New Data on First-In-Class Antipsychotic

Megan Brooks

January 10, 2020

The novel antipsychotic lumateperone (Caplyta, Intra-Cellular Therapies, Inc) significantly improves symptoms in patients with acute exacerbation of schizophrenia without many of the side effects commonly seen with currently available antipsychotics, new phase 3 data suggest.

Lumateperone is a first-in-class antipsychotic that acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

"The unique pharmacologic mechanisms of lumateperone seem to confer antipsychotic efficacy with favorable safety and tolerability. The efficacy and safety profiles of lumateperone may differ in important ways from existing treatments for patients with schizophrenia," the investigators write.

Results of one of two randomized, double-blind, placebo-controlled phase 3 trials that led to approval were published online January 8 in JAMA Psychiatry.

As reported by Medscape Medical News, the US Food and Drug Administration (FDA) approved lumateperone (42 mg once daily) last month for the treatment of schizophrenia in adults.

The trial was funded by Intra-Cellular Therapies. First author Christoph Correll, MD, of Zucker Hillside Hospital, Hempstead, New York, and several coauthors report financial relationships with the company.

Improved Psychosocial Function

The study included 450 patients with schizophrenia (mean age, 42 years; 77% men) who were experiencing an acute exacerbation of psychosis. All participants were randomly assigned to receive 28 mg or 42 mg of lumateperone or placebo once daily for 4 weeks.

The FDA-approved dose of the drug (42 mg daily) met the primary and key secondary efficacy endpoints. There was a statistically significant improvement (vs placebo) from baseline to day 28 on the Positive and Negative Syndrome Scale (PANSS) total score (least-squares mean difference [LSMD], −4.2; 95% confidence interval [CI], −7.8 to −0.6; P = .02; effect size, −0.3) and the Clinical Global Impression–Severity (CGI-S) (LSMD, −0.3; 95% CI, −0.5 to −0.1; P = .003; effect size, −0.4).

The effect sizes for PANSS total and CGI-S reduction in this study are "broadly comparable" with standard of care, the investigators report.

Treatment with lumateperone also led to significant improvements across a broad range of PANSS subscales, including that of psychosocial function, a "highly desired yet often unrealized outcome," they note.

Lumateperone was well tolerated. The safety profile was similar to placebo, and there were no clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors compared with placebo.

Side effects included sedation, somnolence, fatigue, and constipation, all of which were predominantly mild. Lumateperone was administered in the morning to capture key safety measures during the day around the time of peak plasma levels.

"In clinical practice, lumateperone will likely be administered in the evening with maintenance of sleep as a potential benefit of the mild sedative effects in some patients," the investigators note. Additional safety studies are being conducted to evaluate this, they add.

Limitations of the study include the fact that patients had to meet specific inclusion criteria, which may limit generalizability of the data with respect to broader populations.

In addition, the 4-week treatment period precludes conclusions about the safety of longer-term treatment and maintenance of effectiveness. An open-label trial of long-term treatment with lumateperone in patients with schizophrenia is underway.

A "Me Too" Drug?

In an accompanying editorial, Joshua Kantrowitz, MD, of Columbia University in New York City, says that although it's not yet clear what the ultimate comparative advantages of lumateperone will be, "it is encouraging and potentially exciting to see a new drug with novel pharmacologic properties."

It remains possible, Kantrowitz adds, that lumateperone is just another "me-too" second-generation antipsychotic.

"Nevertheless, several of its pharmacologic properties bolster the potential for a novel mechanism," he writes.

He also notes that its comparatively benign safety profile, including minimal weight gain and minimal extrapyramidal effects, suggests it could provide improved tolerability and adherence.

Echoing the authors, Kantrowitz cautions that schizophrenia typically requires long-term treatment with antipsychotics. "Thus, the ongoing long-term study results will be crucial."

JAMA Psychiatry. Published online January 8, 2020. Full text, Editorial

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