Anxiolytic activity of a novel orexin-1 receptor antagonist

The orexin system and particularly the orexin-1 receptor (OX1R) may be involved in the pathophysiology of panic and anxiety disorders. The results of a first-in-human, single and multiple ascending dose study showed that selective OX1R antagonists may constitute a potential new treatment strategy for panic-related and anxiety-related disorders [1].

Dr Mark Schmidt (Janssen, Belgium) shared the results of a study that evaluated the safety, pharmacokinetic, and pharmacodynamic properties of a novel selective OX1R antagonist called JNJ-61393215. Anxiolytic effects were evaluated both in rats and healthy male human participants using CO₂ challenges. Participants were first screened to see whether they were sensitive to the anxiogenic effects of 35% CO₂ inhalation. A total of 39 healthy, male participants were then randomised to receive either placebo or one of the following active treatments: JNJ-61393215 25 mg, JNJ-61393215 90 mg, or alprazolam 1 mg twice daily for 7 days. After 6 days of treatment, participants were subjected to CO₂ exposure. The primary outcome of the study was symptoms of anxiety induced by the CO₂ challenge measured with the Panic Symptom List (PSL-IV).

In rats, JNJ-61393215 demonstrated dose-dependent attenuation of CO₂-induced, panic-like behaviour. In healthy, male humans, 90 mg JNJ-61393215 was associated with a significant reduction in CO₂-induced fear and anxiety symptoms versus placebo. The difference of marginal means in the PSL-IV was -2.3 (P=0.0153; see Figure). The tested therapeutic dose of alprazolam also had a significant anxiolytic effect, with a difference in marginal means versus placebo of -3.4 (P=0.0222). No serious side-effects were detected. The most frequently reported adverse events, all mild in severity, were somnolence and headache.

Figure: Panic symptom list-IV CO₂ challenge results at day 6 [1]



 

 

 

 

 

 

ALP, alprazolam; PBO, placebo.

These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215. They additionally validate CO₂ exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

1. Schmidt M. The anxiolytic activity of the orexin-1 receptor antagonist JNJ-61393215 in preclinical and clinical panic anxiety models. S.09.05, ECNP 2021 Congress, 2–5 October.

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Posted on 26 November, 202126 November, 2021