Intra-Cellular says "high placebo response" to blame as one late-stage study fails, one succeeds for lumateperone in bipolar depression

Intra-Cellular Therapies reported Monday that a Phase III study of lumateperone as monotherapy for the treatment of major depressive episodes associated with bipolar I or bipolar II disorder met its primary endpoint. However, the company noted that a second late-stage trial of the serotonin 5-HT2A receptor antagonist failed to hit its main goal due to "a high placebo response," with shares in the drugmaker falling as much as 22% on the news.

In Study 404, 381 patients with major depressive episodes associated with bipolar disorder were randomised to receive lumateperone or placebo, with top-line results showing that the drug led to a significantly greater improvement over placebo at week six, as measured by change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data indicated that the least squares (LS) mean reduction from baseline for lumateperone was 16.7 points, versus 12.1 points for placebo.

Further, Intra-Cellular said that the trial met its key secondary goal on the Clinical Global Impression Scale for Bipolar for Severity of Illness (CGI-BP-S) Total Score, while lumateperone was also positive on the CGI component that specifically assesses depression. The company added that benefits of the drug were significant in both bipolar I and bipolar II patients.

Meanwhile, Study 401, which was conducted solely in the US, randomised 554 patients with major depressive episodes associated with bipolar disorder to receive one of two doses of lumateperone or placebo, with the trial's primary endpoint measured by change from baseline on the MADRS total score. Intra-Cellular noted that neither dose of lumateperone showed separation from placebo, with top-line results demonstrating a LS mean reduction from baseline on the MADRS total score of 20.7 points and 18.9 points, for the high and low drug doses respectively, versus 19.7 points for placebo.

"We consider today's positive results to be a significant milestone in our bipolar depression programme," remarked Intra-Cellular chief executive Sharon Mates, noting that overall data from the two studies will be discussed with the FDA. "It's too soon to tell what we're going to do in terms of new studies, if we'll do new studies. We do have the adjunctive study that we'll be reading out in the near future. So we'll see what the FDA has to say," Mates said. The executive added "it is an exciting time…as we prepare for the launch of lumateperone for the treatment of schizophrenia, pending FDA approval." In December last year, the agency accepted a filing seeking approval of lumateperone for the treatment of schizophrenia, with a decision expected by September 27.

Prior to the results being announced, Cowen analyst Ritu Baral suggested that if only one of the trials was positive, Intra-Cellular would have to wait for data from the third study, which will be available next year. This late-stage trial, dubbed Study 402, is evaluating lumateperone as an adjunctive therapy to lithium or valproate for the treatment of major depressive episodes associated with bipolar I or bipolar II disorder. Meanwhile, Brian Abrahams of RBC Capital Markets said that results from Study 401 and Study 404 would likely not be adequate for approval, and additional work would be needed. However, Abrahams indicated that the positive data from one of the trials maintains some hope for this indication, which is expected to contribute about $600 million to revenue by 2028.

For related analysis, see ViewPoints: So we meet again – ITCI, placebo response set to do battle once more.

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