Randomized, double-blind study of zervimesine in mild to moderate Alzheimer's disease

Background Zervimesine (CT1812) is a first-in-class, brain-penetrant sigma-2 receptor ligand that prevents binding and displaces Aβ 42 oligomers from receptors on neuronal synapses. Objective This study evaluated the safety and efficacy of zervimesine in mild to moderate Alzheimer's disease (AD). Methods This was a Phase 2, randomized, double-blind, placebo-controlled study . Participants were randomized to zervimesine 100 mg or 300 mg or placebo . In addition to ADAS-Cog11, outcomes were evaluated from baseline plasma p-tau217 in prespecified subgroups. Results Of 153 adults randomized, 150 were included in the mITT population. Adverse events occurred in 70.6% with zervimesine 100 mg, 82.4% with zervimesine 300 mg, and 78.0% with placebo. At Day 182, the ADAS-Cog 11 increased from baseline (indicating a decline in cognitive function) with the LS mean (SE) change of 2.69 (0.81) points in the placebo group versus 1.66 (0.60) points in the pooled zervimesine group [δ = −1.03 (−3.01, 0.96), p = 0.310]. For participants with baseline plasma p-tau217 levels below the median (1.0 pg/mL), the pooled zervimesine group showed greater improvement on the ADAS-Cog 11 at Day 182 relative to placebo (δ = −2.66; p = 0.080). Conclusions This phase 2 study indicated that zervimesine was safe and well tolerated and showed consistently favorable numerical treatment differences versus placebo. More robust treatment differences were observed in the below median baseline plasma p-tau217 group suggesting potentially greater efficacy of zervimesine in less advanced AD. These results support larger pivotal trials with zervimesine. Registered at clinicaltrials.gov: NCT03507790