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

• Published in: Nature medicine Vol. 30; no. 6; pp. 1761 - 1770
• Main Authors: Shanks, Hayley R. C., Chen, Kewei, Reiman, Eric M., Blennow, Kaj, Cummings, Jeffrey L., Massa, Stephen M., Longo, Frank M., Börjesson-Hanson, Anne, Windisch, Manfred, Schmitz, Taylor W.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2024; Nature Publishing Group
• Subjects: 631/154/1438; 631/378/1686; 631/378/1689/1283; 692/699/375/365/1283; Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Biomarkers; Biomarkers - cerebrospinal fluid; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cerebrospinal fluid; Clinical trials; Degeneration; Disease control; Double-Blind Method; Female; Humans; Infectious Diseases; Isoleucine - analogs & derivatives; Magnetic Resonance Imaging; Male; Metabolic Diseases; Middle Aged; Modulation; Molecular Medicine; Morpholines; Nerve Tissue Proteins; Neurodegenerative diseases; Neurologi; Neurology; Neuromodulation; Neurosciences; Placebos; Positron emission tomography; Receptor, Nerve Growth Factor - metabolism; Receptors; Receptors, Nerve Growth Factor - metabolism; Tau protein; Treatment Outcome
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-024-02977-w

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
.
A phase 2a trial of LM11A-31 in mild to moderate Alzheimer disease suggests that p75
NTR
modulation is safe and attenuates measures of degeneration.