CO2 inhalation challenge model

To measure the anxiolytic/panicolytic effects of new test compounds, CHDR uses a so-called ‘CO2 inhalation challenge’ model. CO2 inhalation can induce a panic attack in healthy volunteers and in patients with certain mood and/or anxiety disorders, making it an effective model. Therefore, CHDR acquired and calibrated a CO2 tolerance tester. This tolerance tester delivers a controlled gas mixture consisting of 35% CO2 and 65% O2 through a protected inhalation system. Additionally, it can measure a wide range of physiological parameters, including blood pressure, heart rate and breath frequency, over time. This provides researchers with objective data on a subject’s sensitivity to panic and quantitative data on panic disorders.

Effectiveness of the CO2 inhalation challenge

The CO2 inhalation challenge model is a robust tool for experimentally inducing panic attacks in order to test new anxiolytics. Patients with panic disorder are the most sensitive, with more than 90% experiencing a panic attack after inhaling CO2-enriched air. Patients are followed by healthy first-degree relatives of patients with panic disorder. Inhaling air enriched with CO2 triggers a panic attack in roughly half of healthy volunteers, making them the least sensitive population. Importantly, administering a therapeutic dose of clinically effective anxiolytic drugs, such as benzodiazepines, reduces the sensitivity to CO2-induced panic attacks in all such populations.The panic response induced by acutely inhaling CO2 remains stable and reproducible over time, which curtails concerns about the development of tolerance after repeated challenges. Also, the repeated inhalation of CO2 by healthy subjects who undergo the challenge carries no increased risk of developing a panic disorder. CO2 inhalation therefore represents a reliable, translational challenge model in the development of novel anxiolytic drugs.

The CO2 challenge applied in a clinical trial

CHDR has recently applied the CO2 inhalation challenge in a study with a brain-penetrant, novel, selective and high affinity/potent orexin-1 receptor (OX1R) antagonist. Subjects underwent a 35% CO2 inhalation challenge after 6 days of dosing with the study drug, active comparator or placebo, and the anxiety symptoms induced by the CO2 challenge were measured using the Panic Symptom List (PSL-IV). The study drug induced a statistically significant reduction of anxiety symptoms induced by inhalation of 35% CO2 in healthy volunteers according to the PSL-IV.

With this study we demonstrated anxiolytic effects of a selective OX1R antagonist for the first time in humans. Our findings support further exploration of the efficacy of the study drug in relevant patient populations, and demonstrate the advantage of including the CO2 challenge in future early phase studies investigating innovative anxiolytics and/or panicolytics.

You can read more about the study here.

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