A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.
Cross, David M
Jones, Stephen Paul
Maruff, Paul T
Light, Gregory A
Brown, Alastair JH
Weir, Malcolm Peter
Alzheimers Dement (N Y)
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Nathan, P. J., Millais, S. B., Godwood, A., Dewit, O., Cross, D. M., Liptrot, J., Ruparelia, B., et al. (2022). A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.. Alzheimers Dement (N Y), 8 (1) https://doi.org/10.1002/trc2.12273
Funder: Allergan Incorporated (now AbbVie)
INTRODUCTION: This study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day. METHODS: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition. RESULTS: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7-21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post-dose, HTL0018318-related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up-titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints. DISCUSSION: HTL0018318 was well tolerated in mild-to-moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil.
RESEARCH ARTICLE, RESEARCH ARTICLES, Alzheimer's disease, attention, cholinergic, clinical trial, cognition, Cogstate neuropsychological test battery, electrophysiology, event related potential, HTL0018318, memory, muscarinic M1 receptor, pharmacodynamic, safety, symptomatic, tolerability
External DOI: https://doi.org/10.1002/trc2.12273
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334362