Positive Topline Phase 3 Study Results: Lumateperone for Manic Episodes in Bipolar I Disorder

Johnson & Johnson has shared positive topline results from the pivotal phase 3 study evaluating lumateperone (Caplyta) for the treatment of manic episodes with or without mixed features in adults with bipolar I disorder. The study met its primary endpoint: Caplyta demonstrated a statistically significant and rapid reduction in manic symptoms vs placebo at week 3, with significant improvement seen as early as day 3.¹

"Mania is among the most dangerous and worrisome phases of bipolar disorder, and treating it effectively takes more than partial or temporary relief of symptoms; it means bringing the episode itself under control as quickly as possible," said Michael E. Thase, MD, a professor of psychiatry and chief of the Division of Mood and Anxiety Disorders Treatment & Research Program at the University of Pennsylvania. "These results are encouraging because Caplyta not only significantly improved the symptoms of mania, but did so as early as day 3, with benefits sustained through week 3, supporting its potential to meaningfully advance how we treat acute mania in bipolar I disorder."

Study 451

Study 451 is the first of 2 pivotal phase 3 studies evaluating Caplyta in adults with manic episodes associated with bipolar I disorder.² The phase 3 randomized, double-blind study evaluated once-daily Caplyta 42 mg vs placebo over 3 weeks in adults with manic episodes, with or without mixed features, associated with bipolar I disorder.

The study met the primary endpoint, with Caplyta demonstrating a statistically significant 4.8-point greater reduction in Young Mania Rating Scale (YMRS) total score vs placebo at week 3 (effect size −0.69; P<.0001). Significant improvement was observed as early as day 3 and sustained through week 3.

Participants treated with Caplyta also showed significantly greater improvement in overall illness severity vs placebo at week 3, as measured by the Clinical Global Impression–Severity (CGI-S) score, a key secondary endpoint (least-squares mean difference [LSMD], –0.5; P<.0001). Additionally, twice as many participants treated with Caplyta achieved clinical response, defined as a ≥50% reduction in YMRS total score, compared with placebo (45.8% vs 20.9%; P<.0001).

As to safety profile, Caplyta was well-tolerated, with low rates of discontinuation; this was consistent with its established profile. The most common treatment-related adverse events reported at a rate of at least 5% with Caplyta and at least twice the rate of placebo were dry mouth (7.9% vs 3.4%) and nausea (7.9% vs 2.3%).

These findings build on the established efficacy of Caplyta in bipolar depression and support its potential to address both depressive and acute manic episodes associated with bipolar I disorder.

"Bipolar I disorder is a lifelong, cycling illness, and managing it means navigating both manic and depressive episodes over time, each with distinct treatment needs," said Jane Tiller, the vice president and global head of development of neuroscience at Johnson & Johnson. "These phase 3 results build on the established efficacy of Caplyta in bipolar depression and represent an important step in evaluating its potential to address both depressive and acute manic episodes associated with bipolar I disorder."

Study 452

A second pivotal phase 3 study (Study 452) evaluating Caplyta for the treatment of manic episodes in adults with bipolar I disorder has been completed. Data analysis is underway.

References

1. CAPLYTA^® (lumateperone) shows significant and rapid improvement in bipolar mania in pivotal Phase 3 study. News release. September 21, 2026. Accessed September 21, 2026. https://www.jnj.com/media-center/press-releases/caplyta-lumateperone-shows-significant-and-rapid-improvement-in-bipolar-mania-in-pivotal-phase-3-study

2. Cutler AJ, Earley WR, Hayes R, et al. Lumateperone treatment of manic episodes with or without mixed features in bipolar I disorder: results from a double-blind, placebo-controlled, randomized, phase 3 trial. Poster presented at: Psych Congress 2026; September 15-19, 2026; New Orleans, LA.