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.

Abstract

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.

• Authors: Pradeep J Nathan, S Babli Millais, Alex Godwood, Odile Dewit, David M Cross, Janet Liptrot, Bharat Ruparelia, Stephen Paul Jones, Geor Bakker, Paul T Maruff, Gregory A Light, Alastair J H Brown, Malcolm Peter Weir, Miles Congreve, Tim Tasker
• Journal: Alzheimer's & dementia (New York, N. Y.) (Alzheimers Dement (N Y)) Vol. 8 Issue 1 Pg. e12273 ( 2022) ISSN: 2352-8737 [Electronic] United States
• PMID: 35229025 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.