Abstract
SEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.
Highlights
Introduction SEP363856 is a novel central nervous system (CNS)active compound that has demonstrated significant efficacy in the treatment of the symptoms of acute schizophrenia in a large randomized, double-blind, placebocontrolled trial[1]
The single 50 mg dose of SEP-363856 was associated with a significant reduction versus placebo in rapid eye movement (REM) duration; REM percent; and significant increase in the latency to REM (difference in LS mean change scores +186.0 min [95% confidence interval (CI): 127.1, 244.9] (Table 2)
The aim was to characterize the doses and plasma concentrations of SEP-363856 associated with clinically relevant CNS activity, and use REM effects as a translational pharmacodynamic measure to assist in dose selection for subsequent clinical trials in schizophrenia
Summary
Active compound that has demonstrated significant efficacy in the treatment of the symptoms of acute schizophrenia in a large randomized, double-blind, placebocontrolled trial[1]. Its mechanism of action is not fully elucidated, preclinical studies suggest that agonism at TAAR1 and 5-HT1A receptors contribute to its efficacy[2]. SEP-363856 has been shown to modulate dopaminergic and serotonergic neurotransmission through TAAR1- and 5-HT1A-mediated inhibition of dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) neuronal firing[2]. TAAR1 is a G-protein-coupled receptor that is expressed in cortical, limbic, and midbrain monoaminergic regions and has been shown to modulate dopaminergic, serotonergic, and glutamatergic activity in rodents[4,5,6,7,8,9]. Based on several preclinical studies with selective TAAR1 agonists[10,11,12], and the recent clinical findings with SEP-3638561, TAAR1 has emerged as a promising therapeutic target for mental illness, addiction, and sleep disorders
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