A Phase 1b/2a Multicenter Study of the Safety and Preliminary Pharmacodynamic Effects of Selective Muscarinic M Receptor Agonist HTL0018318 in Patients with Mild-to-moderate Alzheimer's Disease

Overview

Journal Alzheimers Dement (N Y)

Date 2022 Mar 1

PMID 35229025

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

Affiliations

Soon will be listed here.

Abstract

Introduction: This study examined the safety and pharmacodynamic effects of selective muscarinic M 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.

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A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

Nathan P, Millais S, Godwood A, Dewit O, Cross D, Liptrot J Alzheimers Dement (N Y). 2022; 8(1):e12273.

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