5 results
Effect of Lumateperone (ITI-007) on Quality of Life and Functional Disability in the Treatment of Bipolar Depression
- John B Edwards, Suresh Durgam, Susan G Kozauer, Rakesh Jain, Roger S McIntyre
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 238
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Introduction
In patients with bipolar disorder, depression symptoms are associated with greater reduction in function and quality of life than hypomania/mania symptoms. Lumateperone (LUMA), is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder.
In a recent phase 3 clinical trial (Study 404, NCT03249376) in people with bipolar depression, LUMA 42 mg monotherapy significantly improved symptoms of depression compared with placebo (PBO). This analysis of Study 404 investigated the effects of LUMA on functional disability and quality of life as measured using the secondary outcome measure, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF).
MethodsPatients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4) were randomized to LUMA 42 mg or PBO orally, once daily in the evening for 6 weeks. The primary endpoint was the change from baseline to Day 43 in MADRS Total score, analyzed using a mixed-effects model for repeated measures (MMRM) approach in the intent-to-treat population (ITT). This post hoc analysis evaluated the mean change from baseline to Day 43 in the Q-LES-Q-SF individual item scores using an analysis of covariance with last observation carried forward (ANCOVA-LOCF) in the ITT. Categorical shifts in individual items were also analyzed.
ResultsThe ITT comprised 376 patients (LUMA 42 mg, 188; PBO, 188). Patients in the LUMA 42 mg group had significantly greater improvement on MADRS Total score change from baseline to Day 43 compared with PBO (least squares mean difference vs PBO [LSMD], −4.585; 95% CI, −6.344 to −2.826; effect size vs PBO [ES], −0.56; P<.0001). LUMA 42 mg treatment significantly improved Q-LES-Q-SF Total score from baseline to Day 43 compared with PBO (LSMD, 2.9; 95% CI, 1.15 to 4.59; P=.001).
The Q-LES-Q-SF items with the lowest mean scores at baseline in both groups were mood, leisure time activities, and sexual drive, interest, and/or performance. By Day 43, LUMA 42 mg treatment significantly improved 8 of the 14 items in the Q-LES-Q-SF (P<0.05). Overall life satisfaction also significantly improved with LUMA treatment (P=.0016). The largest improvements with LUMA 42 mg compared with PBO (ES>0.3,) were seen for the ability to function in daily life, family relationships, household activities, leisure time activities, and mood (all LSMD=0.3; all P<.01).
ConclusionIn patients with bipolar depression, treatment with LUMA 42 mg compared with PBO significantly improved patient quality of life and functional impairment. These results support LUMA 42 mg as treatment of MDEs associated with bipolar I or bipolar II disorder in adults.
FundingIntra-Cellular Therapies, Inc.
Long-Term Lumateperone Treatment in Bipolar Disorder: Six-Month Open-Label Extension Study
- Mauricio Tohen, Suresh Durgam, Susan Kozauer, Ian D’Souza, Richard Chen, Sharon Mates
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 233
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Introduction
Approved therapeutics for bipolar depression are associated with a range of undesirable side effects. Lumateperone (LUMA), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. The efficacy of LUMA in bipolar depression was previously established in two Phase 3 trials, as monotherapy (NCT03249376) and as adjunctive to lithium or valproate (NCT02600507).
A recent Phase 3 multi-center trial, Study 401 (NCT02600494) investigated the efficacy and safety of LUMA in bipolar depression and comprised a 6-week, randomized, double-blind, placebo-controlled period and a 6-month open-label extension (OLE) period. Here, we report the results of the OLE period, examining long-term safety.
MethodsPatients, aged 18–75 years, with a clinical diagnosis of bipolar I or II disorder who were experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and a Clinical Global Impression Scale-Bipolar Version, Severity [CGI-BP-S] score ≥4) were eligible for Study 401. Patients who completed the double-blind study were eligible for direct rollover into the OLE or were re-screened if completing the double-blind period prior to the initiation of the OLE. During the OLE, LUMA 42 mg was administered once-daily in the evening for 25 weeks.
The primary objective was safety and tolerability of LUMA as measured by incidences of adverse events (AEs) and changes in laboratory parameters, cardiometabolic measurements, electrocardiogram (ECG), and vital signs. The secondary objective was improvement/maintenance of symptoms of depression as measured MADRS and CGI-BP-S Total scores.
ResultsA total of 127 patients were enrolled in the OLE, with 74 (58.3%) completing the study. Treatment-emergent AEs (TEAEs) occurred in 73 patients (57.5%) with 54 (42.5%) experiencing a drug-related TEAE. TEAEs that occurred in ≥5% of patients were headache, dry mouth, dizziness, nausea, somnolence, anxiety, and irritability. Most TEAEs were mild or moderate in severity. Extrapyramidal-symptom-related TEAEs were rare. Most patients who had normal metabolic laboratory values at baseline remained normal during the treatment period. Mean changes in blood pressure, pulse rate, ECG, and body morphology were minimal. Symptoms of depression improved as measured by the mean change from baseline to Day 175 in MADRS Total score (−8.9) and CGI-BP-S Total score (−2.3).
ConclusionIn patients with bipolar depression, long-term LUMA treatment was generally well tolerated with low risk of extrapyramidal symptoms, weight gain, and cardiometabolic effects. These data further support the safety, tolerability, and effectiveness of LUMA in patients with bipolar depression.
FundingIntra-Cellular Therapies, Inc.
Metabolic Syndrome in Bipolar Depression with Lumateperone (ITI-007): A Post Hoc Analysis of 2 Randomized, Placebo-Controlled Trials
- Christoph U Correll, Susan G Kozauer, Micah Lands, Jason Huo, Suresh Durgam
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, pp. 247-248
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Introduction
Treatments for bipolar disorder are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides ≥150mg/dL, high density lipoprotein cholesterol <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) ≥130mmHg or diastolic BP ≥85mmHg, fasting glucose ≥100mg/dL.
MetSy elevates the risk of developing type II diabetes, cardiovascular disease, and premature morbidity. Lumateperone (LUMA), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials.
LUMA 42-mg monotherapy was evaluated in 2 randomized, double-blind, placebo (PBO)-controlled studies (Study 401 [NCT02600494]; Study 404 [NCT03249376]) in patients with a major depressive episode (MDE) associated with bipolar I or bipolar II disorder. This post hoc pooled analysis of these studies compares rates of MetSy with LUMA 42 mg and PBO in the treatment of bipolar depression.
MethodsThe incidence and shift in MetSy were analyzed in data pooled from 2 studies that recruited patients aged 18–75 years with a confirmed diagnosis of bipolar I or bipolar II disorder who were experiencing an MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4). Patients in these studies were randomized 1:1 to LUMA or PBO and treated for 6 weeks.
ResultsThe safety population comprised 746 patients (LUMA, 372; PBO, 374). Rates of MetSy were similar between groups at baseline (LUMA, 20.7%; PBO, 22.2%) and at the end of treatment (EOT, LUMA, 21.8%; PBO, 23.8%). More LUMA patients (36.4%) compared with PBO patients (30.1%) improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. The individual criteria that shifted the most from meeting MetSy criteria at baseline to no longer meeting criteria at EOT was BP for LUMA (46.8%) and glucose for PBO (43.2%). The rate of MetSy developed during treatment was similar for LUMA (10.8%) and PBO (10.7%) with approximately half of these patients (LUMA, 43.8%; PBO, 45.2%) shifting due to a change in ≥2 criteria.
ConclusionIn this post hoc analysis of 2 randomized, PBO-controlled trials in patients with a MDE associated with bipolar I or bipolar II disorder, LUMA 42 mg had similar rates of MetSy compared with PBO. These results suggest that LUMA 42 mg is a promising new treatment for bipolar depression with a favorable metabolic profile.
FundingIntra-Cellular Therapies, Inc.
Lumateperone (ITI−007) in the Treatment of Bipolar Depression: Results from a Randomized Clinical Trial
- Ian D’Souza, Suresh Durgam, Andrew Satlin, Robert E. Davis, Susan G. Kozauer, Richard Chen, Sharon Mates, Joseph R Calabrese
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, p. 150
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Study Objective
Approved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.
MethodPatients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.
ResultsIn this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (least squares mean difference [LSMD]=-4.6; 95% confidence interval [CI]=-6.34, −2.83; effect size vs placebo [ES]=-0.56; P<.0001). Lumateperone treatment was associated with significant MADRS improvement in both patients with bipolar I (LSMD=-4.0; 95% CI=-5.92, −1.99; ES=-0.49; P<.0001) and bipolar II (LSMD=-7.0; 95% CI=-10.92, −3.16; ES=-0.81; P=.0004). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.
ConclusionsLumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.
FundingIntra-Cellular Therapies, Inc.
30 Lumateperone (ITI-007) for the Treatment of Schizophrenia: Overview of Placebo-Controlled Clinical Trials and an Open-label Safety Switching Study
- Kimberly Vanover, Steven Glass, Susan Kozauer, Jelena Saillard, Juan Sanchez, Michal Weingart, Sharon Mates, Andrew Satlin, Robert Davis
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 190-191
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Background
Lumateperone is a first-in-class agent in development for schizophrenia that acts synergistically through serotonergic, dopaminergic and glutamatergic systems. Lumateperone is a potent 5-HT2A antagonist, a mesolimbic/mesocortical dopamine phosphoprotein modulator (DPPM) with pre-synaptic partial agonist and post-synaptic antagonist activity at D2, a glutamate GluN2B receptor phosphoprotein modulator with D1-dependent enhancement of both NMDA and AMPA currents via the mTOR protein pathway and an inhibitor of serotonin reuptake.
MethodsLumateperone was evaluated in 3 controlled clinical trials to evaluate efficacy in patients with acute schizophrenia. The primary endpoint was change from baseline on the PANSS total score compared to placebo. In Study ‘005, 335 patients were randomized to receive ITI-007 60mg or 120mg , risperidone 4mg (active control) or placebo QAM for 4weeks. In Study ‘301, 450 patients were randomized to receive ITI-007 60mg or 40mg , or placebo QAM for 4weeks. In Study ‘302, 696 patients were randomized to receive ITI-007 60mg or 20mg , risperidone 4mg (active control) or placebo QAM for 6weeks. Also, an open-label safety switching study was conducted in which 302 patients with stable schizophrenia were switched from standard-of-care (SOC) antipsychotics and treated for 6weeks with lumateperone QPM and then switched back to SOC.
ResultsIn Studies ‘005 and ‘301, lumateperone (60mg ITI-007) met the primary endpoint with statistically significant superior efficacy over placebo at Day 28. In Study ‘302, neither dose of lumateperone separated from placebo on the primary endpoint; 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 to endpoint 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. 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 medication. In this study, symptoms of schizophrenia generally remained stable or improved. Greater improvements were observed in subgroups of patients with elevated symptomatology (comorbid symptoms of depression and those with prominent negative symptoms).
DiscussionLumateperone represents a novel approach to the treatment of schizophrenia with a favorable safety profile in clinical trials. The lack of cardiometabolic and motor safety issues presents a safety profile differentiated from standard-of-care antipsychotic therapy.
Funding Acknowledgements: Intra-Cellular Therapies, Inc.