U.S. Locations are in Alabama, Illinois, Missouri, Ohio, and South Carolina.
The first six participants were treated with 5 mg of Anavex-2-73, which is taken by mouth, every day for seven weeks. The primary efficacy endpoints were changes in scores on the Rett Syndrome Behavior Questionnaire (RSBQ), which measures symptom severity, and the Clinical Global Impression – Improvement (CGI-I) scale, which assesses an individual’s overall ability to function.
Prior to treatment, the average RSBQ score was 50. After seven weeks on Anavex-2-73, the average score decreased to 35, suggesting a lessening of symptoms. CGI-I scores were significantly correlated with RSBQ scores, suggesting similar improvement; Anavex did not specify values.
Additionally, after seven weeks of treatment, blood levels of the neurotransmitter glutamate decreased significantly, while levels of another neurotransmitter, GABA, or gamma-aminobutyric acid, increased significantly. A neurotransmitter is a chemical molecule that allows nerve cells to communicate. In Rett syndrome, there tend to be abnormally high glutamate levels and abnormally low GABA levels. As such, these results suggest a “balancing” of neurotransmitter levels.
Some of the changes in neurotransmitter levels also were significantly correlated with changes in the RSBQ and the CGI-I.
An independent data and safety monitoring board (DSMB) determined that the treatment was well-tolerated, with no severe adverse effects reported. The DSMB recommended continuation of the study without changing its protocol. Patients are now continuing participation in a 12-week open label extension study.
These preliminary results will soon be submitted for publication in a peer-reviewed journal, according to the company.
“This is a remarkable first strong signal for patients with Rett syndrome, especially given that the strong effects were seen in adult patients, and we look forward to discussing these results with the FDA and the European regulatory agency as we continue our Rett Syndrome Program including pediatric patients,” said Walter E Kaufmann, MD, the trial’s principal investigator and chief medical officer at Anavex.
“Importantly, we’ve now observed that the Anavex-2-73 effect is correlated with changes of glutamate and GABA levels, objective measures and biomarkers in several neurodevelopmental disorders,” Kaufmann said.
The investigational therapy received orphan drug designation from the U.S. Food and Drug Administration in January 2017 for the treatment of Rett syndrome. The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that Anavex-2-73 also receive orphan designation from the European Commission.