The CO2 inhalation challenge model enables the measurement of anxiolytic/panicolytic effects of new test compounds. CO2 inhalation can induce a panic attack in healthy volunteers and in patients with certain mood and/or anxiety disorders. To develop a challenge model using CO2 inhalation, CHDR acquired and calibrated a CO2 tolerance tester. This tolerance tester delivers a controlled gas mixture consisting of 35% carbon dioxide and 65% oxygen 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, yielding 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 to this challenge, with more than 90% experiencing a panic attack after inhaling CO2-enriched air. The next most sensitive group are healthy first-degree relatives of patients with panic disorder. Healthy volunteers form the least sensitive population, with roughly one in two volunteers experiencing a panic attack as a result of inhaling air enriched with CO2. Importantly, administering a therapeutic dose of clinically effective anxiolytic drugs, such as benzodiazepines, reduces the sensitivity to CO2-induced panic attacks in all three populations.

CO2 inhalation represents a reliable, translational challenge model in the development of novel anxiolytic drugs. The panic response induced by acute CO2 inhalation remains stable and reproducible over time, allaying any concerns about the development of tolerance after repeated challenges. In addition, repeated CO2 inhalation by healthy volunteers does not result in any increased risk of developing a panic disorder.

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 six days of dosing with the study drug, an active comparator or placebo. 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 CO2 inhalation-induced anxiety symptoms in healthy volunteers.

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 potential of the CO2 inhalation challenge model for future early phase studies that seek to investigate innovative anxiolytics and/or panicolytics.

Read about the study in more detail here.

The CO2 challenge in action

Watch the video below for a short demonstration of the CO2 challenge.

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