Entry‐into‐humans study with ACT‐462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant

Abstract

A double-blind, placebo- and active comparator-controlled, randomized, single-ascending-dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT-462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT-462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400-mg group received a single oral dose of 400 mg almorexant (two-way crossover). ACT-462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose-dependent. ACT-462206 was absorbed with a median tmax of 1.5-4.0 hours. The elimination half-life varied from 4.8 to 11.2 hours. A clinically relevant reduction in vigilance and attention, alertness, and motor coordination was recorded at ACT-462206 doses ≥200 mg. The onset was between 20 and 45 minutes after drug intake, the maximum effect between 1 and 2 hours after drug administration, and these impairing effects largely disappeared within 8 hours post-dose. Doses of 400-1,000 mg ACT-462206 were similarly efficacious to 400 mg almorexant, with a trend for an earlier onset of action with ACT-462206. The present results confirm the activity of ACT-462206 as an orexin antagonist.

Integrating Modern Concepts of Insomnia and its Contemporary Treatment into Primary Care

“…However, cataplexy and other symptoms of narcolepsy in which orexin neurons are functionally absent had been noted as a potential concern in clinical development of ORAs. 130,133 This is because it was thought that antagonism of the orexinergic system would produce narcolepsy-like or cataplexy-like symptoms. Such effects were not observed in a pivotal phase 3 trial of suvorexant.…”

“…Actelion, the developer of almorexant, has recently published data on ACT-462206, which is another ORA. 130 There is a scarcity of information publicly available, so this new agent's potential development will be interesting to watch. A single ORA in early development is the orexin-2 receptor antagonist, MIN-202, by Minerva Pharmaceuticals in partnership with Johnson & Johnson.…”

Orexins and fear: implications for the treatment of anxiety disorders

“…Three other dual antagonists are also now under development for insomnia treatment. ACT-462206 (NCT01954589) [72] is under development in Phase I, and SB-649868 (NCT00426816) [73] and filorexant (NCT01021852) are both under development in Phase II. The results of these clinical studies could provide additional valuable information to clarify the interest of this novel therapeutic approach for the treatment of insomnia.…”

Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications

“…Published results show generally similar findings to those described above for suvorexant (Black et al., ; Hoever et al., ; Roth et al., ). Development of almorexant was discontinued due to infrequent transient increases in liver enzymes unrelated to the orexin mechanism (Hoch, Van Gorsel, Van Gerven, & Dingemanse, ). A follow‐up DORA, ACT‐541468, is currently in Phase 2 trials (NCT02841709; NCT02839200).…”