Approved GABA receptor-activating drugs (Ambien, Sonata and Lunesta) are designated by the Drug Enforcement Administration (DEA) as Schedule IV controlled substances and thus require registration and administrative controls. In contrast, Silenor is not designated as a Schedule IV controlled substances by DEA, is not scheduled, and so is not subject to the same administrative controls.

Patients will be able to sample the drug during the early stages of the launch, as well as throughout later stages of the launch. Somaxon’s ability to freely provide Silenor to doctors and patients through a sampling program could lead to increased awareness by both doctors and patients, and should increase the ability of insomnia suffers to sample this sleep medicine.

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While both Ambien CR and Lunesta are approved for sleep onset as well as sleep maintenance, Rozerem, Sonata and Ambien are approved only for sleep onset.  All studies were performed by Somaxon. Highlights are as follows:

Phase III Adult Study (NR6-084)

This was a randomized, placebo-controlled, study designed to assess the efficacy and safety of two dose levels of Silenor, 3 mg and 6 mg, in 229 subjects with chronic primary insomnia and sleep maintenance difficulties. In the study, efficacy was evaluated with polysomnography (PSG) over 8 hour periods and the data averaged across the doubleblind (DB) period are reported. PSG measures in this study included wake time after sleep (WTAS), sleep efficiency in the last quarter-of-the-night (SE-LQN) and sleep efficiency (SE) in hour 8.

This was a randomized, placebo-controlled, study designed to assess the efficacy and safety of two dose levels of Silenor, 3 mg and 6 mg, in 229 subjects with chronic primary insomnia and sleep maintenance difficulties. In the study, efficacy was evaluated with polysomnography (PSG) over 8-hour periods and the data averaged across the doubleblind (DB) period are reported. PSG measures in this study included wake time after sleep (WTAS), sleep efficiency in the last quarter-of-the-night (SE-LQN) and sleep efficiency (SE) in hour 8.

Results from this study showed that SE in the last quarter of- the-night was significantly improved at the Silenor 3 mg and 6 mg doses versus placebo across the double-blind period. SE in hour 8 was significantly improved at the Silenor 3 mg and Silenor 6 mg doses across the double-blind period. WTAS was significantly improved at the Silenor 3 mg and 6 mg doses across the DB period.

Phase III Transient Study

In this randomized, double-blind, placebo-controlled, single-dose study in healthy adults, subjects received a single nighttime dose of placebo (N=282) or Silenor 6 mg (N=283) in a sleep lab. The study was intended to measure the efficacy and safety of Silenor 6 mg tablets in healthy adults using a model of transient insomnia.

In this study, efficacy was evaluated using a PSG and subjective morning questionnaire. The primary endpoint in this study was latency to persistent sleep (LPS). Secondary PSG endpoints included wake after sleep onset (WASO), total sleep time (TST), wake time after sleep (WTAS) and sleep efficiency. Secondary subjective endpoints included latency to sleep onset (LSO), subjective WASO (sWASO), subjective TST (sTST) and sleep quality.

Results of this study showed that Silenor 6 mg statistically significantly improved LPS (13 minute improvement versus PBO; p<0.0001), WASO (39 minute improvement versus PBO; p<0.0001), TST (51 minute improvement versus PBO; p<0.0001), WTAS (p<0.0001), overall SE (p<0.0001), SE in each third-of-the-night (p<0.0001) and SE in all eight hours (p≤0.0003), all versus PBO.

Phase III Elderly Study (NR6-090)

This 240-patient randomized, double-blind, placebo-controlled, 3-month study was designed to assess the efficacy and safety of Silenor 1 mg and 3 mg in elderly subjects. Insomnia patients were randomized to 12 weeks of Silenor 1 mg (N=77), 3 mg (N=82), or placebo (N=81). The primary efficacy endpoint was WASO on night 1, with secondary efficacy endpoints including PSG assessments of TST, SE, wake time after sleep (WTAS), and sleep architecture. SE was assessed in the last quarter of the night and by hour.

In terms of sleep maintenance measures, this study showed that WASO was significantly improved on night one for Silenor 1 mg and 3 mg, and WASO was also significantly improved on night 85 for Silenor 1 mg and 3 mg. Silenor also resulted in significant improvement in other sleep maintenance measures at multiple time-points, including TST, sTST, and SE overall.

In term of prevention of early morning awakenings, Silenor 1 mg and 3 mg significantly improved several PSG measures associated with the prevention of early morning awakenings, including SE in the last quarter-of-the-night and SE in hour 8. In terms of sleep onset, latency sleep onset (LSO) was significantly improved at weeks 1 and 12 for Silenor 3mg, and at Week 12 for Silenor 1 mg. However, latency to persistent sleep (LPS) was not significantly improved at any time-point. In terms of sleep quality, it was significantly improved at week 1 and 12 for Silenor 3 mg, and at Week 12 for Silenor 1 mg.

Phase III Elderly Study (NR6-091)

In this double-blind, placebo-controlled outpatient trial, Elderly insomnia patients were randomized to 4 weeks of nightly treatment with either Silenor 6mg (N=130) or placebo (N=125). Efficacy in this study was assessed with patient-reports and clinician ratings. Patient-reported endpoints included total sleep time (sTST), wake after sleep onset (sWASO), latency to sleep onset (LSO), and patient global impression scale (PGI). The primary analysis of the study was sTST at week 1.

In terms of sleep maintenance and duration, sTST was significantly improved at Week 1 and at weeks 2, 3 and 4 for Silenor 6 mg. sWASO was significantly improved at all 4 weeks for Silenor 6 mg. In terms of sleep onset, while LSO was decreased relative to baseline across the study, it was not significantly different versus placebo at any time.

Silenor Sleep Maintenance – Ambien CR and Lunesta

Silenor Compared to Ambien CR

Two phase III studies were run for Ambien CR. Study EFC 4529 was run in 212 adult patients and study EFC 4530 was run in elderly patients. Study EFC 4529 assessed WASO (wake after sleep onset), LPS (latency to persistent sleep) and TST (total sleep time). A significant decrease was seen in objective WASO for the active group compared to placebo for the first two nights, but that effect did not persist to nights 15 and 16. Study EFC 4530 had primary objectives that were similar to study EFC 4529.

The difference between Ambien CR and placebo was -19.4 on nights 1 and 2 and -2.4 on nights 15 and 16 for study ’29 while the mean difference between Ambien CR and placebo was -25.4 on night 1 and night 2 and -11.3 on nights 15 and 16 for study ’30. For the most direct comparison possible, we compared results from Ambien CR study ’30 to Silenor data from the elderly study (NR6-091). Data from study NR6-091 showed that mean WASO change from baseline was -38 for Silenor 6mg at week 1 versus placebo of -12 and was -50 at week 4 versus placebo of -30. While not directly comparable, this data demonstrates that Silenor is at least on par with, if not superior to, Ambien CR in terms of improving sleep maintenance.

Silenor Compared to Lunesta

Silenor is also compared to Lunesta, in order to make a comparison with regard to sleep maintenance. WASO for Lunesta was only about 5.5 minutes better than placebo at the 2mg dose, and was about 12.0 minutes better than placebo at the 3mg dose in Study ’046. At the 3mg dose in Study ‘049, WASA for Lunesta was about 9.5 minutes better than placebo. Silenor could be better in the measure of sleep maintenance.

Silenor Sleep Onset – Razorem, Sonata, Ambien CR and Lunesta

Rozerem

A Phase III Rozerem study shows what comparable sleep drugs have shown in terms of sleep onset. Study TL023 was a doubleblind randomized, single dose, 2-day study in 289 Rozerem patients versus 97 placebo patients. Patients in the Rozerem group were given either 8mg or 16mg of the drug, with primary efficacy endpoint of latency to persistent sleep (LPS or LS) by PSG. Both the 8mg and 16mg dose of Rozerem reduced LS relative to placebo, but while the difference was statistically significant for the 8mg dose, it was not statistically significant for the 16mg dose.

Sonata

For Sonata, there were a total of 13 fixed dose studies run with endpoints of latency to persistent sleep (LPS) or time to sleep onset (TSO). Similar to the Rozerem study, while it is difficult to make a direct comparison, experts believe that this data shows Silenor on par with Sonata for the measure of sleep onset.

Ambien CR

For Ambien CR, Latency to persistent sleep (LPS) was a secondary endpoint in the two phase III studies that were run, while subjective sleep onset latency was a secondary endpoint in study ‘4530.

Lunesta

For Lunesta, approval was based on a total of 6 studies, 5 in patients with chronic insomnia and 1 in a transient insomnia model. Four of the six studies had latency to persistent sleep (LPS) as their primary endpoint, two of the six used subjective sleep latency as their primary endpoint. WASO was the secondary endpoint in several of the studies.

While it is difficult to make a direct comparison between any of these studies, experts believe Silenor is on par with Ambien CR, Rozerem, Sonata and Lunesta for the measure of sleep onset, as measured by LPS. While Silenor is approved only for sleep maintenance, a degree of off-label use as a treatment for sleep onset is expected. Usage of Silenor in the sleep onset setting will pick up as SOMAXON reports additional data in this indication.

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Why Is There a Need for Silenor

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