Efficacy and Safety of the Selective, Brain-Penetrant P2X7 Receptor Antagonist JNJ-55308942 (Zanvipixant) in Bipolar Depression: A Phase 2a Study.

BACKGROUND

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.

METHODS

Outpatients ages 18 to 64 years with bipolar I/II disorder, who were experiencing a major depressive episode and carried a specific gain-of-function P2RX7 mutation without either of 2 specific loss-of-function P2RX7 mutations, were randomized at a 1:1 ratio to receive 50 mg JNJ-55308942 or placebo once daily. The primary end point was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

RESULTS

The mean (SD) change in the MADRS total score from baseline to 6 weeks was -16.0 (10.43) for the JNJ-55308942 group (n = 42) and -15.4 (9.81) for the placebo group (n = 50), with a nonstatistically significant least squares (LS) mean difference of -0.3 (95% CI, -4.21 to 3.59). However, the ability to detect an effect was obscured by a high placebo response, rendering this study inconclusive. Notably, the week-6 LS mean difference between treatment groups in MADRS total score among participants homozygous for a P2RX7 gain-of-function allele (JNJ-55308942, n = 11; placebo, n = 16) was -3.5 (95% CI, -11.32 to 4.26), and the week-6 LS mean difference between treatment groups in Patient-Reported Outcomes Measurement Information System Ability to Participate in Social Roles and Activities T score (JNJ-55308942, n = 42; placebo, n = 50) was 3.32 (95% CI, 0.12 to 6.52). Adverse events were generally mild or moderate, with no clear differences between treatment groups.

CONCLUSIONS

While the primary end point was not achieved, clinically meaningful findings in secondary outcomes and a tolerable safety profile warrant further investigation into P2X7 receptor antagonism in bipolar depression.