Blarcamesine Shows Promise as Potential Rett Syndrome Treatment, New Data Indicate


Treatment with blarcamesine resulted in statistically significant improvements on the new primary end point and significantly reduced Rett syndrome symptoms through changes in potential biomarkers of disease pathology.

Terence O’Brien, MD, FRACP

Terence O’Brien, MD, FRACP

Newly published topline data from the phase 3 AVATAR study (NCT03941444) showed that blarcamesine (Anavex Life Sciences), an investigational agent also known as ANAVEX 2-73 that activates the sigma-1 receptor (SIGMAR1), demonstrated a statistically significant improvement in primary and secondary end points relative to placebo in patients with Rett syndrome.1 Anavex noted that results from this study, along with data from a previously successful phase 2 study (NCT03758924), will be used to plan a meeting with the FDA about potential next steps.

Clinically meaningful improvements on Rett Syndrome Behavior Questionnaire (RSBQ) area under the curve (AUC), the primary end point, were observed in 72.2% of patients on the study drug compared with 38.5% on placebo (P = .037; Cohen d = 1.91). Dose of up to 30-mg blarcamesine were safe, well tolerated with good medication compliance of 95%.

"The outcome of this trial has confirmed the promising results of the early lower-dose study in adults with Rett syndrome," principal investigator Terence O’Brien, MD, FRACP, chair of medicine and head, The Central Clinical School, Monash University, said in a statement. "ANAVEX 2-73 was not only safe but it also demonstrated clinically meaningful improvements in multiple common areas of impairment, which are known to impair the quality of life of girls and women affected by the disorder."1

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Although promising, it should be noted that there were changes made to the design of the trial. Less than 2 weeks ago, the trial information on the NIH registry site was updated from phase 2 to phase 3, with RSBQ as the new primary end point rather than a secondary outcome, as it was originally. 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.2 The company did not report how the drug fared on the original main end point in this data release.

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 Anxiety, Depression, and Mood Scale (ADAMS) was shifted from an “other” outcome measure to a secondary outcome measure, and was assessed on a drug exposure-dependent response as well.

This double-blind, placebo-controlled clinical study randomized 36 adult patients 1:1 to either blarcamesine or placebo for a 7-week treatment period. Preceding the placebo-controlled randomization of 33 patients (Part B), a 3-patient cohort (Part A) underwent a pharmacokinetic (PK) assessment with safety, tolerability, PK, and efficacy evaluation of blarcamesine.

Clinically meaningful and statistically significant reductions of ADAMS, a measure of emotional behavior symptoms, were found in blarcamesine-treated patients (52.9%) compared with those on placebo (8.3%; P = .010; Cohen d = .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%; P = .037; Cohen d = 1.91).

Between the 2 arms, similar rates of treatment-emergent adverse events (AEs) were observed. There were no clinically significant differences in vital signs, lab values, and EKG parameters between the active drug and placebo groups. Investigators found no increased risk of common disorder-related manifestations and the overall safety data appears to be consistent with what had been previously observed.

Treatment with blarcamesine resulted in changes in potential biomarkers of disease pathology, including significant increase of GABA (P = .0205) and decreased l-alpha-aminoadipic acid (L-AAA; P = .0392). All told, patients demonstrated statistically significant and clinically meaningful reductions in their Rett syndrome symptoms.

"The constant efficacy across primary and secondary end points in the phase 3 AVATAR study confirms the potential of ANAVEX 2-73 for treating Rett syndrome, which has been suggested by a prior phase 2 study,” Walter E. Kaufmann, MD, chief scientific officer, Anavex, said in a statement.1 "Moreover, the convergent clinical evidence is supported by parallel changes in blood-based biomarkers of disease, including the key neurotransmitter GABA. This strong body of data opens the possibility of successful treatment for both adults and children with Rett syndrome and early interventions for modifying the course of the disease."

Anavex released data from a phase 2 clinical trial of blarcamesine in 2021, with the treatment resulting in significant increases in the expression of the SIGMAR1 mRNA biomarker that significantly correlated with improvements in RSBQ (P = .035) and CGI-I (P = .029). The RSBQ demonstrated balanced improvements across all the instruments subscales during the trial period of 7 weeks, including general mood, breathing, hand behavior, repetitive face movements, body rocking, night-time behavior, fear/anxiety, and walking/standing.3

To date, blarcamesine has shown potential as a treatment for patients with Parkinson disease dementia and Alzheimer disease (AD). In July 2021, the company announced that it had exceeded its enrollment target for its ongoing phase 2b/3 study (NCT03790709) evaluating blarcamesine in patients with AD. Results for that study are expected to be released by mid-2022.

1. 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 February 2, 2022.
2. History of changes for study: NCT03941444. Updated January 18, 2022. Accessed February 2, 2022.
3. Anavex Life Sciences announces Anavex 2-73 (Blarcamesine) biomarker correlated with efficacy end points in placebo-controlled US Phase 2 clinical trial for the treatment of adult patients with Rett syndrome. News release. Anavex Life Sciences. June 21, 2021. Accessed February 2, 2022.
4. Anavex Life Sciences announces exceeding of enrollment target for the precision medicine ANAVEX 2-73 (blarcamesine) phase 2b/3 clinical trial in patients with Alzheimer disease. News release. June 8, 2021. Accessed February 2, 2022.
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