p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. A 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD showed the drug met its primary endpoint of safety and tolerability. Significant drug-placebo differences were found in secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), suggesting LM11A-31 slows progression of AD pathophysiological features; however, no significant effect was observed on cognitive tests. Targeting p75NTR with LM11A-31 warrants further investigation in larger trials.

Hayley R. C. Shanks, Kewei Chen, Eric M. Reiman, Kaj Blennow, Jeffrey L. Cummings, Stephen M. Massa, Frank M. Longo, Anne Börjesson-Hanson, Manfred Windisch, Taylor W. Schmitz