Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

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.

TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation

“…We observed a statistically significant decrease in TAAR1 mRNA in MS patient monocytes compared to controls, a pronounced shift in sub-cellular localization following pro-inflammatory stimulation in peripheral macrophages, and TAAR1 colocalization with the macrophage and microglia marker IBA-1 within the inflamed border region of an MS lesion. These findings support further study towards the role of TAAR1 in monocyte and macrophage populations and warrants that pharmacological investigation using selective TAAR1 agonists [ 7 , 8 ] in animal models of MS [ 33 ].…”

“…Following stimulation, the altered sub-cellular localization of TAAR1 suggests variable TAAR1 function that may be dependent on the state of macrophage polarization, thereby implicating TAAR1 as a novel target through which inflammatory cellular processes such as migration and proliferation, both of which are associated with the neuroinflammation occurring in an active MS lesion. From a clinical and potentially MS-relevant perspective, TAAR1 is now established as a viable target for human pharmacotherapy of disorders of the CNS [ 7 , 8 ].…”

“…Of the different TAARs expressed in humans, the vast majority of research has focused on TAAR1 and its role in modulating neurotransmission within the CNS. With an established function of TAAR1 in the CNS and the availability of selective and safe TAAR1 agonists, pharmacologically targeting TAAR1 within the CNS has resulted in successful clinical trials for treatment of neurological disorders, such as schizophrenia [ 7 , 8 ], which also is accompanied by an inflammatory component [ 9 ]. In addition to the established role in the CNS, TAAR1 has also been associated with putative roles in regulation of the immune system including chemotactic migration, cytokine secretion, and differentiation of various immune cell populations [ 10 ].…”

Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia

“… 16 Suppression of rapid eye movement sleep has also been reported in both rats and humans. 16 , 17 In addition, ulotaront attenuated the ketamine‐induced increase in striatal dopamine synthesis capacity without producing an effect in naïve mice, suggesting that it may modulate presynaptic dopamine dysfunction observed in patients with schizophrenia. 18 In a randomized, double‐blind, placebo‐controlled clinical trial in patients with an acute exacerbation of schizophrenia, treatment with ulotaront (50 or 75 mg/day) demonstrated significant reduction in symptoms of schizophrenia.…”

Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study

“…Suppression of rapid eye movement sleep has also been reported after single doses of ulotaront in both rats and humans and was utilized as a translational pharmacodynamic measure to guide dose selection in subsequent clinical trials in schizophrenia patients 10 .…”