S44. Lumateperone (Iti-007) for the Treatment of Schizophrenia: Placebo-Controlled Clinical Trials and an Open-Label Safety Switching Study

Abstract

BackgroundLumateperone (ITI-007) is a first-in-class investigational agent in development for the treatment of schizophrenia. Acting synergistically through serotonergic, dopaminergic and glutamatergic systems, lumateperone represents a new approach to the treatment of schizophrenia and other neuropsychiatric disorders. Lumateperone is a potent antagonist at 5-HT2A receptors and exhibits serotonin reuptake inhibition. Lumateperone also binds to dopamine D1 and D2 receptors acting as a mesolimbic/mesocortical dopamine phosphoprotein modulator (DPPM) with pre-synaptic partial agonism and post-synaptic antagonism at D2 receptors and as an indirect glutamatergic (GluN2B) phosphoprotein modulator with D1-dependent enhancement of both NMDA and AMPA currents via the mTOR protein pathway.MethodsLumateperone was evaluated in 3 controlled clinical trials to evaluate efficacy in patients with acute schizophrenia. In Study ITI-007-005, 335 patients were randomized equally across 4 treatment arms: one of two doses of lumateperone, risperidone (active control) or placebo QAM for 4 weeks. In Study ITI-007-301, 450 patients were randomized equally across 3 treatment arms: one of two doses of lumateperone or placebo QAM for 4 weeks. In Study ITI-007-302, 696 patients were randomized equally across 4 treatment arms: one of two doses of lumateperone, risperidone (active control) or placebo QAM for 6 weeks. In all 3 studies, the primary endpoint was change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo. Also, a 6-week open-label safety switching study was conducted. In this ITI-007-303 study 302 patients with stable schizophrenia were switched from standard-of-care (SOC) antipsychotics and treated for 6 weeks with lumateperone QPM outpatient and then switched back to SOC for 2 weeks.ResultsTwo of the 3 randomized studies were positive. In Studies ITI-007-005 and ITI-007-301, lumateperone (60 mg ITI-007, equivalent to 42 mg active base) met the primary endpoint with statistically significant superior efficacy over placebo at Day 28 as measured by the PANSS total score (Study ITI-007-005 p=0.017; Study ITI-007-301 p=0.022). In Study ITI-007-302, neither dose of lumateperone separated from placebo on the primary endpoint in the intent-to-treat population; a high placebo response was observed in this study. Across all 3 efficacy trials, lumateperone improved symptoms of schizophrenia with the same trajectory and same magnitude of improvement from baseline on the PANSS total score.Lumateperone was well-tolerated with a favorable safety profile in all studies. In the two studies with risperidone included as an active control, lumateperone was statistically significantly better than risperidone on key safety and tolerability measures including prolactin, glucose, lipids and weight. In the open-label safety switching study statistically significant improvements from SOC were observed in body weight, cardiometabolic and endocrine parameters worsened again when switched back to SOC me...

Experimental Serotonergic Agents for the Treatment of Schizophrenia

“…The combined effects of this compound (strong block of 5-HT2ARs, dopamine modulation, serotonin reuptake inhibition and indirect glutamatergic activity) resulted in reducing positive and negative symptoms, as well as in improving social functioning of SCZ patients, with low rates of EPS or metabolic side effects. 19 Since many compounds binding to 5-HT2ARs also exhibit high affinity to 5-HT2CRs, it was hypothesized that 5-HT2CR antagonism may reduce the activity of dopaminergic neurons in mesolimbic and nigrostriatal pathways. 63 However, the role of 5-HT2CRs in the pathophysiology of SCZ is still poorly understood and requires further studies.…”

“…17 In this regard lumateperone, an investigational drug displaying high-affinity binding to the 5-HT2AR as well to D1 and D2Rs, but with minimal binding affinity for 5-HT2CR, histaminergic and muscarinic receptors, received its first global approval in the USA for the treatment of SCZ in adults, in view of its efficacy with a favorable safety profile. [18][19][20] So far, other 5-HTR targeted compounds are emerging as possible pharmacological treatments for SCZ. Therefore, the purpose of this review is to evaluate the main preclinical and clinical pharmacological findings concerning the therapeutic potential of 5-HTR-targeted therapies in SCZ patients.…”

Using Long-acting Injectable Antipsychotics to Enhance the Potential for Recovery in Schizophrenia

“…Risperidone also had the highest dropout rate, calling into question whether more poorly responsive patients dropped out early on risperidone. 56 Across the 3 trials, lumateperone had minimal adverse effects, with sedation/somnolence and dry mouth being present in at least 5% and at twice the rate as with placebo.…”

Lumateperone: A Novel Antipsychotic for Schizophrenia

“…7,10 Lumateperone has been shown to indirectly modulate glutamatergic activity by increasing phosphorylation of the GluN2B subunit of the N -methyl- d -aspartate channels as a result of the mTOR protein pathway. 11,12…”

“…17 Trial NCT02469155 demonstrated that after 6 weeks of treatment for schizophrenia, the doses of lumateperone 20 and 60 mg were not efficacious because they failed to separate from placebo. 12 Trial NCT03249376 was a 6-week phase III study for bipolar depression in which lumateperone 42 mg separated from placebo after 8 days of treatment in the total MADRS score; the difference was maintained through day 43 ( E = −0.56; P < 0.0001). 18 Finally, an open-label 12-month study of lumateperone 42 mg showed that 39% of the patients were PANSS responders, with ≥20% PANSS improvement from baseline.…”