T205. LUMATEPERONE IN THE TREATMENT OF SCHIZOPHRENIA: EVALUATION OF EXTRAPYRAMIDAL AND MOTOR SYMPTOMS IN 4 LATE-PHASE CLINICAL TRIALS

Abstract Background Standard of care (SOC) antipsychotics exhibit efficacy at high dopamine D2 receptor occupancy (60%-80%), which is associated with increased risk of extrapyramidal symptoms (EPS). Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. Efficacy of lumateperone 42 mg (ITI-007 60 mg) has been established in randomized placebo-controlled trials and, in contrast to other antipsychotics, occurs at low D2 receptor occupancy (40%). In controlled trials, lumateperone 42 mg was well tolerated with a favorable safety profile. An open-label long-term study of patients with stable symptoms of schizophrenia switched from SOC antipsychotics to lumateperone 42 mg further supported the safety and effectiveness of lumateperone treatment. This post hoc analysis evaluated the incidence of EPS across short- and long-term studies of lumateperone in patients with schizophrenia. Methods EPS data were pooled from 3 short-term placebo-controlled studies of lumateperone 42 mg in patients with an acute exacerbation of schizophrenia (Studies 005, 301, and 302); 2 of the studies (Studies 005 and 302) had risperidone 4 mg as an active control. Data from the open-label 1-year trial (Study 303) in patients who were switched from SOC antipsychotics to lumateperone 42 mg were utilized to evaluate EPS risk with long-term treatment. EPS assessments included incidence and time to onset of EPS-related treatment-emergent adverse events (TEAEs). EPS assessment scales included the clinician-rated Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), and the Simpson Angus Scale (SAS). Patients without akathisia (BARS ≤2) or parkinsonism (SAS ≤3) at baseline were evaluated for the emergence of BARS-confirmed akathisia (BARS >2) and SAS-confirmed parkinsonism (SAS >3) during treatment. Results The pooled short-term safety population comprised 1,073 patients (placebo, 412; lumateperone 42 mg, 406; risperidone 4 mg, 255). The long-term open-label safety population comprised 239 patients who completed 1 year of treatment. In the pooled controlled studies, rates of EPS-related TEAEs were less for lumateperone 42-mg (3.0%) and placebo patients (3.2%) than risperidone (6.3%) patients. The most common EPS-related TEAE with lumateperone was akathisia (2.0%), which occurred less often than with placebo (2.9%) or risperidone (4.7%). Mean time to onset of EPS-related TEAEs was higher for the lumateperone group (17 days) compared with risperidone (9 days), and similar to placebo (14 days). Benztropine use was similar in lumateperone (2.5%) and placebo groups (2.2%) and higher in the risperidone group (9.0%); propranolol use was similar across groups (2.4–3.4%). Change from baseline in AIMS, BARS, and SAS scores was similar across groups. Similar to short-term treatment, long-term treatment with lumateperone was associated with a low incidence of EPS-related TEAEs (0.8%). In patients switched from SOC treatment to lumateperone 42 mg, the mean time to onset of EPS was 38 days. Initiation rates of benztropine and propranolol were low in the long-term study (1.7% and 0.3%, respectively). There were no notable changes in AIMS, BARS, or SAS scores during the 1-year treatment. In patients without BARS-assessed akathisia at baseline, BARS-confirmed akathisia occurred in 0.3% of patients. In patients without SAS-assessed parkinsonism at baseline, no patients had SAS-confirmed incidences of parkinsonism. Discussion This post hoc analysis supports the favorable EPS profile of lumateperone 42 mg in both acute and long-term treatment of patients with schizophrenia.