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The schizophrenia drug lumateperone (Caplyta) improved psychotic symptoms versus placebo in one of the two randomized phase III trials leading up its recent FDA approval.

Among 435 adults with schizophrenia, lumateperone at 42 mg daily was associated with significantly improved total scores on the Positive and Negative Syndrome Scale (PANSS) compared with placebo at 4 weeks (least-squares mean difference [LSMD] −4.2, 95% CI −7.8 to −0.6, P=0.02), reported Kimberly Vanover, PhD, of drugmaker Intra-Cellular Therapies in New York City, and colleagues in , in the first publication of the trial's results.

This dose was also associated with significant improvements on the Clinical Global Impression-Severity of Illness (CGI-S) versus placebo at day 28 (LSMD −0.3, 95% CI −0.5 to −0.1, P=0.003), the team indicated.

"The mechanism of action of lumateperone for the treatment of schizophrenia is unknown, but the efficacy of lumateperone could be mediated by a combination of antagonism to serotonin [5-HT]_2A and postsynaptic [dopamine] D₂ receptors," Vanover told MedPage Today in an interview with a media representative present. "Lumateperone has a high affinity for serotonin [5-HT]_2A and moderate affinity for D₁ and D₂, and serotonin transporters."

Most "second-generation" antipsychotics, which tend to have lower dopamine D₂ affinities and a higher serotonin 5-hydroxytryptamine (HT)_2A antagonist affinity compared with older classes of antipsychotics, generally demonstrate improved safety and tolerability at the cost of increased metabolic side effects and weight gain, noted Joshua Kantrowitz, MD, of Columbia University in New York City, in an .

Compared with other antipsychotics, the molecular structure of lumateperone allows for increased binding to the serotonin 5-HT_2A receptor without excess binding to the dopamine D₂ receptor, he explained, adding that the drug may also help modulate presynaptic D₂ activity without full antagonism.

"Although it remains unclear whether this potentially novel receptor-binding profile, particularly its serotonergic and glutamatergic activity, is clinically relevant, it raises the possibility that in addition to being a general treatment for schizophrenia, lumateperone may be helpful for a subset of treatment-resistant patients with schizophrenia," Kantrowitz wrote.

He noted that patients in the lumateperone and placebo groups in the study had similar changes in weight (median 0.9 vs 0.7 kg) and other metabolic parameters including glucose, cholesterol, and triglycerides levels. Lumateperone was also associated with reduced extrapyramidal symptoms, although longer-term data is needed to confirm how well the drug mitigates all of these side effects, Kantrowitz said, adding that future studies should also compare lumateperone with leading antipsychotics on the market, such as clozapine (Clozaril).

Compared with the placebo group, patients in the 42-mg lumateperone arm of the trial had higher rates of somnolence (17.3% vs 4%), sedation (12.7% vs 5.4%), fatigue (5.3% vs 1.3%), and constipation (6.7% vs 2.7%), Vanover and co-authors reported.

One patient also had orthostatic hypotension and another convulsions, although the latter patient had a preexisting history of seizures that was missed at screening, the researchers added. A third patient (in the placebo arm) died from unknown causes about 2 weeks after discontinuing the study.

Intra-Cellular Therapeutics has also completed a , with lumateperone doses of 20 and 60 mg in addition to risperidone (Risperdal) as well as placebo as comparators. Top-line results released by the company in 2016, however, indicated that both doses . Full results have yet to be published.

Study Details, Further Findings

Patients enrolled in from 12 U.S. sites had moderate to severe schizophrenia, confirmed by a structured clinical interview, with an acute exacerbation of psychosis as measured through scores on the Brief Psychiatric Rating Scale of 40 or more. Eligible patients were assigned to a 42-mg or 28-mg lumateperone group, or placebo.

PANSS scores in the 449 eligible patients -- mean age of 42 -- averaged about 90 at baseline. Most were male (77.1%) and black (66.4%), and mean time since schizophrenia diagnosis was about 15 years.

Lumateperone at 28 mg did not significantly improve symptoms compared with placebo as measured through either PANSS (LSMD -2.6, 95% CI -6.2 to 1.1, P=0.16) or CGI-S scores (LSMD −0.2, 95% CI −0.5 to 0, P=0.02), Vanover and colleagues reported.

Notably, a found that an even higher dose of 84 mg lumateperone did not improve symptoms in patients with schizophrenia, establishing an "unexplained narrow therapeutic window," as Kantrowitz noted.

The 42-mg dose used in this trial significantly improved PANSS positive but not negative subscales compared with placebo at week 4, the authors reported. That dose also improved both general psychopathology and psychosocial functioning on subscales compared with placebo, although this may have been driven by improvements in positive and not negative symptom improvements, the team added.

The study excluded patients with a history of seizure disorder or other conditions, so the findings may not be generalizable to patients with certain comorbid conditions, which is a limitation, Vanover and co-authors noted, adding that the long-term safety profile and efficacy also require further study, Finally, because lumateperone was given in the morning to track adverse events throughout the day, additional studies to determine the safety of evening administration are needed, the team concluded.

Lumateperone for the treatment of schizophrenia is expected to hit the market in March, and is for the treatment of bipolar depression, dementia, and depression, Intra-Cellular Therapies noted.

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