Efficacy and safety of the selective, brain-penetrant P2X7 receptor antagonist JNJ-55308942 (zanvipixant) in bipolar depression: Phase 2a study

This double-blind, placebo-controlled, Phase 2a clinical trial evaluated the efficacy and safety of JNJ-55308942 (zanvipixant), a selective, brain-penetrant P2X7 receptor antagonist, in bipolar depression. Outpatients with bipolar disorder Types I/II aged 18-64 years experiencing a major depressive episode, with a specific gain of function P2RX7 mutation and without either of two specific loss of function P2RX7 mutations, were randomized 1:1 to receive 50 mg JNJ-55308942 or placebo once daily. The primary endpoint was change from baseline at Week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Week 6 mean (SD) change from baseline in MADRS total score was -16.0 (10.43) for JNJ-55308942 (n=42) and -15.4 (9.81) for placebo (n=50) with a non-statistically significant least squares (LS) mean difference of ‐0.3 (95% CI: -4.21, 3.59). However, the ability to detect an effect was obscured by a high placebo response, rendering this study inconclusive. Notably, Week 6 LS mean difference in MADRS total score from participants homozygous for a P2RX7 gain of function allele (JNJ-55308942, n=11; placebo, n=16) was -3.5 (95% CI: -11.32, 4.26), and in Patient-Reported Outcomes Measurement Information System Ability to Participate in Social Roles and Activities T-score (JNJ-55308942, n=42; placebo, n=50), it was 3.32 (95% CI: 0.12, 6.52). Adverse events were generally mild or moderate with no clear differences between treatment groups. While the primary endpoint was not achieved, clinically meaningful findings in secondary outcomes and a tolerable safety profile warrants further investigation into P2X7 receptor antagonism in bipolar depression. ClinicalTrials.gov–NCT05328297 ( https://clinicaltrials.gov/study/NCT05328297 ).