Sodium Oligomannate

A Chinese Phase 3 RCT (n=818, 36 weeks) found a statistically significant improvement in ADAS-Cog12 scores (-2.15 points vs placebo, p<0.0001), but secondary endpoints (CIBIC+, ADCS-ADL) were not significant. A Phase 2 RCT (n=242, 24 weeks) did not reach significance on the primary ADAS-Cog12 endpoint (p=0.30 for 900mg). A small RCT (n=72, 48 weeks) reported improvements comparable to donepezil. A meta-analysis of 3 RCTs (n=1,108) favored GV-971 on ADAS-Cog12 but not other scales. Graded C rather than B due to inconsistent primary endpoint results across trials, failure to meet secondary endpoints, early termination of the global Phase 3 replication trial, and non-renewal of China's conditional approval in 2024.

In preclinical studies using 5xFAD transgenic Alzheimer's mouse models, oral GV-971 remodeled gut microbiota composition, reduced phenylalanine and isoleucine concentrations in feces and blood, and shifted microbial enterotypes. Two small human MCI cohorts showed elevated amino acid levels and Th1 frequency consistent with animal findings, but no controlled human trials have evaluated microbiome changes as a primary endpoint.

In 5xFAD transgenic mice, GV-971 reduced Th1-mediated peripheral immune cell infiltration into the brain, decreased M1 microglial activation, and lowered hippocampal amyloid-beta and tau accumulation. These preclinical findings suggest an anti-neuroinflammatory mechanism via gut-brain axis modulation, but no human trials have directly measured neuroinflammation as an outcome.