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.

Abstract

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.