SAN ANTONIO—The novel dual orexin receptor antagonist MK-4305 may be an effective and safe treatment for insomnia, according to findings presented at the 24th Annual Meeting of the Associated Professional Sleep Societies.
The drug significantly increased total sleep time and sleep efficiency compared with placebo in a population of healthy subjects, per results of a phase I study. In a phase IIb study, it significantly increased sleep efficiency, along with sleep induction and maintenance parameters, compared with placebo in patients with primary insomnia.
The phase IIb study results “truly confirm the importance of the orexin system to arousal and insomnia and of MK-4305 antagonism,” said W. Joseph Herring, MD, of Merck, West Point, Pennsylvania. “So we’re excited to move onto phase III of the program.”
Phase III trials studying the efficacy and safety of MK-4305 in elderly and nonelderly insomnia patients are under way. Merck Research Laboratories, the drug’s manufacturer, plans to file regulatory applications for the drug in 2012.
Targeting Orexin Receptors
Christopher Winrow, PhD, of Merck, described preclinical research on MK-4305. He noted that the drug targets the neuropeptides orexin receptor-1 and orexin receptor-2, which help to regulate the brain’s sleep-wake process.
The orexin system was identified “only 12 years ago,” said Dr. Winrow. Since then, he said, “A very elegant set of genetic experiments have determined a causal link between arousal and this neuropeptide system. This is across species, and it translates into clinical observations in human subjects.”
MK-4305 is believed to block the brain’s arousal system by inhibiting orexin A and orexin B, which bind with orexin receptors 1 and 2. Thus, researchers investigated the drug’s potential to shorten sleep onset time, reduce wake time after sleep, and increase total sleep time. “This targeted approach to the arousal system offers the unique opportunity to develop a new therapy for insomnia,” said Dr. Winrow.
MK-4305 and other dual orexin receptor antagonists “effectively block orexin-induced locomotor activity, demonstrate receptor engagement in an ex vivo occupancy assay, and dose-proportionately promote sleep in multiple species,” the researchers found. It significantly reduced active wake and increased both rapid eye movement (REM) and slow-wave sleep in rats, dogs, and rhesus monkeys.
Decreased Sleep Latency and Wake After Sleep
The phase I study, presented by Hong Sun, PhD, of Merck, was conducted during the course of one night and the next morning. The researchers randomized 20 healthy male subjects to receive placebo or MK-4305 at 10 mg, 50 mg, or 100 mg one hour before an eight-hour polysomnography (PSG) recording.
The results indicated that the drug’s 50-mg and 100-mg doses significantly reduced latency to persistent sleep and increased sleep efficiency, while all three doses significantly decreased wake after sleep onset time. None of the doses had a significant effect on slow wave activity or REM stage duration, however. At 10 hours, the 50-mg and 100-mg doses were associated with a decrease in alertness on the Leeds Sleep Questionnaire, a subjective evaluation, and the 100-mg dose was associated with an increase in reaction time.
“MK-4305 was generally safe and well-tolerated at the three dose levels tested in this study,” Dr. Sun noted. She added that the study results aided the dose selection in the phase IIb study.
Improvement in Sleep Efficiency
The double-blind, crossover phase IIb study included 254 patients with primary insomnia, said Dr. Herring. During the first phase, patients were randomized to receive placebo or MK-4305 at 10 mg, 20 mg, 40 mg, or 80 mg each night before bedtime for four weeks. During the second phase, which began after a one-week wash-out period, patients from the placebo group crossed over to receive treatment and vice-versa for an additional four weeks. PSG was recorded 30 minutes after dosing at night one and night 28 of each of the study phases.
Of the study patients, 220 were in the United States and 34 were in Japan. The patients’ mean age was 44, and 58% were female. During the entire study, 249 patients received placebo and 243 patients received MK-4305.
All four doses of the drug were significantly superior to placebo for change from baseline sleep efficiency at night 1 and night 28. At night one, the improvements were 6.2% for the 10-mg MK-4305 group, 6.6% for the 20-mg group, 11.6% for the 40-mg group, and 12.2% for the 80-mg group, compared with placebo. At night 28, the improvements were 4.7% for the 10-mg group, 10.4% for the 20-mg group, 7.9% for the 40-mg group, and 7.7% for the 80-mg group, compared with placebo.