BI 1358894 · program
BI 1358894 for Major depressive disorder
BI 1358894 for major depressive disorder (adjunctive to ongoing antidepressants). The pivotal Phase 2 dose-ranging trial (NCT04521478; 5/25/75/125 mg with a quetiapine 150-300 mg active reference vs placebo, n=389) failed: no non-flat dose-response on change in MADRS total score at week 6 (MCPMod p>0.85 for all models). A separate decentralized Phase 2 (NCT04423757; 125 mg vs placebo) was terminated for deficient enrollment and was underpowered. The molecule's global highest R&D status is Discontinued at Phase 2.
Development timeline
Readouts
Clinical trials in Major depressive disorder
NCT04521478Phase 2Completedn=389
A Study to Test the Effect of Different Doses of BI 1358894 and Quetiapine in People With Depression
missedprimaryChange from baseline in MADRS total score at week 6 (BI 1358894 5/25/75/125 mg vs placebo, MCPMod) (0.85)
Negative dose-ranging trial: none of the MCPMod dose-response models indicated a non-flat dose-response for BI 1358894; all model p-values exceeded 0.85. Proof of concept not established. BI 1358894 was well tolerated with no increase in self-harm or suicidality. (p_value field records the >0.85 lower bound reported across models.)
NCT04423757Phase 2Discontinuedn=45
A Home-based Study Using Mobile Technology to Test Whether BI 1358894 is Effective in People With Depression
terminatedprimaryChange from baseline in MADRS total score at week 6 (BI 1358894 125 mg vs placebo) — fully decentralized trial
Decentralized (fully remote, home-based) trial run with Science 37; terminated early for deficient enrollment (only 45 randomized; 43 treated: 20 BI 1358894, 23 placebo). Underpowered for efficacy; descriptive mean MADRS change -10.44 (drug) vs -13.35 (placebo). Well tolerated; no new safety signals.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| BI 1358894 oral tablet 125 mg once daily (Phase II MDD); doses up to 200 mg tested in Phase I, with higher exposure in fed vs. fasted state | Oral | Once daily | — |
Mechanism of action
Potent, highly selective inhibitor of TRPC4 and TRPC5 (transient receptor potential canonical) cation channels. TRPC4/5 channels are expressed in cortico-limbic circuits processing emotion and fear; their inhibition was hypothesized to dampen amygdala/insula hyperreactivity in internalizing disorders. In Phase 1 the compound attenuated CCK-4-induced panic/anxiety and reduced cortico-limbic fMRI reactivity, but this did not translate into antidepressant efficacy in Phase 2.
| Target | Action | Affinity |
|---|---|---|
| TRPC4primaryTRPC4 | Inhibitor | IC50 1.2 nMⓘ |
| TRPC5TRPC5 | Inhibitor | IC50 0.2 nMⓘ |
← Full BI 1358894 compound page (identity, identifiers, all indications)
Sources
- A Home-based Study Using Mobile Technology to Test Whether BI 1358894 is Effective in People With Depression (NCT04423757) — ClinicalTrials.gov
- BI 1358894 and Quetiapine in Depressive Disorder, Major (NCT04521478) — ClinicalTrials.gov
- BI-1358894 drug profile (global highest R&D status: Discontinued; originator Hydra Biosciences) — Synapse / PatSnap
- 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 — Journal of Clinical Psychiatry
- Safety of BI 1358894 in patients with major depressive disorder: Results and learnings from a phase II randomized decentralized clinical trial — Clinical and Translational Science
- TRPC4/5 inhibitors: Phase I results and proof of concept studies — European Archives of Psychiatry and Clinical Neuroscience