Oral Anavex 2-73 Safely Eases Rett Symptoms, Severity in Phase 3 Trial

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by Marta Figueiredo, PhD |

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Anavex 2-73 (blarcamesine), Anavex Life Sciences’ investigational oral therapy, safely and effectively eased the characteristic behavioral features and severity of Rett syndrome in treated women, while improving their quality of life, according to top-line data from the Phase 3 AVATAR trial.

The findings, indicating that the trial met its main and secondary goals, were detailed on a recent webcastAnavex plans to meet with the U.S. Food and Drug Administration (FDA) to discuss a pathway to the therapy’s possible approval for adults with Rett.

“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,” Terence O’Brien, MD, a principal trial investigator, said in a press release.

O’Brien is also chair of medicine and head of Monash University’s Central Clinical School, and the deputy director of research at Alfred Health and program director of Alfred Brain, all in Australia.

“The consistent efficacy across primary and secondary endpoints 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” said Walter E. Kaufmann, MD, Anavex’s chief scientific officer.

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Evidence of clinical benefit is also “supported by parallel changes in blood-based biomarkers of disease,” Kaufmann said, adding that “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 2-73 is an orally available small molecule designed to modulate multiple cellular pathways implicated in neurodegenerative and neurodevelopmental diseases by activating a protein receptor called SIGMAR1.

The therapy is expected to help restore nerve cell balance and improve neuroplasticity by targeting neuroinflammation, protein misfolding, oxidative stress, and problems in mitochondria (the cells’ powerhouses) — all implicated in Rett syndrome.

Neuroplasticity is the brain’s ability to adapt to new information and compensate for injury. Oxidative stress is an imbalance between the production and clearance of toxic reactive species that are harmful to cells.

In a previous Phase 2 trial (NCT03758924) involving 31 women with Rett, a low dose of Anavex 2-73 (5 mg) was significantly superior to a placebo at reducing behavioral symptoms and disease severity.

The now completed Phase 3 AVATAR trial (NCT03941444) evaluated the therapy’s safety and effectiveness in 33 women with Rett syndrome, who had been on stable treatment for at least four months. Their median age was 24.3 (range, 18–40).

Participants, recruited at sites in Australia and the U.K., were randomly assigned to Anavex 2-73 at up to 30 mg as an oral solution (20 patients) or a placebo solution (13 patients), given every day for seven weeks.

The trial’s main goals were changes in characteristic behavioral features, as assessed with the caregiver-reported Rett Syndrome Behaviour Questionnaire, and safety measures. Characteristic behaviors may include mood disturbances, stereotypies (repetitive, purposeless movements), hyperventilation, and breath holding.

Secondary goals included changes in disease severity — using the Clinical Global Impression Improvement Scale — and emotional behaviors, as measured with the Anxiety, Depression, and Mood Scale (ADAMS). ADAMS assesses anxiety, depression, social avoidance, obsessive compulsive behavior, and manic/hyperactive behavior.

Among exploratory measures were changes in seizure frequency, quality of life, and the levels of disease biomarkers.

Top-line data showed that a significantly greater proportion of Anavex 2-73-treated patients had clinically meaningful reductions in Rett behaviors and disease severity relative to those on a placebo (72.2% vs. 38.5%).

Clinically meaningful reductions in emotional behaviors were also observed in over five times more patients in the Anavex 2-73 group than in the placebo group (52.9% vs. 8.3%).

In addition, the experimental oral therapy was associated with a 50.7% drop in weekly seizure risk and a significant improvement in quality of life relative to placebo.

These clinical benefits were also associated with positive changes in the levels of potential biomarkers of disease mechanisms.

Specifically, GABA, a major brain molecule with anti-seizure and anti-anxiety effects that’s typically at lower levels in Rett patients, was significantly increased. Likewise, there was a significant drop in L-AAA, a molecule linked to seizures and neurodegenerative processes and typically increased in Rett.

Anavex 2-73 was generally well-tolerated, with a safety profile consistent with that reported in previous trials and with good treatment compliance (95%).

The rate of adverse events was similar between the groups, with most reported events being mild or moderate in severity. The most common adverse event in both groups was somnolence, while lack of energy (20%), sedation (lower response to the environment; 10%), and a poorer appetite (10%) occurred only in the Anavex 2-73 group.

No significant group differences were evident in terms of patients’ vital signs, lab values, and heart-related parameters.

These findings highlight that AVATAR met both its main and secondary efficacy and safety goals, and that this higher dose of Anavex 2-73 (up to 30 mg) was associated with a greater effect than the lower, 5 mg dose tested in the Phase 2 trial.

Eligible patients who completed the trial could choose to enter an ongoing open-label extension study, running for 48 weeks (almost one year).

Christopher U. Missling, PhD, Anavex’s president and CEO, thanked “the patients and caregivers who participated in this trial, the Anavex team, trial clinics, and doctors who have worked tirelessly on this program.”

And he sent a “special thanks … to the supportive Rett Syndrome advocacy groups in the countries where our program has been implemented.”

Paramala J. Santosh, MD, PhD, a professor of developmental neuropsychiatry and psychopharmacology at King’s College London,  noted that AVATAR’s results  “indicate a high likelihood of marked improvements in younger, usually more drug-responsive, patients with Rett syndrome, such as those participating in the ongoing pediatric EXCELLENCE study.”

The three-month Phase 2/3 EXCELLENCE trial (NCT04304482) is testing Anavex 2-73 against a placebo in up to 84 girls with Rett, ages 5 to 17. The study may still be recruiting at sites in Australia and Canada; more information can be found here.

Anavex 2-73 received fast track, rare pediatric disease, and orphan drug designations from the FDA for the treatment of Rett syndrome.

The therapy is also being tested in people with Alzheimer’s disease and in those with Parkinson’s disease dementia — diseases where cognitive impairment is also prevalent.