So it looks like Lumateperone was plagued by high placebo response rates as it was in some of the schizophrenia studies as well. In the study that was successful, the mean reduction was 16.7 points vs 12.1 for placebo. In the one that failed, 20.7 points (42mg) and 18.9 points (28mg), versus 19.7 points on placebo.
Side effects were similar to the schizophrenia studies and 1% or less (similar to placebo) for akathisia or extrapyramidal side effects.
Study 404 topline results
Study 404 was conducted globally including in the U.S. A total of 381 patients were randomized 1:1 to lumateperone 42 mg or placebo. In this trial, once-daily lumateperone 42 mg met the primary endpoint with statistically significant greater improvement over placebo at week 6 (trial endpoint), as measured by change from baseline on the MADRS total score. In the intent-to-treat (ITT) study population, the least squares (LS) mean reduction from baseline for lumateperone 42 mg was 16.7 points, versus 12.1 points for placebo (LS mean difference = 4.6 points; effect size = 0.56, p<0.001). Moreover, lumateperone 42 mg showed statistically significant separation from placebo as early as week 1, which was maintained at every time point throughout the trial.
Lumateperone 42 mg also met the key secondary endpoint of statistically significant improvement on the CGI-BP-S Total Score (p<0.001; effect size = 0.46) and on the CGI component that specifically assesses depression (CGI-BP-S Depression Score; p<0.001; effect size = 0.50).
These results were supported by statistically significant benefits on responder rates and remission rates, demonstrating the clinical meaningfulness of the primary outcome. In addition, in subgroup analyses of patients with Bipolar I and patients with Bipolar II disorder lumateperone 42 mg demonstrated statistically significant improvement versus placebo on the MADRS total score in both subgroups.
Study 401 topline results
Study 401 was conducted solely in the U.S. A total of 554 patients were randomized 1:1:1 to lumateperone 42 mg, lumateperone 28 mg, or placebo. In this trial, neither dose of lumateperone met the primary endpoint of statistical separation from placebo as measured by change from baseline on the MADRS total score. There was a high placebo response in this trial. Lumateperone 42 mg and 28 mg demonstrated a LS mean reduction from baseline on the MADRS total score of 20.7 points and 18.9 points, respectively, versus 19.7 points on placebo.
Safety and Tolerability Results
Consistent with previous studies in schizophrenia, lumateperone was well-tolerated in both bipolar depression studies, with a favorable safety profile. The rates of discontinuation due to treatment emergent adverse events for both doses of lumateperone were low.
In Study 404, the most commonly reported adverse events that were observed at a rate greater than 5% and higher than placebo were headache, somnolence and nausea.
In Study 401, the most commonly reported adverse events that were observed at rates greater than 5% and higher than placebo for either dose were somnolence, headache, nausea, dry mouth, dizziness, diarrhea, vomiting and fatigue.
Importantly, the rates of akathisia, restlessness and extrapyramidal symptoms combined were less than 1% and similar to placebo in both studies. These findings are consistent with previous lumateperone trials in patients with schizophrenia and provide further evidence supporting lumateperone’s favorable safety and tolerability profile across different patient populations.