p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial.
Nat Med
; 30(6): 1761-1770, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38760589
ABSTRACT
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. 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 p75NTR 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 .
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Positron-Emission Tomography
/
Alzheimer Disease
Limits:
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Nat Med
/
Nat. med
/
Nature medicine
Journal subject:
BIOLOGIA MOLECULAR
/
MEDICINA
Year:
2024
Document type:
Article
Affiliation country:
Canadá
Country of publication:
Estados Unidos