p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

p75 neurotrophin receptor (p75NTR) signaling overlaps with degenerative networks active in Alzheimer disease (AD). The small molecule LM11A-31, a first-in-class p75NTR modulator, mitigates amyloid- and tau-induced synaptic loss in preclinical models. We conducted a 26-week randomized, placebo-controlled, double-blind phase 2a trial of LM11A-31 in 242 participants with mild to moderate AD, assigning placebo, 200 mg, or 400 mg twice daily. The primary endpoint of safety and tolerability was met. Within prespecified secondary and exploratory domains (structural MRI, [18F]-FDG PET, and CSF biomarkers), significant drug–placebo differences were observed consistent with slowing of AD pathophysiological progression; no significant cognitive effects were detected. These results support further evaluation of LM11A-31 targeting p75NTR in larger, longer trials. EU Clinical Trials: 2015-005263-16; ClinicalTrials.gov: NCT03069014.

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