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

Abstract

Background The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 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 (± 4.61) in younger adult subjects and 14.3 h (± 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.

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

“…The pharmacokinetics of HTL0018318 were well-characterized in plasma and urine. The characteristics were comparable to the pharmacokinetic data observed in previous studies [ 12 , 14 ]. Median t max (1.74–2.5 h) and mean half-life following the fifth dose (10.5–13.7 h) did not appear to change with respect to HTL0018318 dose level and co-dosing with donepezil.…”

“…The side effect profile observed in this study was comparable to that observed in the single ascending dose (SAD) and multiple ascending dose (MAD) studies with HTL0018318 [ 12 , 14 ]. Only nausea and vomiting were reported more frequently than in the SAD and MAD study.…”

“…To mask the difference in taste between HTL0018318 and placebo, a peppermint strip (Listerine) was administered 1 minute before and after the administration of the oral solution. In humans, the time to maximum observed plasma concentration ( t max ) of HTL0018318 was 1–2 h, and the half-life was approximately 16 h, which permits once-daily dosing [ 12 , 14 ]. Steady state was reached after two or three daily doses [ 12 ].…”

“…In humans, the time to maximum observed plasma concentration ( t max ) of HTL0018318 was 1–2 h, and the half-life was approximately 16 h, which permits once-daily dosing [ 12 , 14 ]. Steady state was reached after two or three daily doses [ 12 ]. Donepezil (manufactured by Aliud Pharma GmbH, Laichingen, Germany) was administered as 5 mg tablets.…”

“…Pre-clinical data show that HTL0018318 has approximately a twofold selectivity for M 1 over M 4 receptors with no detectable functional agonist activity at human M 2 and M 3 receptors [ 11 ]. Multiple doses in healthy elderly humans resulted in an acceptable side effect profile, with hyperhidrosis, nausea, and hot flushes the most prevalent adverse events (AEs) [ 12 ]. As a treatment for AD, HTL0018318 will very likely be given in combination with standard-of-care cholinesterase inhibitors such as donepezil.…”