Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

Abstract

The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10-80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5-30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased C(max). The typical estimated half-life of SB-649868 was 3-6 h - comparable with currently used hypnotic agents. Repeated administration of SB-649868 dose-dependently increased exposure to simvastatin (10 mg), suggesting CYP3A4 inhibition ranging from very mild (5 mg) to strong (30 mg). Evening dosing resulted in significant dose-dependent improvement in latency to persistent sleep, total sleep time and wake after sleep onset as measured by polysomnography. Next-morning testing did not detect evidence of residual cognitive effects. Results of these trials support further investigation of SB-649868 and other dual orexin receptor antagonists as potentially effective and well-tolerated treatments for patients with sleep disorders.

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

“…GlaxoSmithKline's SB-649868 is a piperidine but its carboxamide benzofuran group is instrumental for its activity [66]. Following evidence of sleep-promoting effects in rats [66], its tolerability and favourable 3-6 h half-life was demonstrated in Phase I clinical trials [67]. However, its development was later discontinued by GlaxoSmithKline [68].…”

“…Phase I clinical trials for another DORA, SB-649868, did not raise tolerability issues [67] however GlaxoSmithKline discontinued its development following the discovery of an unspecified safety issue in rats [68]. Published reports of the binding affinity and potency of SB-649868 (summarized in Table 3) show that it has high affinity and is a potent antagonist in the nM range [66,197].…”

Update on emerging drugs for insomnia

“…Several groups have pursued development of orexin receptor antagonists, with OX1/OX2 antagonists almorexant (ACT-078573) and suvorexant (MK----4305) in Phase III trials and several others in preclinical trials [9,10]. Actelion, GlaxoSmithKline (GSK) and Merck all reported clinical development of orexin antagonists for insomnia in recent years, and others have also identified orexin antagonists.…”

Discovery and in vitro and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide as a novel class of dual orexin receptor antagonist

“…11 SB-649868 has been reported to have a half-life in the range of 3.4-3.9 h in healthy volunteers. 12 Furthermore, patients with primary insomnia reported that SB-649868 significantly improved the quality of their sleep, while objectively increasing the total sleep time, reducing sleep latency, and suppressing nighttime awakenings. 14 The assessment of next-day residual effects indicated no significant differences between SB-649868 and placebo.…”