Merck & Co's sleep drug beats placebo in Phase IIb trial

Merck & Co's novel sleep product MK4305 met its co-primary endpoints, improving sleep efficiency, in patients with sleep disorders, show Phase IIb data presented at the SLEEP 2010 Associated Professional Sleep Societies meeting.

The company has already initiated three Phase III trials of the drug, and plans to file for marketing approval in 2012.

MK4305 is among the most advanced of the new class of sleep drug, the orexin receptor antagonists. Acetlion's almorexant is also already in Phase III trials, whereas GlaxoSmithKline's GSK649868 is in Phase II trials. Orexins are known to be produced in the in hypothalamus, and to play a key role in the regulation of the brain's sleep-wake cycle through the activation of their receptors. By blocking the receptors (OX1R and OX2R), companies hope they can prevent the stimulation of the brain's arousal system.

"The key question is of course safety," comment Jefferies analysts in a research note. Back in December, Actelion reported that its almorexant had met its primary endpoint in its first Phase III trial, but that "certain safety observations" were seen. As Actelion has not yet disclosed what these observations entailed, analysts are unsure what kind of shadow they may cast over almorexant specifically and the entire drug class more generally.

To assess the safety and efficacy of MK4305, Merck enrolled 254 patients to the crossover trial, in which subjects were placed on two four-week treatment arms (one active and one placebo) separated by a one week washout period. Four doses of oral MK4305 were tested: 10, 20 40 or 80mg administered 30 minutes before bedtime.

All doses of drug met the co-primary endpoints, difference from placebo in change in sleep efficiency (the percentage of time spent asleep from a total of the time spent in bed) on night one and on night 28, with p values of <0.005. on="" night="" one,="" the="" mean="" improvements="" over="" placebo="" were="" 6.2%,="" 6.6%,="" 11.6%="" and="" 12.2%="" for="" the="" low="" to="" high="" doses,="" respectively.="" on="" night="" 28,="" they="" were="" 4.7%,="" 10.4%,="" 7.7%="" and="" 7.7%="" for="" the="" low="" to="" high="" doses,="">

In a single-dose Phase II trial of almorexant, Jefferies analysts point out, 100mg of drug improved sleep efficiency by 5% and 200mg of drug improved sleep efficiency by 8%.

For MK4305, dose-related effects were observed for sleep induction and maintenance parameters, said the investigators.

The most common adverse events were upper respiratory tract infection, urinary tract infection, alanine aminotransferase increase, creatinine phosphokinase increase, dizziness, drowsiness on awakening, headache, sedation, somnolence and vivid dreams. No serious adverse events were noted.