Oral SIGMAR1 Targeting Agent Looks Promising in Early Alzheimer Disease Trial

Blarcamesine significantly slowed cognitive decline in patients with early Alzheimer disease (AD), according to data from a 48-week phase 2b/3 study.

Blarcamesine is an investigational oral sigma-1 receptor (SIGMAR1) agonist. Activation of SIGMAR1 is expected to restore cellular homeostasis by inducing autophagy, which may slow neurodegeneration in patients with early AD.

The randomized, double-blind, placebo-controlled ANAVEX2-73-AD-004 trial (ClinicalTrials.gov Identifier: NCT03790709) enrolled 508 study participants aged 60 to 85 years with early stage mild dementia due to AD or mild cognitive impairment due to AD, as assessed by the National Institute on Aging Alzheimer’s Association 2011 criteria. 

Study participants were randomly assigned 1:1:1 to receive blarcamesine 30mg, blarcamesine 50mg, or placebo once daily for 48 weeks. The coprimary endpoints were the change from baseline in cognitive decline (using the 13-item Alzheimer Disease Assessment Scale-Cognition [ADAS-Cog13]) and functional decline (using the Activities of Daily Living [ADCS-ADL] scale). 

Findings showed treatment with blarcamesine led to a 36.3% reduction in clinical decline compared with placebo at 48 weeks (treatment difference, -2.027 [95% CI, -3.522, -0.533]; P =.008); similar results were seen within the individual group comparisons with placebo. Statistical significance was not observed for the coprimary endpoint of ADCS-ADL (treatment difference, 0.775 [95% CI, -0.874, 2.423]; P =.357). 

For the secondary endpoint of Clinical Dementia Rating Scale Sum of Boxes score,  significant improvement was observed with blarcamesine vs placebo, resulting in a 27.6% reduction in clinical decline at week 48 (treatment difference, -0.483 [95% CI, -0.853, -0.114]; P =.010). Notably, in the blarcamesine group, plasma Aβ42/40-ratio increased (P =.048) and whole brain volume loss decreased (P =.002) compared with placebo. 

The most common adverse events reported with blarcamesine during treatment titration and maintenance were mild to moderate dizziness and confusion.

“We are now seeing in the data what we suspected about blarcamesine for a long time – that it has the potential to make a clinical difference for people living with early Alzheimer’s disease,” said senior author behavioral neurologist Professor Dr Marwan Noel Sabbagh MD, Chairman of the Scientific Advisory Board. “The advantage of blarcamesine lies in its small oral formulation, which offers clinical benefits for cognition and neurodegeneration. Its ease of administration and favorable safety profile make it an appealing option.”

Blarcamesine is also being studied in patients with Parkinson disease dementia and Rett syndrome. 

This article originally appeared on MPR