Safety and Pharmacokinetics of HTL0018318, a Novel M1 Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects

Abstract

Introduction HTL0018318 is a selective muscarinic M 1 receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil). Objective We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil. Methods This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics. Results AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] −3.1 to −0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI −3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics. Conclusion HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil. Clinical trial registration Netherlands Trial register identifier NL5915, registered on

Predictive Power of Cognitive Biomarkers in Neurodegenerative Disease Drug Development: Utility of the P300 Event-Related Potential

“…Treatment with donepezil and rivastigmine (acetylcholinesterase inhibitors) also resulted in reduced P300 latency and improved cognitive scores in patients with AD [68][69][70][71][72]. A recent randomized trial showed an increase in amplitude of the ERP P300 in patients with cognitive impairment after treatment with HTL0009936 (a selective muscarinic M 1 -acetylcholine receptor agonist) compared to treatment with placebo [73]. Most recently, a double-blind, placebo-controlled phase 1 clinical trial showed a reduction in P300 latency in patients with AD treated with fosgonimeton (a hepatocyte growth factor (HGF)/MET-positive modulator) compared with placebo [74].…”