Background

This small-molecule drug selectively activates the muscarinic acetylcholine receptor M1, which is expressed in the central nervous system and peripheral secretory glands. HTL0018318 was developed by Heptares Therapeutics, a subsidiary of the Sosei Group Corporation, headquartered in Tokyo. Allergan Pharmaceuticals, headquartered in Dublin, licensed the rights to it in 2016. The companies were jointly developing this compound as a symptomatic treatment for the cognitive deficits in Alzheimer’s disease.

No preclinical data on HTL0018318 are published. Company and academic scientists did formally publish a description of their structure-based design, synthesis, and preclinical results of a prior, related selective partial M1 receptor agonist called HTL9936, which was itself briefly trialed in Phase 1 in 2014 (Brown et al., 2021; see also May 2013 conference news).

Findings

In 2015 and 2016, Heptares ran two Phase 1 trials of HTL0018318 in Japan, in 84 and 28 participants, respectively. In 2016 and 2017, Heptares ran two Phase 1 trials in London, one to evaluate bioavailability of doses up to 35 mg in 40 healthy volunteers, and one to study single- and multiple-dose administration in 57 healthy elderly volunteers. Results of both trials are published. The drug was well-tolerated in single doses, and in multiple doses up to 25 mg. Cholinergic adverse events included nausea, sweating, and increased blood pressure and heart rate, especially at higher doses and in elderly participants. Pharmacokinetics were dose-proportional, and CSF concentrations reached 30 percent of blood levels. Single and multiple doses were associated with some improvements on tests of working memory and learning (Bakker et al., 2020; Bakker et al., 2021). In another study, adding 15 or 25 mg HTL0018318 to 10 mg donepezil in 42 healthy elderly people produced no additional side effects or drug interactions (Bakker et al., 2021).

In 2018, Heptares ran a Phase 1b study  in four European countries, comparing 5, 15, and 25 mg daily of drug to placebo given in 60 AD patients as an add-on to donepezil. A two-week titration was followed by two weeks treatment at the target dose. According to published results, the drug caused mild side effects, mainly during the titration period, that were similar to those seen in previous studies (Nathan et al., 2022). Measures of attention improved. Other cognitive and electroencephalogram measures were unchanged or trended toward improvement.

In July 2018, Heptares listed a 12-week Phase 2 trial in Japan. It was designed to compare three doses of HTL0018318 against placebo in 172 people with dementia with Lewy bodies (DLB) who had never taken, or stopped taking, acetylcholinesterase inhibitors. Measuring safety, cognitive impairment, and psychosis as outcomes, the trial was to start in August 2018; however, on September 18, 2018, Allergan and Sosei announced they were delaying this trial due to toxicology findings in nonhuman primates. In a nine-month dose-finding study, some animals had developed tumors at doses higher than those used in humans. The companies have suspended development of HTL0018318, including a planned Phase 2 study in AD, while they investigate, but claimed that no serious adverse effects have emerged in the 310 people who have taken the drug so far (see company press release).

In May 2020, AbbVie acquired Allergan. In January 2021, AbbVie terminated the licensing agreement, and returned to Sosei Heptares all rights to HTL0018318 and other muscarinic agonists (press release).