Lumateperone for schizophrenia

Until novel mechanisms are discovered that increase schizophrenia response rates, the availability of newer antipsychotics with more favorable tolerability profiles presents clinicians and patients with added options when adverse effects interfere with prior treatment. In all phases of the adult schizophrenia trial program for luma­teperone, 811 patients received short-term (4- to 6-week) exposure (dose range: 14 to 84 mg/d), while 329 had ≥6 months exposure and 108 had ≥1 year of exposure to the 42-mg/d dose. In these studies, there was no single adverse reaction leading to discontinuation that occurred at a rate >2%. The only adverse events that occurred at rates ≥5% and more than twice the rate of placebo were somnolence/sedation (lumateperone 24%, placebo 10%), and dry mouth (lumateperone 6%, placebo 2%). Nausea was present in 9% of the lumateperone group compared with 5% for placebo.⁷ In the short-term studies, the combined rate of EPS and akathisia was 6.7% for lumateperone and 6.3% for placebo.⁷ This difference translates to a number needed to harm of 250 for these neurologic adverse effects. The functional impact of lumateperone’s glutamatergic mechanisms is not well characterized within the schizophrenia population, but the antidepressant potential has been studied for patients with bipolar depression, with 1 positive phase III trial.¹⁹

Efficacy in adults with schizophrenia. The efficacy of lumateperone has been established in 2 pivotal, double-blind, placebo-controlled trials. The first was a 4-week, phase II trial (Study 005) in which 335 adults age 18 to 55 with an acute exacerbation of schizophrenia were randomized in a 1:1:1:1 manner to lumateperone, 42 mg/d (60 mg of lumateperone tosylate), luma­teperone, 84 mg/d (120 mg of lumateperone tosylate), risperidone, 4 mg/d, or placebo, all taken once daily.²⁰ For the 4 treatment arms, the least squares mean changes from baseline to the Day 28 endpoint on the primary outcome measure, Positive and Negative Syndrome Scale (PANSS) total score, were: lumateperone, 42 mg/d: −13.2 points; lumateperone, 84 mg/d: −8.3 points; risperidone, 4 mg/d: −13.4 points; and placebo: −7.4 points. Both lumateperone, 42 mg/d, and risperidone, 4 mg/d, were significantly different than placebo, and with identical moderate effect sizes of 0.4.²⁰ Lumateperone, 84 mg/d, did not separate from placebo on the primary outcome. The responder analysis also indicated that a similar proportion of patients (40%) randomized to lumateperone, 42 mg/d, or risperidone, 4 mg/d, improved by ≥30% on PANSS total score.

The second pivotal trial (Study 301) was a phase III, double-blind, placebo-controlled trial of 450 adults, age 18 to 60, with an acute exacerbation of schizophrenia who were randomized in 1:1:1 manner to receive lumateperone, 42 mg/d (lumateperone tosylate 60 mg), lumateperone, 28 mg/d (lumateperone tosylate 40 mg), or placebo once daily for 4 weeks.²¹ For the 3 treatment arms, the least squares mean changes on PANSS total score from baseline to the Day 28 endpoint were: lumateperone, 42 mg/d: −14.5 points; lumateperone, 28 mg/d: −12.9 points; and placebo: −10.3 points. Lumateperone, 28 mg/d, did not separate from placebo on the primary outcome. The responder analysis also indicated that 36.5% of those receiving lumateperone, 42 mg/d, and 36.3% of those receiving lumateperone, 28 mg/d, improved by ≥30% on PANSS total score, compared with 25.5% of patients treated with placebo.

Unlike the 2 positive trials in which placebo change in total PANSS scores were −7.4 and −10.3 points, respectively, in a phase III trial (Study 302) with 696 participants, placebo showed a 15.1-point decrease from baseline PANSS total score.¹⁹ Among the 3 treatment arms of this study (lumateperone, 14 mg/d, lumateperone, 42 mg/d, and risperidone, 4 mg/d), only risperidone was superior to placebo.

Adverse events

In the phase II pivotal study, completion rates among the 4 arms were comparable: lumateperone, 42 mg/d: 71%; lumateperone, 84 mg/d: 76%; risperidone, 4 mg/d: 77%; and placebo: 72%.²⁰ There were no serious adverse events (SAEs) associated with lumateperone; the 2 SAEs that occurred involved worsening of schizophrenia/psychotic disorder for risperidone (n = 1) and for placebo (n = 1). Five participants discontinued the study due to an adverse event: 2 who were receiving lumateperone (1 due to dry mouth, and 1 due to worsening of schizophrenia) and 3 who were receiving risperidone (2 due to akathisia, and 1 due to blood creatine phosphokinase increase).²⁰ The most frequent adverse event was somnolence/sedation (placebo: 13%; lumateperone, 42 mg/d: 17%; risperidone, 4 mg/d: 21%; and lumateperone, 84 mg/d: 32.5%). Neither dose of lumateperone was associated with increased rates of EPS. Median weight gain to Day 28 was 1 kg for placebo and for each dose of lumateperone, and 2.5 kg for risperidone. Compared with risperidone, lumateperone showed statistically significantly lower prolactin levels (lumateperone, 42 mg/d and 84 mg/d: P < .001), and metabolic parameters, including fasting glucose (lumateperone 42 mg/d: P = .007; lumateperone, 84 mg/d: P = .023), total cholesterol (lumateperone, 42 mg/d: P = .012; lumateperone, 84 mg/d: P = .004), and triglycerides (lumateperone, 42 mg/d: P = .074; lumateperone, 84 mg/d: P = .002).²⁰ There was no significant impact on the corrected QT interval.

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