Anavex 2-73 (blarcamesine), an investigational treatment for Rett syndrome, lessened the disease’s characteristic behavioral features, its severity, and levels of the glutamate biomarker with no serious side effects, top-line results of a Phase 2 clinical trial in adult patients show.
Based on these findings, Anavex Life Sciences, the company developing Anavex 2-73, plans to consult with the U.S. Food and Drug Administration (FDA) regarding next steps in working toward regulatory approval of the therapy.
“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,” Walter Kaufmann, MD, chief medical officer of Anavex and the study’s principal investigator, said in a press release.
The double-blind and placebo-controlled Phase 2 trial (NCT03758924) evaluated the safety, pharmacological profile, and efficacy of Anavex 2-73, given orally as a liquid, in 25 women with Rett syndrome. They were randomized to once-daily doses of either 5 mg Anavex 2-73 or a placebo for seven weeks.
Results showed that 66.7% of treated patients had statistically significant reductions in the disease’s characteristic behavioral features, which can include hand stereotypies, hyperventilation, and breath holding, as assessed by the caregiver-reported Rett Syndrome Behaviour Questionnaire (RSBQ), compared with 10% of those on a placebo.
RSBQ score improvements corresponded with lower blood levels of glutamate, a marker of Rett development, a neurotransmitter that works to activate nerve cells.
Likewise, treated patients showed a statistically significant easing in disease severity, as measured by the Clinical Global Impression Improvement Scale (CGI-I) that clinicians use to assess changes over time. Data found that 86.7% of patients using Anavex 2-73 experienced a sustained improvement, as did 40% of those given placebo.
These improvements in an adult Rett population are considered clinically meaningful, and significant symptom differences between treated and placebo groups were evident as early as four weeks after dosing started, the company reported.
Anavex 2-73 was found to be safe and well-tolerated, meeting the trial’s main goal, with no serious adverse events reported. The incidence of mild or moderate side effects related to treatment was 13.3% with Anavex 2-73 and 10% with a placebo. All 25 patients completed the trial, and all chose to continue or start treatment in the trial’s 12-week and open-label extension phase.
“The outcome of this trial is very promising in terms of both safety and clinical improvement. Despite the challenges of the older age of the cohort (patients were over 18 years of age) and the relatively low dose (5 mg daily), ANAVEX 2-73 demonstrated clinically meaningful improvements in outcome measures evaluating multiple impairments,” Kaufmann said.
A small molecule, Anavex 2-73 is designed to activate the protein sigma-1 receptor, better ensuring that proteins made are more likely to fold properly and be functional. The therapy is thought to help ease cellular stress and aid mitochondria, the energy sources of cells, by reducing the accumulation of misfolded proteins within cells.
The FDA granted fast track, rare pediatric disease, and orphan drug designations to Anavex 2-73, supporting and speeding its development as a possible treatment of Rett.
Anavex 2-73 is also being evaluated in two studies: the Phase 2 AVATAR trial (NCT03941444, still recruiting in Australia and the U.K.) in women with Rett, and in the global EXCELLENCE Phase 2/3 trial (NCT04304482) in girls ages 5 to 18. EXCELLENCE is also still enrolling and expected to add sites beyond Australia; contact information is available here.
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