RARE Daily

Anavex Misses Key Enpoint in Rett Syndrome Study

January 2, 2024

Rare Daily Staff

Anavex Life Sciences said topline results from its phase 2/3 EXCELLENCE study of its experimental ANAVEX 2-73 in pediatric patients with the rare, progressive, neurodevelopmental disorder Rett syndrome failed to meet a key endpoint.

Shares in Anaxex fell nearly 35 percent on the news in early trading. The results were the first study of the drug in pediatric patients with the condition.

The study did not meet the endpoint of the Clinical Global Impression – Improvement scale (CGI-I), which is an assessment by the site investigators using a seven-point scoring. It did, however, show improvement on the other primary endpoint, Rett Syndrome Behaviour Questionnaire (RSBQ), which is a detailed 45-item questionnaire for assessing multiple Rett syndrome characteristics by the patients’ caregivers.

Rett syndrome occurs almost exclusively in girls and leads to severe impairments, affecting nearly every aspect of the child’s life: their ability to speak, walk, eat and even breathe easily. The hallmark of Rett syndrome is near constant repetitive hand movements while awake. It is characterized by normal early development (6 to 18 months) followed by slowing of development, loss of purposeful use of the hands and spoken language, distinctive hand movements, problems with walking, seizures, and intellectual disability. Currently, there are no approved disease-modifying therapies that treat the genetic root cause of the disease. Management of symptoms is done through a multidisciplinary approach utilizing medication for motor difficulties, breathing irregularities, and control of seizures through anticonvulsant drugs. Rett syndrome is caused by mutations in the MECP2 gene, striking all racial and ethnic groups and occurring worldwide in approximately one in every 10,000 to 15,000 live female births.

ANAVEX 2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors and is in development to treat multiple neurological conditions. ANAVEX 2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of homeostatic function within the body and is pivotal to restoring neural cell balance and the promotion of neuroplasticity.

In addition to Rett syndrome, Anavex is evaluating ANAVEX 2-73 in other neurodevelopmental disorders, including Fragile X syndrome, and in neurodegenerative disorders like Parkinson’s disease. Anavex recently received agreement from the Committee for Medicinal Products for Human Use (CHMP) within the European Medicines Agency (EMA) for the submission of a Marketing Authorization Application of ANAVEX 2-73 for Alzheimer’s disease.

The Excellence study was a randomized, double-blind, placebo-controlled, phase 2/3 trial that evaluated the clinical efficacy, safety, and tolerability of ANAVEX2-73 in 92 pediatric patients with Rett syndrome between the ages of 5 through 17 years. Participants were randomized 2:1 (ANAVEX 2-73 to) for 12 weeks, followed by a week 16 safety visit.

The company said a key secondary endpoint, the Anxiety, Depression, and Mood Scale (ADAMS), trended favorably. In the same analysis, scores for all RSBQ and ADAMS subscales improved over the course of the study. Collectively, the RSBQ and ADAMS demonstrated improvements in multiple areas, impacting positively in particular repetitive movements, nighttime disruptive behaviors, and social avoidance.

A preliminary review of the safety results indicates there were no new safety signals in the EXCELLENCE study. The most common treatment-related adverse events in the drug-treated group were somnolence and lethargy and were predominantly mild to moderate in severity. There were no clinically meaningful changes observed in serious adverse events associated with known risks of ANAVEX 2-73.

The company believes a large placebo effect was observed in the study, which may have masked the compound’s therapeutic effect. Anavex said it identified the probable causes as a slight imbalance in disease severity at baseline across the treatment arms and the 2 to 1 placebo randomization ratio.

The company said it would further assess the collective results and discuss with the regulatory authorities next steps.

“We believe that ANAVEX 2-73, as a new, potential convenient treatment option in the future, can contribute to patients and healthcare professionals by addressing unmet needs in the treatment of Rett syndrome,” said Christopher Missling, president and CEO of Anavex.

Photo: Christopher Missling, president and CEO of Anavex


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