Available orally: Blarcamesine for Alzheimer's disease in the approval process

Autophagy is often referred to as cellular garbage disposal. The sigma-1 receptor plays an important role in autophagy processes in the body. When activated, it can lead to the degradation of misfolded proteins, which are a problem in many neurodegenerative diseases. Blarcamesine is a sigma-1 receptor agonist that is thought to stimulate autophagy and thus reduce harmful protein deposits in the brain.

According to manufacturer Anavex, impaired autophagy precedes both β-amyloid and tau protein deposition in the brain, thus preceding the neurodegenerative process in Alzheimer's disease. Therefore, stabilizing or restoring autophagy could be considered an early preventative measure against the pathology of Alzheimer's disease.

The US pharmaceutical company has EMA submitted an application for the orally available active ingredient for the treatment of Morbus Alzheimer's disease, which is currently under investigation. According to Anavex, blarcamesine could be a complement or alternative to parenterally administered monoclonal Alzheimer's antibodies.

A key basis for the approval application are results from the Phase IIb/III study ANAVEX2-73-AD-004, published in the Journal of Prevention of Alzheimer's Disease . This study was a randomized, placebo-controlled, double-blind study involving 508 patients with early-stage Alzheimer's disease. They received either 30 or 50 mg of blarcamesine or a placebo once daily for 48 weeks.

The primary endpoint included the change from baseline in the ADAS-Cog-13 score. This is a proven, standardized scale for assessing cognitive impairment in people with Alzheimer's disease and other forms of dementia.

In the 30 mg group, cognitive decline slowed by 34.6 percent compared to placebo, and in the 50 mg group by 38.5 percent. The significance level was reached. The difference on the ADCS-ADL scale, another instrument for assessing the daily functioning of Alzheimer's patients, was not significant but showed a positive trend.

There are also positive results from the evaluation of secondary endpoints. The Aβ42/40 ratio increased significantly with blarcamesine compared to placebo, which could indicate that the deposition of harmful amyloids is slowed down. Furthermore, total brain volume decreased significantly less in the active group than with placebo.

Commonly observed side effects include dizziness, which occurred temporarily and was generally mild to moderate in severity. According to Anavex, the safety profile of blarcamesine shows that routine MRI monitoring is not required. This would be an important distinction from the already approved antibody lecanemab and the recently recommended donanemab .