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Randomized Controlled Trial
. 2021 Nov;87(11):4439-4449.
doi: 10.1111/bcp.14872. Epub 2021 May 8.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial

Charlotte Bakker  1   2 , Samantha Prins  1   2 , Jan Liptrot  3 , Ellen P Hart  1 , Erica S Klaassen  1 , Giles A Brown  3 , Alastair Brown  3 , Miles Congreve  3 , Malcolm Weir  3 , Fiona H Marshall  3   4 , Jasper Stevens  1   5 , David M Cross  6 , Tim Tasker  3 , Pradeep J Nathan  3   7   8 , Geert Jan Groeneveld  1   2
Affiliations
Randomized Controlled Trial

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial

Charlotte Bakker et al. Br J Clin Pharmacol. 2021 Nov.

Abstract

Aims: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF).

Methods: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.

Results: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.

Conclusions: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Keywords: Alzheimer's disease; M1 receptor; cholinergic system; elderly; muscarinic receptors; pharmacokinetics; safety.

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Conflict of interest statement

This study was sponsored by Sosei Heptares. J.L., G.A.B., A.B., M.C., M.W., F.H.M., T.T. and P.J.N. are employees of Sosei Heptares and hold shares in the company.

Figures

FIGURE 1
FIGURE 1
Study design of part A (four‐treatment open label sequential design) and B (five‐treatment randomized, placebo and positive comparator‐controlled crossover design) and the number of subjects that started and completed the treatment
FIGURE 2
FIGURE 2
A. Concentration–time profiles of HTL0009936 single IV infusion at 0.1 mg (n = 2), 1 mg (n = 2) and 10 mg in part A (mean ± SD for n = 6). B. Concentration–time profiles at 13.5, 40 and 79.5 mg HTL0009936 by dual IV infusion in part B (arithmetic mean ± SD; n = 28–29). Profile truncated at 8 hours to show plateau during maintenance dose
FIGURE 3
FIGURE 3
A. Systolic blood pressure (mm Hg) shown as change from baseline and B. Diastolic blood pressure (mm Hg) shown as change from baseline
FIGURE 4
FIGURE 4
A. P300 results shown as change from baseline and B. Adaptive tracking test results shown as change from baseline
See this image and copyright information in PMC

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