Phase II Studies Show Investigational Insomnia Agent Gaboxadol Improved Deep Sleep and Key Sleep Measures in Adults with Primary and Transient Insomnia.

SALT LAKE CITY -- Results from phase II studies presented this week demonstrated the effects of gaboxadol on sleep architecture (visual polysomnograph and computerized analysis of the waveform through the stages of sleep) in both primary and transient insomnia. In a model of transient insomnia the traditional measures of sleep onset and maintenance were also reported. Gaboxadol, an investigational agent under clinical development by Merck & Co., Inc. and H. Lundbeck A/S for the treatment of insomnia, is a first-in-class selective extrasynaptic GABA(A) receptor agonist (SEGA). The data were presented at the SLEEP 20th Anniversary Meeting of the Associated Professional Sleep Societies (APSS).

In the clinical studies presented in primary and transient insomnia, electroencephalogram (EEG) analyses showed that gaboxadol (5, 10, 15 and 20 mg) caused statistically significant increases in deep sleep, i.e. visually scored slow wave sleep or objectively measured slow wave activity (SWA) as compared to placebo (5 mg: p<0.05; 10, 15 and 20 mg: p<0.001; respectively). Slow waves are the characteristic and predominant waveform during sleep stages 3 and 4. Combined sleep stages 3 and 4 are commonly known as slow wave sleep. Slow wave sleep and slow wave activity are associated with deep and/or restorative sleep. Slow wave activity refers to a low frequency band on the EEG and is an objectively scored measure of the slow wave sleep process. Zolpidem 10 mg was used as an active reference for these studies. These studies were not designed to compare the use of gaboxadol versus zolpidem.

"These data showed that gaboxadol consistently increased the intensity of, and time spent in, deep or restorative sleep," said Stephen Deacon, Ph.D., a lead investigator and head of Clinical Development, Sleep Disorders, Lundbeck U.K. "The research helps to support gaboxadol's potential as a new and different treatment for insomnia."

Gaboxadol improved deep sleep in primary insomnia patients

Power spectral analysis was performed on data collected from the non-rapid eye movement (NREM) EEG data collected from two separate randomized, double-blind, cross-over polysomnograph (PSG) studies to compare the dose response characteristics of gaboxadol to placebo after two nights of treatment. Patients aged 18-65 years diagnosed with primary insomnia (DSM-IV criteria) were included in both of the studies. Study 1 evaluated 40 patients treated with gaboxadol (10 and 20 mg), zolipdem (10 mg) or placebo in a 4-way cross-over trial. Study 2 evaluated 26 patients treated with gaboxadol (5 and 15 mg) and placebo in a 3-way cross-over trial.

Power spectral analyses were performed on the NREM EEG on the second night of treatment (using 38 patients for study 1 and 23 patients for study 2 per protocol). Night 1 was used as an adaptation night to avoid first night effects. Gaboxadol (10, 15 and 20 mg) increased spectral power in the lower frequency bands, defined as slow wave activity and theta activity - in a dose dependent manner, compared to placebo (p<0.05). Theta activity is another frequency band adjacent to SWA seen on the EEG, however, the significance of theta activity is unknown.

In Study 1, gaboxadol 10 and 20 mg, when compared to placebo, increased slow wave activity (0.5 - 3.5Hz), by a rate of 33 and 54 percent, respectively (p<0.01) and increased theta activity (4 - 7.5Hz) by a rate of 24 and 34 percent, respectively (p<0.01 and p<0.001) relative to placebo, but did not have any statistically significant effect on the alpha, beta 1, beta 2, and spindle bands.

In Study 2, gaboxadol 15 mg increased slow wave activity by 21 percent relative to placebo (p<0.05), and increased theta activity by 20 percent, relative to placebo (p<0.001) with no significant effect at the 5 mg dose.(1) No effect was seen on the other measures (i.e. alpha, beta 1, beta 2, and spindle bands) for either of these two doses.

Safety was not an endpoint for this analysis. However, in a previously reported presentation of data for 40 patients included in this analysis, the most common adverse events included tachycardia, headache, nausea, vomiting and fatigue. Gaboxadol (10 mg and 20 mg) was generally well tolerated. No patients had serious adverse events, and no patients withdrew from the study due to adverse events.

Gaboxadol improved deep sleep and key sleep measures in transient insomnia

A randomized, double-blind, 5-way cross-over study of 109 healthy subjects aged 18-58 years was conducted to evaluate the efficacy of gaboxadol (5, 10 and 15 mg) in a model of transient insomnia. The primary objective of the study was to evaluate the efficacy of gaboxadol on traditional self-reported and visually scored PSG sleep measures when compared with placebo in a model of transient insomnia. Secondary objectives were to evaluate measures of slow-wave sleep (SWS), residual sedative effects and safety and tolerability. Sleep architecture was also assessed using EEG power spectral analysis on NREM sleep.

On self-reported measures, subjects who were administered gaboxadol 10 and 15 mg reported improvements in the time it took them to fall asleep (sTSO) (34 percent, 29.2 minutes; 27 percent, 32.2 minutes; respectively, both p<0.05), compared with placebo (44.4 minutes). Gaboxadol 5 mg did not demonstrate a significant effect on sTSO. Patients treated with all three doses of gaboxadol (5, 10 and 15 mg) reported significant improvement in the overall time spent asleep (sTST) (5 mg: 6 percent, 414.8 minutes; 10 mg: 7 percent, 419.2 minutes; and 15 mg: 9 percent, 426.8 minutes; all p<=0.05) compared to placebo (391.2 minutes) and the amount of time they spent awake following sleep onset (sWASO) (5 mg: 47 percent, 20.8 minutes; p<0.01; 10 mg: 31 percent, 27.2 minutes; p<=0.05; and 15 mg: 37 percent, 24.9 minutes; p<0.01) compared to placebo (39.5 minutes). Patients also reported that they woke up significantly fewer times throughout the night (sNAW) (5 mg: 32 percent, 1.9 times; 10 mg: 39 percent, 1.7 times; and 15 mg: 36 percent, 1.8 times) compared to placebo (2.8 times).

On polysomnographic measures of sleep efficacy, gaboxadol 10 and 15 mg significantly decreased the time it took for participants to fall asleep by 31 and 33 percent (latency to persistent sleep, 10 mg: 27.0 minutes; p<0.05 and 15 mg: 26.1 minutes; p<0.01), compared with placebo (39.2 minutes). Gaboxadol at any dose did not significantly affect the number of awakenings, relative to placebo. All three doses significantly increased total sleep time (5mg: 8 percent, 393.1 minutes, 10 mg: 10 percent, 398.2 minutes, and 15 mg: 8 percent, 393.1 minutes; all p<0.001) and decreased wakefulness after sleep onset (5mg: 25 percent, 56.8 minutes, p<0.01; 10 mg: 27 percent, 55.0 minutes; p<0.01; and 15 mg: 22 percent, 58.8 minutes; p<0.05) compared to placebo (75.8 minutes).

Gaboxadol significantly increased spectral power in the lower frequency bands defined as slow wave and theta activity (5 mg, 6 percent, p<=0.05; 10 mg, 19 percent, p<0.001 and, 15 mg, 27 percent, p<0.001 compared to placebo), and increased visually scored slow wave sleep (5 mg, 12 percent, p<=0.05; 10 mg, 37 percent; 15 mg, 42 percent; both p<0.001, compared to placebo).

Treatment with gaboxadol was generally well tolerated in the study with the majority of adverse events mild to moderate in nature. There were no serious adverse events and no adverse events that lead to withdrawal from the study. The most common adverse events occurring in patients treated with gaboxadol were nausea and dizziness. There were no consistent next day residual effects observed in either the gaboxadol or placebo arms of the study.

About gaboxadol

Gaboxadol is a novel compound currently in phase III development for the treatment of insomnia. Merck and Lundbeck are collaborators in the clinical development and commercialization of gaboxadol.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

About Lundbeck

H. Lundbeck A/S is an international pharmaceutical company engaged in the research and development, production, marketing and sale of drugs for the treatment of psychiatric and neurological disorders. In 2005, the company's revenue was DKK 9.1 billion (approx. EUR 1.2 billion). The number of employees is approx. 5,000. For further information, visit www.lundbeck.com

Merck Forward-Looking Statement 

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

(1) These values are calculated based on dose minus placebo divided by placebo