Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

Giacomo Salvadore,Luc G M Van Nueten,Brock T Shireman,Philip L Johnson,Brian Lord,Abigail I Nash ,Rob Zuiker,Christine Dugovic,Kanaka Tatikola,Sander Brooks,Bart Remmerie,Gabriël Jacobs ,Cathy Bleys,Pascal Bonaventure,Anantha Shekhar,John A Moyer ,Koen Schruers,Terry P Lebold,Diane Nepomuceno,Wayne C Drevets

doi:10.1038/s41398-020-00937-9

Abstract

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

Highlights

Orexin neuropeptides, known as hypocretins, are critically involved in coordinating adaptive physiological, behavioral, and endocrine responses to salient stimuli or Salvadore et al Translational Psychiatry (2020)10:308 amplification of their firing activity in anxiety, fear, and motivated states[3].At the terminals of these projections, orexin interacts with two distinct receptors, orexin-1 (OX1R) and orexin-2 receptor (OX2R) subtypes
We have shown that while selective orexin-1 receptor (OX1R) antagonism did not affect sleep–wake states, blockade of both OX1R and OX2R elicited a disinhibition of rapid eye movement (REM) sleep at the expense of non-REM (NREM) sleep in rodents[11,12,18]
The binding selectivity of JNJ61393215 for human OX1R compared with human OX2R was substantial

Summary

Introduction

Known as hypocretins, are critically involved in coordinating adaptive physiological, behavioral, and endocrine responses to salient stimuli or Salvadore et al Translational Psychiatry (2020)10:308 amplification of their firing activity in anxiety, fear, and motivated states[3].At the terminals of these projections, orexin interacts with two distinct receptors, orexin-1 (OX1R) and orexin-2 receptor (OX2R) subtypes. Known as hypocretins, are critically involved in coordinating adaptive physiological, behavioral, and endocrine responses to salient stimuli or Salvadore et al Translational Psychiatry (2020)10:308 amplification of their firing activity in anxiety, fear, and motivated states[3]. The key role of the orexin system in sleep/wakefulness regulation is characterized by the specific anatomical distribution of OX2Rs in histaminergic neurons in the tuberomammillary nucleus[7]. OX1Rs are more selectively expressed in bed nucleus of the stria terminalis, amygdala, cingulate cortex, and the noradrenergic neurons of the locus coeruleus[8]. Consistent with the anatomical distribution of OX1R, a critical role for this receptor is emerging in complex emotional behavior, such as association of OX1R pathway overactivation with panic or anxiety states[9,10,11,12,13]

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Results

Conclusion