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

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.

Hypocretins (orexins): The ultimate translational neuropeptides

“…To date, a number of Hcrt‐R1 selective antagonists have been described in the scientific and patent literature (reviewed in [6, 29]; see also [90]). Clinical data of Hcrt‐R1 drug candidates have been published for ACT‐539313 [Idorsia Pharmaceuticals Ltd., 91, 92]–the first report of a Hcrt‐R1 antagonist in humans and JNJ‐61393215 [Janssen Research & Development LLC; 93]. ACT‐539313 was tested for PK/PD, single and multiple ascending dose safety and tolerability and drug‐drug interaction potential [91, 92, 237].…”

“…This is supported by a plethora of preclinical evidence in models of fear, stress, PTSD and panic (e.g., [87, 173–177] and reviewed in [88, 178–180]) and the association of Hcrt‐R1 polymorphisms such as HCRTR1 C/T Ile408Val with panic and agoraphobia, including limited responses to cognitive behaviour therapy [181], although the mechanism of altered‐signalling for this variant has not yet been deciphered [182]. Hcrt‐R1 antagonists are being investigated in clinical studies for panic [JNJ‐61393215, 93]. A study investigating suvorexant in panic disorder is also listed on clinicaltrials.gov (NCT02593682).…”

“…ACT‐539313 was tested for PK/PD, single and multiple ascending dose safety and tolerability and drug‐drug interaction potential [91, 92, 237]. A Phase I study with JNJ‐61393215 provided positive proof of concept in CO 2 ‐induced panic in male healthy volunteers [93].…”

“…Preclinical studies comparing individually and co-dosed Hcrt-R1 and Hcrt-R2 antagonists and dosing selective antagonists into the opposing receptor KO mouse, suggest that this is due to the combined effects of blocking both Hcrt-Rs simultaneously [83,85,131]. This effect is present to such a degree that REM sleep disinhibition in Hcrt-R2 KO mice has become routinely used for in vivo validation of Hcrt-R1 antagonist target engagement (e.g., with JNJ-54717793 [87] and JNJ-61393215 [93]). Although it can be debated as to whether REM sleep enhancement may be beneficial or detrimental, REM sleep is a normal component of sleep architecture, and no other hypnotic principle replicates this effect.…”

Selective Orexin Receptor Antagonists as Novel Augmentation Treatments for Major Depressive Disorder: Evidence for Safety and Efficacy From a Phase 2B Study of Seltorexant

“…The development selective antagonists for OX1R [such as JNJ-61 393 215 (NCT04080752) ( Salvadore et al, 2020 ) and AZD4041 (NCT04076540)] and OX2R (seltorexant) are of great interest to the scientific community. These medications offer the potential for treatment of various psychiatric disorders, ranging from MDD with insomnia symptoms ( Savitz et al, 2021 ) or with anxious distress (NCT04080752) to cocaine ( Hollander et al, 2012 ; James et al, 2021 ) or nicotine use disorder ( Kenny 2011 ).…”