Safety, cand exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study

• Published in: Alzheimer's research & therapy Vol. 13; no. 1
• Main Authors: Bakker, Charlotte, Tasker, Tim, Liptrot, Jan, Hart, Ellen P, Klaassen, Erica S, Doll, Robert Jan, Brown, Giles A, Brown, Alastair, Congreve, Miles, Weir, Malcolm, Marshall, Fiona H, Cross, David M, Groeneveld, Geert Jan, Nathan, Pradeep J
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 21.04.2021
• Subjects: Aged; Chemical properties; Dementia; Dosage and administration; Drug therapy; Muscarinic antagonists; Pharmacokinetics; Pharmacology, Experimental; Physiological aspects; Young adults
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-021-00816-5

Background The cholinergic system and M.sub.1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M.sub.1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. Methods This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. Results HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h ([+ or -] 4.61) in younger adult subjects and 14.3 h ([+ or -] 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. Conclusion Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Trial registration Netherlands Trial Register identifier NTR5781. Registered on 22 March 2016. Keywords: Muscarinic M.sub.1, M.sub.1 receptor, Cholinergic, Dementia, Safety, Pharmacokinetics, Cognition, Memory, Healthy subjects