spec sheet5 rows
SB-649868 was GlaxoSmithKline's entry in the dual orexin receptor antagonist race that eventually produced approved drugs like suvorexant; in a controlled trial in men with primary insomnia it significantly cut time to persistent sleep, reduced wake after sleep onset, and increased total sleep time compared with placebo. Despite that positive Phase II signal, GSK put the whole program on hold in 2007 after an unspecified preclinical toxicity finding, well before the class's eventual commercial success proved the mechanism out. The published Phase I and Phase II data came out only after the hold, leaving SB-649868 as a case of a dual orexin antagonist that worked clinically but got stopped anyway, on safety grounds the company never fully detailed publicly.
- significantly reduced latency to persistent sleep versus placebo
- reduced wake after sleep onset (WASO)
- increased total sleep time in a dose-dependent manner
- helped validate the dual orexin antagonist mechanism years before suvorexant's approval
- cognitive impairment on next-dose testing (digit symbol substitution) at peak drug levels, though not persisting the next morning
- headache, nasopharyngitis, and dry mouth reported in insomnia patients
- unspecified preclinical toxicity finding that triggered the program hold
- SB-649868's positive Phase I and Phase II results were only published after GlaxoSmithKline had already put the program on hold, an unusual sequence for a discontinued drug.
Mechanism
Dual 1 and orexin 2 (OX1/OX2) receptor ; blocking orexin signaling in the wake-promoting circuits of the lateral reduces arousal and promotes sleep onset and maintenance.
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
GlaxoSmithKline put this on hold in 2007 over a preclinical toxicity finding it never described publicly, which is the most important thing about its safety and also the one thing nobody can check. What was published looks ordinary for the class: 103 volunteers tolerated it well, with somnolence and fatigue in most people at 60 and 80 mg, and next-morning cognitive testing was clean. Two findings do matter. Repeated dosing inhibited CYP3A4 strongly enough at 30 mg to raise simvastatin exposure, and the 60 mg dose pushed REM sleep up and REM latency down.
History
Developed by GlaxoSmithKline through the mid-2000s; completed Phase I safety/PK studies and a Phase II trial showing significant sleep-promoting effects in men with primary insomnia; the overall program was placed on hold in 2007 following an unspecified preclinical toxicity signal, and it was never revived.
Subjective profileweighing the evidence above
A dual orexin antagonist that proved the mechanism worked in patients but was pulled anyway over an undisclosed preclinical safety flag.
Resources
This entry is here for reference.
Research
- 1.The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia
- 2.Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist
2 listed here; entry last updated July 2026
Reviews
My notesprivate to this device
FAQ
Why was SB-649868 discontinued if it worked in trials?
GSK placed the program on hold in 2007 after an unspecified preclinical toxicity finding, despite positive Phase I and Phase II sleep data; the company never fully detailed the safety concern publicly, and the program was never restarted.
How does SB-649868 relate to approved sleep drugs like suvorexant?
It uses the same dual orexin receptor antagonist mechanism that later reached the market in drugs like suvorexant and lemborexant; SB-649868 was one of the earlier clinical proofs that the mechanism could work in insomnia patients.
Adverse effects
- cognitive impairment on next-dose testing (digit symbol substitution) at peak drug levels, though not persisting the next morning
- headache, nasopharyngitis, and dry mouth reported in insomnia patients
- unspecified preclinical toxicity finding that triggered the program hold
Notes and cautions
- dose-dependent increase in REM sleep and reduced REM latency at the highest tested dose