Results Presented from Phase IIb Clinical Study of Merck's Investigational Insomnia Therapy MK-4305
Data Reported at SLEEP 2010 24th Annual Meeting of the Associated Professional Sleep Societies
SAN ANTONIO--(BUSINESS WIRE)--Jun 9, 2010 - Clinical results from a Phase IIb study showed that MK-4305, Merck's investigational dual orexin receptor antagonist, was significantly more effective than placebo (p<0.005) in improving overall sleep efficiency at night one and at the end of week four in patients with primary insomnia. MK-4305 was generally well-tolerated in the study. Orexins are neuropeptides (chemical messengers) that are released by specialized neurons in the hypothalamus region of the brain and are believed to be an important regulator of the brain's sleep-wake process. The data were presented for the first time at the SLEEP 2010 24th Annual Meeting of the Associated Professional Sleep Societies.
Phase III trials studying the efficacy and safety of MK-4305 in elderly and non-elderly insomnia patients are ongoing. Merck anticipates filing regulatory applications for MK-4305 in 2012.
"Since the discovery and characterization of orexin over the past decade as an important component of the sleep-wake system, Merck has been actively committed to discovering and developing potential interventions for sleep disorders that target the orexin receptors. We are encouraged by these phase II results showing positive effects of MK-4305 in patients with primary insomnia,” said David Michelson, M.D., vice president of Neuroscience Clinical Research, Merck. “Phase III research will provide further insight into the safety and efficacy profile of MK-4305, which, if approved, would provide a new class of insomnia treatments.”
MK-4305 is an investigational dual orexin receptor antagonist (DORA) compound that is thought to inhibit the actions of the neuropeptides orexin A and orexin B, which bind with the OX1R and OX2R receptors. These neuropeptides are produced by neurons, located within the hypothalamus region of the brain, and play a key role in regulation of the brain's sleep-wake process. Orexin antagonists are thought to block the stimulation of the brain's arousal system.
The findings reported today are from a multicenter, randomized, double-blind, placebo-controlled crossover dose-ranging study designed to evaluate the safety and efficacy of four doses of MK-4305 (10, 20, 40 and 80mg) in patients with primary insomnia as defined by criteria from the Diagnostic and Statistical Manual of Mental Disorders DSM-IV, a manual published by the American Psychiatric Association that covers all mental health disorders for both children and adults. These criteria include difficulty falling asleep, difficulty remaining asleep, or difficulty receiving restorative sleep for a period of no less than one month.
A total of 254 patients were randomized: 243 patients received MK-4305 at one of the four doses (10mg n=62, 20mg n=61, 40mg n=59, 80mg n=61) and 249 patients received placebo. The primary endpoint was improvement in sleep efficiency (total sleep time divided by eight hours of time in bed), compared to placebo on night one and at the end of four weeks of treatment. The secondary endpoints were improvement in wake after sleep onset (WASO) and latency to persistent sleep (LPS, or the delay in time to persistent sleep) compared to placebo on night one and at the end of four weeks of treatment. All endpoints were measured using polysomnography (PSG, also known as a sleep study), a comprehensive recording of the biophysiological changes that occur during sleep.
Significant increases from baseline sleep efficiency (SE) versus placebo (p-values <0.005) were observed for all doses of MK-4305 for the co-primary endpoints of SE at night one (least square (LS) mean percentage difference: 10mg = 6.2%, 20mg = 6.6%, 40mg = 11.6%, 80mg = 12.2%) and at the end of week four (10mg = 4.7%, 20mg = 10.4%, 40mg = 7.9%, 80mg = 7.7%).
Significant dose-related effects were also generally observed for sleep induction and maintenance parameters, for most doses and time points. All doses of MK-4305 improved objectively measured sleep maintenance, as evidenced by significant reductions in the secondary endpoint of baseline-adjusted WASO versus placebo (p-values <0.0005) both at night one (LS mean difference in minutes: 10mg = -26.9 minutes, 20mg = -22.9 minutes, 40mg = -33.2 minutes, 80mg = -37.9 minutes) and at the end of week four (10mg = -23.0 minutes, 20mg = -26.9 minutes, 40mg = -32.3 minutes, 80mg = -28.4 minutes).
MK-4305 significantly improved objectively-measured sleep onset, as evidenced by significant reduction in the secondary endpoint of baseline-adjusted LPS versus placebo (p-values <0.05) at night one (LS mean difference in minutes: 80mg = -21.3 minutes), and at the end of week four (80mg = -10.7 minutes). The data also suggest that MK-4305 was effective in improving sleep onset at other doses but not at both time points, with nominal p-values < 0.05 at night one (LS mean difference in minutes: 40mg = -21.6 minutes), and at the end of week four (20mg = -24.0 minutes). Of note, this initial Phase IIb study was not aimed at definitively assessing LPS, as this would have required a markedly larger number of patients than the number required to achieve the sleep efficiency primary endpoint.
In the study, treatment with MK-4305 was generally well-tolerated with no reports of serious adverse events. The most common adverse experiences occurring in patients treated with MK-4305 (incidence ‰¥ 3% for one or more doses studied) were upper respiratory tract infection, urinary tract infection, alanine aminotransferase increase, creatinine phosphokinase increase, dizziness, drowsy on awakening, headache, sedation, somnolence and vivid dreams.
Insomnia is a sleep disorder that affects about 10 percent of the general population. People with insomnia may have one or more sleeping problems including difficulty falling asleep, staying asleep and returning to sleep. Sleep disorders may also impact next day functioning. Insomnia affects women more often than men and the condition can occur at any age however, there is an increased prevalence in the elderly.
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Ian McConnell, 908-423-3046
Kim Hamilton, 908-423-6831
Joe Romanelli, 908-423-5088
Posted: June 2010