Phase 2/3 Study of Blarcamesine in Pediatrics With Rett Syndrome Completes Enrollment


After discussions with the FDA, the study will assess 2 co-primary end points of change in Rett Syndrome Behavior Questionnaire total score and Clinical Global Impression Improvement Scale score.

Christopher U. Missling, PhD, president and chief executive officer, Anavex

Christopher U. Missling, PhD

According to a recent announcement, all participants have been dosed in the placebo-controlled phase 2/3 EXCELLENCE study (NCT04304482), assessing blarcamesine (Anavex Life Sciences), a small-molecule activator of sigma-1 receptor (SIGMAR1), in pediatric patients with Rett syndrome. Topline data is expected to be reported in the second half of 2023.

The trial, which features 92 pediatric patients with Rett syndrome, aged 5 to 17 years old, is a multi-center, double-blind trial assessing the safety, tolerability, and efficacy of oral blarcamesine, otherwise known as ANAVEX 2-73. After discussions with the FDA, the trial will use the Rett Syndrome Behavior Questionnaire (RSBQ) total score and Clinical Impression Improvement Scale (CGI-I) as co-primary end points. Effects on these end points will be calculated through a statistical analysis plan that includes specified linear mixed-effects models for repeated measures.

"We would like to thank the investigators and clinical site coordinators as well as all the participating families for their dedication to this clinical study completed with ANAVEX®2-73 (blarcamesine)," Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement. “Rett syndrome is a devastating, non-inherited genetic post-natal progressive neurodevelopmental disorder that occurs almost exclusively in girls and leads to severe impairments, affecting nearly every aspect of the child’s life, hence we continue our fast-paced development program of ANAVEX®2-73 (blarcamesine) in Rett syndrome."

Blarcamesine is an orally administered drug that restores cellular homeostasis by targeting SIMGAR1 and muscarinic receptors. Prior to this study, the agent was assessed in adult populations of Rett syndrome, specifically, the phase 2 ANAVEX 2-73-RS-001 study (NCT03758924) and the phase 3 AVATAR trial (NCT03941444). Additionally, the therapy has received fast track, rare pediatric disease, and orphan drug designations from the FDA.

In February 2022, Anavex announced promising topline data from AVATAR, with blarcamesine demonstrating statistically significant improvement in primary and secondary end points relative to placebo. The double-blind, placebo controlled trial, which featured 36 adults with Rett syndrome, resulted in clinically meaningful improvements on RSBQ area under the curve in 72.2% of patients treated with active drug compared with 38.5% on placebo (P = .037; Cohen d = 1.91). Across the 7-week trial, doses of up to 30-mg blarcamesine were safe, well-tolerated, with good medication compliance of 95%.2

READ MORE: Vatiquinone Shows Additional Benefits on Friedreich Ataxia Disease Progression Despite Failing to Meet Primary End Point

Clinically meaningful and statistically significant reductions of Anxiety, Depression, and Mood Scale (ADAMS), a measure of emotional behavior symptoms, were found in blarcamesine-treated patients (52.9%) compared with those on placebo (8.3%; = .010; Cohen = .609). Additionally, a significantly greater proportion of patients on study drug (72.2%) achieved clinically meaningful response on Clinical Global Impression-I (CGI-I) scores throughout the trial relative to those on placebo (38.5%; = .037; Cohen = 1.91).

In AVATAR, changes were made to the design of the trial weeks before results were announced. Specifically, the study was updated from a phase 2 to phase 3 study, with RSBQ as the primary end point rather than a secondary outcome. Prior to the changes, maximum plasma concentration, PK AUC, lipid panels, and significant laboratory findings, such as incidence of AEs, were the primary outcome measures. The company did not report how the drug fared on the original main end point in this data release.3

For secondary outcome measures, CGI-I was originally being observed from baseline to end of treatment but was changed to drug exposure-dependent response upon revision. Additionally, the ADAMS was shifted from an “other” outcome measure to a secondary outcome measure, and was assessed on a drug exposure-dependent response as well.

Data from the phase 2 study was announced in 2021, with blarcamesine-treated patients showing significant increases in the expression of the SIGMAR1 mRNA biomarker, which correlated significantly with improvements in RSBQ (P = .035) and CGI-I (P = .029). Additionally, findings on the RSBQ demonstrated balanced improvements across all the instrument’s subscales during the 7-week trial, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior, fear/anxiety, and walking/standing.

1. Anavex Life Sciences announces completion of ANAVEX 2-73 (blarcamesine) EXCELLENCE phase 2/3 Rett syndrome clinical trial. News release. Anavex Life Sciences. June 6, 2023. Accessed June 7, 2023.
2. Anavex 2-73 (blarcamesine) AVATAR phase 3 trial met primary and secondary efficacy end points for the treatment of adult patients with Rett syndrome. News release. Anavex Life Sciences. February 1, 2022. Accessed June 7, 2023.
3. History of changes for study: NCT03941444. Updated January 18, 2022. Accessed June 7, 2023.
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