Pharmaceutical Pipeline of BI 1358894: Clinical Evidence for an Emerging Drug for the Treatment of Mental Health Conditions

This work was sponsored by Boehringer Ingelheim Rationale Amygdala hyperreactivity is thought to be a major contributor to anxiety and mood disorders, with associations to both posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Inhibition of transient receptor potential canonical (TRPC) 4/5 ion channels, which are highly expressed in human and rodent amygdala, may reduce anxiety and stress-related symptoms by reducing amygdala hyperreactivity. Here, we provide an overview of early studies into BI 1358894; a small-molecule inhibitor of TRPC4/5 ion channels, which may provide a novel mechanism of attenuating amygdala hyperreactivity to treat symptoms in disorders such as PTSD and MDD. Methods Five Phase I studies were performed in healthy male volunteers. Pharmacodynamic effects of BI 1358894 versus placebo were assessed following cholecystokinin tetrapeptide (CCK-4) administration to induce panic symptoms in healthy volunteers. Functional magnetic resonance imaging (fMRI) was used to investigate the effects of BI 1358894 on amygdala reactivity in patients with MDD during exposure to negative emotional faces and scenes. Results Across the clinical studies, BI 1358894 ≤200 mg was generally well tolerated. Compared with placebo, BI 1358894 reduced the physiological and psychological response to CCK-4, measured both by the Panic Symptom Scale and levels of stress biomarkers (adrenocorticotropic hormone and serum cortisol), indicating target engagement. A fMRI study in people with MDD demonstrated that BI 1358894 attenuated activity in the amygdala in response to negative emotional faces and scenes. Conclusions Ongoing Phase II trials will determine the potential for BI 1358894 in the treatment of PTSD and MDD. Funding: Boehringer Ingelheim.