On 1 February, Anavex Life Sciences announced positive results from a Phase III trial of its innovative drug, blarcamesine, for the treatment of adult females with Rett syndrome. Rett syndrome is a rare, genetic neurological disorder that predominantly affects females. It is a progressive syndrome that affects the way the brain develops and can result in severe impairments in speech, mobility and other aspects of life.  Blarcamesine activates the sigma-1 receptor, which is thought to be pivotal to restoring neural cell balance, the promotion of neuroplasticity and restoration of homeostatic function within the body. Currently, there are no US Food and Drug Administration (FDA) approved drugs specifically for the indication, and treatment is mainly focused on improving specific symptoms of the syndrome, such as anticonvulsants to manage seizures. The approval of blarcamesine would provide a breakthrough therapy for Rett syndrome patients; however, it remains unclear how soon this approval will come.

Anavex’s double-blind, randomised, placebo-controlled AVATAR (NCT03941444) trial demonstrated that blarcamesine was well tolerated and that the convenient once-daily oral dosing of blarcamesine resulted in good compliance. The trial met its primary endpoint of Rett Syndrome Behavior Questionnaire (RSBQ) area under the curve (AUC) response, which evaluated patients’ neurobehavioral symptoms related to quality of life, with a statistically significant improvement in 72.2% of blarcamesine-treated patients compared to 38.5% in the placebo group. Additionally, blarcamesine demonstrated statistically significant and clinical meaningful improvements in secondary efficacy endpoints, including the Anxiety, Depression and Mood Scale response and Clinical Global Impression – Improvement scale (CGI-I) response.

Despite the positive reported results, questions remain whether this trial will be sufficient for a new drug application (NDA) submission to the FDA. In fact, the share price for Anavex dropped after the positive results were released. The uneasy market response is due to some confusion surrounding the company’s late announcement of changes to both the trial’s phase and endpoints. The AVATAR trial was originally planned as a Phase II trial and was changed midway to a Phase III following positive results from an earlier Phase II trial (NCT03758924). Additionally, the original endpoints of the trial were shifted from the change from baseline in RSBQ and CGI-I scores to AUC responder analysis of these scores. These changes were only made in the FDA’s clinical trial database two weeks prior to the announcement of the AVATAR trial results. However, Anavex has said that this does not reflect when the changes to the trial were actually made and that the changes were made according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (Anavex, press release, February 4, 2022). It remains unclear whether the FDA will require an additional Phase III study, or if the upgraded AVATAR trial will be enough. Questions have also been raised regarding the new endpoints’ ability to demonstrate the size of the clinical effect of blarcamesine.

Blarcamesine’s biggest looming source of competition comes from Acadia Pharmaceuticals’ pipeline drug for Rett syndrome, trofinetide. In December 2021, Acadia Pharmaceuticals announced positive results from its Phase III LAVENDER (NCT04181723) trial. In contrast to the AVATAR trial, the LAVENDER trial’s primary endpoint was changed from baseline in RSBQ. This casts some doubt over the endpoint change for blarcamesine and makes it harder to evaluate its efficacy compared to that of trofinetide.

Acadia Pharmaceuticals has announced plans to submit an NDA to the FDA in mid-2022, giving trofinetide the potential to become the first approved product for Rett syndrome, before blarcamesine. Anavex is currently in discussion with the FDA over the next steps for blarcamesine’s development. If the FDA accepts the AVATAR trial as a pivotal trial, blarcamesine will likely be able to launch in lock-step with trofinetide, the two drugs sharing the first-to-market advantage. As such, a request for an additional Phase III trial for blarcamesine would provide a competitive edge to Acadia Pharmaceuticals. Once an NDA is ready, blarcamesine will likely see an accelerated approval based on the fast-track designation, orphan drug designation and rare pediatric disease designation granted by the FDA for Rett syndrome. However, this is also the case for trofinetide, which has received the same three designations from the FDA.

Overall, things look good for the Rett syndrome market, with two promising late-stage pipeline agents. However, it remains to be seen if the market will see those new products enter the market together, or if blarcamesine will be held up by the FDA requiring further clinical data.