Clinical Development

Silenor® (doxepin)

Our NDA for Silenor® (doxepin) includes the data from our completed clinical program for Silenor, which included six randomized, double-blind, placebo-controlled, multi-center clinical trials designed to assess the efficacy and safety of Silenor for the treatment of insomnia. All of the clinical trials demonstrated statistically significant differences relative to placebo on their primary endpoints and multiple secondary endpoints. Four of these were Phase 3 clinical trials, the results of which are summarized as follows:

• In a clinical trial to evaluate Silenor 3 mg and 6 mg in the treatment of adults (n=229) with chronic insomnia in a sleep laboratory setting, Silenor demonstrated a statistically significant improvement compared to placebo for both doses on the primary endpoint of wake after sleep onset (WASO) as well as a range of secondary endpoints including latency to persistent sleep (LPS) total sleep time (TST) sleep efficiency (SE), subjective Wake After Sleep Onset (sWASO), and subjective Total Sleep Time (sTST) in each case at night one. Statistical significance was also achieved for WASO, TST and SE on night 29, which was the final timepoint in the study; we believe that our further analyses of the subjective sleep maintenance data at the final timepoint included in our NDA resubmission provides evidence sufficient to support a determination of sustained subjective efficacy.

• In a clinical trial to evaluate Silenor 6 mg in the treatment of healthy adults (n=565) experiencing transient insomnia in a sleep laboratory setting, Silenor demonstrated a statistically significant improvement compared to placebo on the primary endpoint of LPS, as the well as a range of secondary endpoints including WASO, TST, SE, latency to sleep onset (LSO), sWASO and sTST.

• In a clinical trial to evaluate Silenor 6 mg in the treatment of elderly subjects (n=255) with primary sleep maintenance insomnia in an outpatient setting, Silenor demonstrated a statistically significant improvement compared to placebo on the primary endpoint of sTST at week one, as the well as a range of secondary endpoints including sWASO. This benefit was sustained for both of these endpoints at the final timepoint of four weeks.

• In a clinical trial to evaluate long-term use of Silenor 1 mg and 3 mg in elderly subjects (n=240) in both the sleep laboratory and outpatient settings, Silenor demonstrated a statistically significant improvement compared to placebo on the primary endpoint of WASO at night one. Silenor also demonstrated statistical significance at night one for both doses on the secondary endpoints of TST and SE, at week one for the 3 mg dose on sTST as measured in the outpatient setting and at night one on LSO as measured in the outpatient setting for the 3 mg dose. At night 85, which was the final timepoint, statistical significance was achieved for both doses for WASO, TST and SE, as well as for sTST and LSO as measured in the sleep lab and the outpatient setting, and sWASO as measured in the sleep lab (sWASO was not measured in the outpatient portion of the study).

• Across all of the Phase 3 clinical trials, the most frequently reported adverse events were somnolence, upper respiratory tract infection, sinusitis, nausea and hypertension; of these, somnolence was the only adverse event that was dose-related.