Search

Objective: A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) has been approved in the United States for the treatment of adults with schizophrenia or adults with bipolar I disorder. In a phase 3 study in adults with schizophrenia (ENLIGHTEN-2), OLZ/SAM treatment was associated with significantly less weight gain compared with olanzapine. Prespecified subgroup analyses explored the consistency of the weight mitigation effect of OLZ/SAM vs olanzapine across demographic subgroups in ENLIGHTEN-2., Methods: The multicenter, randomized, double-blind ENLIGHTEN-2 study (NCT02694328) included outpatients aged 18-55 years with a diagnosis of schizophrenia based on DSM-5 criteria, a body mass index (BMI) of 18 to 30 kg/m 2 , and stable body weight (self-reported change ≤5% for ≥3 months before study entry). Patients were randomized 1:1 to receive OLZ/SAM or olanzapine for 24 weeks. Co-primary endpoints (previously reported) were percent change in body weight and proportion of patients with at least 10% weight gain from baseline at week 24. Prespecified exploratory subgroup analyses by sex, age, self-reported race, and baseline BMI were conducted., Results: At week 24, treatment with OLZ/SAM resulted in numerically less percent weight gain than with olanzapine across all subgroups evaluated. The proportion of patients with at least 10% weight gain was smaller in each subgroup treated with OLZ/SAM vs olanzapine., Conclusion: In these exploratory subgroup analyses from the ENLIGHTEN-2 study, weight-mitigating effects of OLZ/SAM vs olanzapine were observed consistently across patient subgroups and were in line with results from the overall study population.

Background: Combination olanzapine and samidorphan (OLZ/SAM), in development for schizophrenia and bipolar I disorder, is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. OLZ/SAM safety, tolerability, and efficacy from a 52-week open-label extension study in patients with schizophrenia are reported., Methods: Patients previously completing the 4-week, double-blind ENLIGHTEN-1 study switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Assessments included adverse events (AEs), weight, vital signs, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression-Severity (CGI-S) scores. Baseline was prior to first dose of OLZ/SAM in the extension study., Results: In total, 281 patients enrolled, 277 received ≥1 OLZ/SAM dose, and 183 (66.1%) completed 52 weeks. Reasons for discontinuation included patient withdrawal (15.5%), loss to follow-up (6.9%), AEs (5.8%), and lack of efficacy (1.8%). AEs were reported in 136 (49.1%) patients; increased weight (13%) and somnolence (8%) were most common. Ten serious AEs were reported in eight patients (2.9%); none were considered treatment related. There were no deaths. Mean (SD) baseline weight was 79.1 (17.8) kg. Mean weight change from baseline to week 52 was 1.86 kg (2.79% increase). PANSS total and CGI-S scores continued to decline over 52 weeks (mean [95% CI] changes from baseline to week 52: -16.2 [-18.5, -14.0] and -0.9 [-1.0, -0.8], respectively)., Conclusion: OLZ/SAM was generally well tolerated in this extension study; most patients completed the 52-week treatment period with sustained improvement in schizophrenia symptoms. Mean increases in weight stabilized by week 6 with limited subsequent change through end of treatment.

Objective: A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single-tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia., Methods: Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured., Results: Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments., Conclusions: Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.

Background: OLZ/SAM is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, and is in development for the treatment of schizophrenia and bipolar I disorder. OLZ/SAM is under development with the intent to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This thorough QT study assessed the effects of therapeutic and supratherapeutic doses of OLZ/SAM on cardiac repolarization in patients with schizophrenia., Methods: In this randomized, double-blind, placebo- and positive (moxifloxacin)-controlled, parallel-group study, 100 patients aged 18 to 60 years with stable schizophrenia were randomized 3:2 to the active arm and control arm. Subjects in the active arm received a therapeutic dose of 10/10 mg (10 mg olanzapine/10 mg samidorphan) on days 2-4, 20/20 mg on days 5-8, and a supratherapeutic dose of 30/30 mg (1.5 times and 3 times the maximum recommended daily dose of olanzapine and samidorphan, respectively) on days 9-13, and moxifloxacin-matched placebo on days 1 and 14. Subjects in the control arm received a single oral dose of moxifloxacin 400 mg and moxifloxacin-matched placebo on days 1 and 14 in a nested crossover fashion, along with OLZ/SAM-matched placebo on days 2-13. Serial electrocardiograms (ECGs) and simultaneous plasma drug concentrations were determined pre- and post-dose. The effects of OLZ/SAM on heart rate and ECG parameters (QT interval with Fridericia's correction [QTcF], PR and QRS interval, and T-wave morphology) were evaluated, and the primary endpoint was change from baseline in QTcF (ΔQTcF). The relationship between drug concentration and ΔQTcF (C-QTc) was evaluated using a linear mixed-effects model. Safety monitoring included adverse events reporting and clinical laboratory assessments., Results: Based on primary analysis using C-QTc modeling, no clinically concerning QTc effect (ie, placebo-corrected ΔQTcF [ΔΔQTcF] ≥10 msec) was observed across the OLZ/SAM dose range tested (10/10 to 30/30 mg), up to olanzapine and samidorphan concentrations of approximately 110 and 160 ng/mL, respectively. The slope (90% confidence interval [CI]) of the C-QTc relationship was shallow and not significant for either olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). The predicted ΔΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration (C max ) of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL) on day 13, respectively. The study's assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated at all doses; adverse events occurring in >5% of subjects treated with OLZ/SAM were somnolence, weight increased, nausea, and dizziness., Conclusions: This thorough QT study in patients with stable schizophrenia demonstrated that OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, does not have a clinically relevant effect on ECG parameters, including QT/QTc prolongation., Competing Interests: Declaration of Competing Interest Lei Sun, Sergey Yagoda, Narinder Nangia, Bhaskar Rege, and Lisa von Moltke are or were employees of Alkermes, Inc. Hongqi Xue and Randy Brown are employees of ERT. David McDonnell is an employee of Alkermes Pharma Ireland Limited. Borje Darpo is a consultant for ERT and Alkermes, Inc., and is eligible for stock options and holds stock in ERT., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Alcohol use disorder (AUD) is a common comorbidity of schizophrenia. No effective pharmacologic treatment is available for both disorders to date., Methods: In a phase 2, double-blind study, patients with schizophrenia and AUD experiencing ≥ 10 drinking and ≥ 2 heavy-drinking days in the previous month and recent (≤ 6 mo) disease symptom exacerbation were recruited between June 2014 and March 2017. DSM-IV-TR and DSM-5 criteria were used to assign the diagnoses of schizophrenia and AUD, respectively. After a 6-week lead-in period, 234 eligible patients were randomized (1:1) to olanzapine + 10 mg samidorphan tablets (OLZ/SAM) or olanzapine + placebo tablets (olanzapine) for 36-60 weeks of treatment. The primary outcome of time to the first event of exacerbation of disease symptoms (EEDS) was evaluated using the log rank test for treatment comparison, and the Cox proportional-hazards model was used to estimate hazard ratio. Safety was assessed as adverse events and laboratory measures., Results: No significant difference was observed between groups in the time to first EEDS (hazard ratio = 0.91; 95% CI, 0.53-1.56; P = .746). Patients treated with OLZ/SAM vs olanzapine had numerically lower rates in 6 of 8 criteria to evaluate EEDS. Change from baseline in percentage of heavy-drinking days during the double-blind treatment period was similar in OLZ/SAM- vs olanzapine-treated patients. OLZ/SAM was generally well tolerated with a safety profile similar to olanzapine., Conclusions: OLZ/SAM was not superior to olanzapine in the time to EEDS and was well tolerated in patients with schizophrenia and AUD. Further research is needed to identify effective treatments for this difficult-to-treat population., Trial Registrations: ClinicalTrials.gov identifier: NCT02161718; EudraCT number: 2014-001211-39 ​., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Objective: To assess the antipsychotic efficacy and safety of a combination of olanzapine and samidorphan (OLZ/SAM)., Methods: This 4-week, phase 3, randomized, double-blind, placebo- and olanzapine-controlled study was conducted from December 2015 to June 2017 in adults with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who were experiencing an acute exacerbation. Patients were randomized 1:1:1 to OLZ/SAM, olanzapine monotherapy, or placebo. The primary and key secondary efficacy endpoint assessed was the change in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness Scale (CGI-S) score between baseline and week 4, respectively, for OLZ/SAM versus placebo. Safety monitoring occurred throughout., Results: 401 patients received ≥ 1 dose of study drug; 352 completed treatment. Treatment with OLZ/SAM resulted in significant improvements versus placebo in PANSS total and CGI-S scores from baseline to week 4 (least squares [LS] mean ± SE: -6.4 ± 1.8 [P < .001] and -0.38 ± 0.12 [P = .002], respectively). Olanzapine treatment resulted in similar improvements (PANSS and CGI-S LS mean ± SE of -5.3 ± 1.84 [P = .004] and -0.44 ± 0.12 [P < .001], respectively). Adverse events (AEs) occurred in 54.5%, 54.9%, and 44.8% of patients on OLZ/SAM, olanzapine, and placebo, respectively. Weight gain, somnolence, dry mouth, anxiety, and headache were the most common AEs (ie, ≥ 5%) with active treatment., Conclusions: OLZ/SAM treatment resulted in statistically and clinically significant efficacy improvements over 4 weeks versus placebo in adults with acutely exacerbated schizophrenia. Improvements were similar to those observed with olanzapine. OLZ/SAM was well tolerated, with a safety profile similar to that of olanzapine., Trial Registrations: ClinicalTrials.gov identifier: NCT02634346; EudraCT number: 2015-003373-15​​., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Background: A combination of the atypical antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of schizophrenia. The goal of OLZ/SAM is to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain and many associated long-term metabolic consequences. The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4 and cytochrome P450 (CYP)-mediated oxidation, mainly by CYP1A2. In contrast, the samidorphan metabolic pathway is mediated predominantly by CYP3A4., Objective: The aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects., Methods: In this phase I, single-center, open-label, two-period study, 24 healthy volunteers received a single oral dose of OLZ/SAM 10/10 (10 mg olanzapine/10 mg samidorphan) on day 1. After a 14-day washout, 600 mg of rifampin (rifampicin), a strong CYP3A4 inducer, as well as an inducer of UGT enzymes and a weak inducer of CYP1A2, was administered once daily on days 15‒21. A single oral dose of OLZ/SAM 10/10 was coadministered with rifampin 600 mg on day 22. Olanzapine and samidorphan pharmacokinetic parameters were determined after OLZ/SAM dosing on days 1 and 22. The geometric mean ratio of maximum plasma concentration (C max ) and area under the plasma concentration-time curve from zero to infinity (AUC ∞ ) for olanzapine and samidorphan in the presence and absence of rifampin, along with its two-sided 90% confidence interval, were derived from a linear mixed-effects model. Safety was monitored throughout the study., Results: Compared with OLZ/SAM alone, coadministration of OLZ/SAM with rifampin decreased the C max and AUC ∞ of olanzapine by 11% and 48%, and that of samidorphan by 44% and 73%, respectively. OLZ/SAM 10/10 was generally well tolerated in this study., Conclusion: Coadministration with rifampin decreased total systemic exposure (based on AUC ∞ ) of olanzapine and samidorphan by 48% and 73%, respectively.

ALKS 3831 is a combination of olanzapine and samidorphan (OLZ/SAM), intended to provide the antipsychotic efficacy of OLZ while mitigating its known weight gain and metabolic effects. This randomized, 2-way crossover study evaluated the effect of food on the pharmacokinetics (PK) of OLZ and SAM (both are Biopharmaceutics Classification System class 3 compounds) given in combination as OLZ/SAM. Thirty-six healthy volunteers were randomized to receive a single dose of OLZ/SAM (10 mg OLZ/10 mg SAM) in either fasted or fed conditions. After a 14-day washout period, study participants received the same OLZ/SAM dose in the opposite condition. PK profiles of OLZ and SAM were similar in fed and fasted conditions. The 90% confidence intervals (CIs) for the fed/fasted ratio of the geometric means for OLZ AUC 0-∞ and C max and SAM AUC 0-∞ were within the equivalence limit of 80%-125%. Although the lower bound of the 90%CI for the fed/fasted ratio of SAM C max (76%-94%) was slightly below the 80% equivalence limit, this slight decrease was not considered clinically meaningful. The results indicated that food does not have a clinically relevant impact on the PK of OLZ and SAM given as OLZ/SAM., (© 2019, The American College of Clinical Pharmacology.)

The objective of this study was to evaluate the relative bioavailability of olanzapine in 3 olanzapine-containing tablet formulations. ALKS 3831 is a fixed-dose combination of olanzapine (OLZ, an atypical antipsychotic) and samidorphan (SAM, a μ-opioid receptor antagonist with low intrinsic activity at δ- and κ-opioid receptors), intended to provide the efficacy of OLZ while mitigating its known weight and metabolic effects. Relative bioavailability of OLZ in ALKS 3831, a bilayer tablet containing OLZ and SAM, a matching bilayer tablet containing OLZ only (OLZ), and Zyprexa (brand olanzapine [B-OLZ]) was assessed in an open-label study. Forty-eight healthy volunteers were randomly assigned to receive single oral doses of ALKS 3831 (10 mg OLZ/10 mg SAM), OLZ (10 mg OLZ), and B-OLZ (10 mg B-OLZ) on day 1 of each treatment period. Blood samples for pharmacokinetic evaluation were collected before and after each dose. Ratios of OLZ AUC 0-∞ , AUC 0-t , and C max were compared between treatments and tested for bioequivalence, determined by 90%CIs of the geometric mean ratios (GMRs). GMRs of OLZ AUC 0-∞ , AUC 0-t , and C max were close to 1, and the 90%CIs of the GMRs were contained within the bioequivalence limit of 80%-125% for comparison of ALKS 3831 with B-OLZ, ALKS 3831 with OLZ, and OLZ with B-OLZ, demonstrating bioequivalence of OLZ in ALKS 3831, OLZ, and B-OLZ., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Purpose: ALKS 3831 is composed of a flexible dose of olanzapine and a fixed dose of 10-mg samidorphan (a novel opioid system modulator), designed to provide the established antipsychotic efficacy of olanzapine and to mitigate olanzapine-induced weight gain. To support clinical development of ALKS 3831, we conducted a multicenter, randomized, open-label, Phase I study to obtain steady-state exposure for olanzapine and samidorphan and short-term safety at the intended therapeutic dose range of ALKS 3831 10/10 (10-mg olanzapine/10-mg samidorphan) to ALKS 3831 20/10 (20-mg olanzapine/10-mg samidorphan) in subjects with schizophrenia., Methods: After a 1-week olanzapine lead-in period, 42 subjects (14 women) with schizophrenia were randomly assigned (1:1) to receive ALKS 3831 10/10 or ALKS 3831 20/10 bilayer oral tablets once daily for 14 days. Plasma concentrations of olanzapine and samidorphan were quantified by using an LC-MS/MS method. Pharmacokinetic parameters were calculated according to noncompartmental analysis. Safety was monitored throughout the study., Findings: After a 1-week olanzapine lead-in phase with titration of olanzapine dose up to 15 mg/d, the steady-state concentration of olanzapine was reached in 3-4 days and that of samidorphan was reached in 5 days after initiation of once-daily oral administration of ALKS 3831 10/10 or ALKS 3831 20/10. At steady state, exposure to olanzapine increased dose proportionally from 10 mg (ALKS 3831 10/10) to 20 mg (ALKS 3831 20/10), and exposure to samidorphan was similar between the 2 ALKS 3831 dose groups, indicating that different dose levels of olanzapine in ALKS 3831 had no impact on the pharmacokinetic profile of samidorphan. ALKS 3831 was well tolerated, and no safety concerns unique to ALKS 3831 compared with olanzapine monotherapy were identified., Implications: In the present study, samidorphan exposure was not affected by different dose levels of olanzapine in ALKS 3831. In addition, olanzapine exposure as a component of ALKS 3831 was comparable with previously published data for olanzapine monotherapy. The present data indicate that combining olanzapine with samidorphan does not affect the pharmacokinetic profile of either drug and support continued clinical evaluation of ALKS 3831. ClinicalTrials.gov identifier: NCT02804568., (Copyright © 2018 Alkermes, Inc. Published by Elsevier Inc. All rights reserved.)

Leslie Citrome,1 Christine Graham,2 Adam Simmons,2 Ying Jiang,2 Mark S Todtenkopf,2 Bernard Silverman,2 Lauren DiPetrillo,2 Hannah Cummings,2 Lei Sun,2 David McDonnell3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Alkermes, Inc., Waltham, MA, USA; 3Alkermes Pharma Ireland Limited, Dublin, IrelandCorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 102, Pomona, NY, 10970, USATel +1-845-362-2081Email citrome@cnsconsultant.comAbstract: Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥ 5 cm by half, compared with olanzapine at week 24. Based on open-label extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.Keywords: antipsychotic agents, clinical efficacy, olanzapine, opioid antagonists, safety, weight gain