Efficacy, Tolerability, and Safety of TRPC4/5 Inhibitor BI 1358894 in Patients With Major Depressive Disorder and Inadequate Response to Antidepressants: A Phase 2 Randomized, Placebo-Controlled, Parallel Group, Dose-Ranging Trial.

Objective

To assess proof-of-concept (PoC) for efficacy, tolerability, and safety of TRPC4/5 inhibitor BI 1358894 vs placebo in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressants.

Methods

In this phase 2, multicenter, randomized, double-blind, dose-finding trial (December 2020-February 2024), patients with MDD (per DSM-5) and current depressive episode of ≥8 weeks and ≤24 months were randomized (3.5:1:1:1:2:2) to receive placebo or BI 1358894 (5 mg, 25 mg, 75 mg, or 125 mg) or quetiapine 150-300 mg orally, once daily for 6 weeks. Primary end point was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. Secondary end points included ≥50% reduction from baseline in MADRS total score at Week 6, change from baseline in State-Trait Anxiety Inventory scores, Clinical Global Impression Severity Scale score, and Symptoms of Major Depressive Disorder Scale total score at Week 6.

Results

Of 940 enrolled patients, 389 were randomized, and 361 (93.0%) completed the trial. No differences were observed between BI 1358894 treatment groups and placebo for primary and secondary end points. Adverse events were slightly more frequent in the BI 1358894-total group (66.7%) vs placebo (53.9%). No worsening of Columbia-Suicide Severity Rating Scale was observed for most patients; serious adverse events of suicidal ideation were reported for 4.7% (placebo), 5.1% (BI 1358894 75 mg group), and 1.4% (quetiapine) of patients.

Conclusion

Although this was a negative trial in MDD with PoC not established, BI 1358894 was well tolerated with no increase in self-harm or suicidality. Trial Registration: ClinicalTrials.gov identifier: NCT04521478.