Abuse Liability of the Melatonin Agonist PD6735

DESCRIPTION (provided by applicant): P2D, Inc. is developing a synthetic melatonin analog (PD6735) for treating sleep disorders and circadian rhythm disorders. Clinical studies suggest that PD6735 is safe, well tolerated and effective in reducing sleep latency in non-elderly adults with primary insomnia when used at doses up to 100 mg. A major FDA concern of all sleep medications is abuse potential. Current frontline sleep drugs have considerable abuse potential and are FDA schedule IV. No data exist concerning the abuse liability of PD6735 in humans. Because PD67735 is a melatonin analog, it is hypothesized to have little to no abuse liability. This SBIR Phase 1 proposal will examine the abuse potential of PD6735 in a population of known recreational users of sleep medications by accomplishing the following specific aims: Specific Aim 1: Manufacture clinical trial supplies. Study medication (PD6735, placebo and triazolam) will be manufactured and packaged for the proposed clinical study and tested for purity, stability and microbial contamination. All study medication will be identical in appearance, consistent with the double-blind study design. Prediction: Study medication will be stable, pure and non-contaminated. Specific Aim 2: Evaluate abuse liability of the melatonin analog PD6735 in experienced sleep medication abusers at doses up to 500 mg. Single doses of 50, 100, 250 and 500 mg PD6735 will be administered to experienced sleep medication abusers in a randomized, double-blind, placebo and active comparator controlled seven period cross-over study. Placebo and triazolam (0.25 and 0.75 mg) will serve as negative and positive controls, respectively. Drug liking will be evaluated using validated instruments. Prediction: PD6735 at all doses will not be differentiated from placebo whereas triazolam will be readily distinguished from placebo. Specific Aim 3: Evaluate the safety and tolerability of the melatonin analog PD6735 in experienced sleep medication abusers at doses up to 500 mg. Safety measures will be performed during the trial described in Specific Aim 2 and clinical adverse events will be recorded. The frequency and severity of adverse events will be analyzed as a function of PD6735 dose. Prediction: PD6735 at all doses will be well tolerated with a frequency and severity of adverse events not different from placebo. The prevalence of sleep disorders in the United Sates was approximately 60 million in 1990 and is projected to rise to 80 million by 2010. Current frontline insomnia medications have abuse liability and are FDA Schedule IV drugs. A considerable unmet need exists for a safe, effective sleep medication without abuse potential (i.e. are non-scheduled). The applicant organization, P2D, is developing a melatonin analog, PD6735, that has been shown effective in treating insomnia in three Phase 2 clinical efficacy studies. Further, PD6735 appears to have no abuse liability in preclinical studies performed in animals. The present application describes a PD6735 abuse liability study in humans that is required by the FDA for approval of PD6735 as an insomnia treatment in humans. It is anticipated that PD6735 will not demonstrate abuse liability study in human subjects. In discussions held between P2D and the FDA at FDA headquarters in Rockville, MD, the design of an FDA- required PD6735 abuse liability study was discussed and the study design described in the present application was found acceptable by the FDA.