Reduction in Multiple Cardiometabolic Risk Factors With Combined Olanzapine/Samidorphan Compared With Olanzapine: Post Hoc Analyses From a 24-Week Phase 3 Study.

BACKGROUND AND HYPOTHESES: Weight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine. STUDY DESIGN: This phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids. RESULTS: After 24 weeks' treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, -2.63 mm Hg; 95% CI: -4.78, -0.47), diastolic blood pressure (LSM difference, -0.75 mm Hg; 95% CI: -2.31, 0.80), and BMI (LSM difference, -0.65 kg/m2; 95% CI: -1.01, -0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia. CONCLUSIONS: OLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.

A phase 3, multicenter study to assess the 1-year safety and tolerability of a combination of olanzapine and samidorphan in patients with schizophrenia: Results from the ENLIGHTEN-2 long-term extension.

AIM: A combination of olanzapine and samidorphan (OLZ/SAM) is in development for the treatment of patients with schizophrenia or bipolar I disorder and is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. This 52-week open-label extension (NCT02873208; ENLIGHTEN-2-EXT) assessed the long-term safety and tolerability of OLZ/SAM in patients with schizophrenia. METHODS: Patients completing the 24-week randomized, double-blind, phase 3 ENLIGHTEN-2 study (NCT02694328) comparing weight change from baseline to week 24 with OLZ/SAM versus olanzapine were eligible to enroll in the 52-week ENLIGHTEN-2-EXT study. Assessments included adverse events (AEs; each visit), weight/waist circumference (every other week for the first 8 weeks, then every 4 weeks thereafter), metabolic laboratory parameters (weeks 4, 12, 24, 36, and 52), Positive and Negative Syndrome Scale (PANSS) scores (weeks 2, 4, 8, 12, 24, 36, and 52), and Clinical Global Impression-Severity (CGI-S) scores (weeks 2 and 4, then every 4 weeks thereafter through week 48, and at week 52). Analyses were based on observed results using descriptive statistics. Baseline was relative to the first OLZ/SAM dose in the extension study. RESULTS: In total, 265 patients were enrolled and received at least 1 dose of OLZ/SAM; 167 (63.0%) completed the 52-week extension study. Common AEs (≥5%) were weight decreased (n = 23; 8.7%), extra dose administered (n = 21; 7.9%), headache (n = 18; 6.8%), and weight increased (n = 16; 6.0%). At week 52, the mean (SD) change from baseline for weight and waist circumference was -0.03 (6.17) kg and - 0.35 (6.12) cm, respectively. Changes in fasting lipid and glycemic parameters were generally small and remained stable over 52 weeks. During the extension, PANSS total scores remained stable, and at week 52, 81.3% of patients had CGI-S scores of 3 or less, reflecting mild illness severity. CONCLUSIONS: OLZ/SAM was generally well tolerated over 52 weeks. Weight, waist circumference, metabolic laboratory parameters, and schizophrenia symptoms remained stable throughout the study.

Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study.

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.