p75 neurotrophin receptor (p75(NTR)) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75(NTR) with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted 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 with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75(NTR) with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU

Clinical trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .