(P-313) Utilizing a Structured Benefit-risk Assessment to Evaluate a Combination of Olanzapine and Samidorphan for the Treatment of Schizophrenia and Bipolar I Disorder

Background: A combination of olanzapine and the opioid antagonist samidorphan (OLZ/SAM) is being developed for schizophrenia and bipolar I disorder. An overall benefit-risk assessment of a medical product is a key aspect of regulatory decision-making and clinical practice.

Objectives: Utilize the Benefit-Risk Action Team (BRAT) framework to evaluate the benefit-risk balance of OLZ/SAM.

Methods: The BRAT framework was used in a post hoc analysis of two phase 3 pivotal studies in schizophrenia patients: ENLIGHTEN-1 (4-week study evaluating antipsychotic efficacy and safety of OLZ/SAM vs placebo [PBO]) and ENLIGHTEN-2 (24-week study evaluating the weight profile, antipsychotic efficacy, and safety of OLZ/SAM vs OLZ). Benefit outcomes were selected based on efficacy parameters. Risk outcomes were selected based on known risks of atypical antipsychotics and opioid antagonists along with clinical and public health relevance. A subset of opioid antagonist risks were not assessed due to clinical trial exclusions; however, they were factored into the overall evaluation. Continuous measurements were dichotomized into categorical variables. Risk differences (RD) per 1000 patients and associated 95% confidence intervals (CIs) were provided.

Results: In ENLIGHTEN-1, compared with PBO, OLZ/SAM had a lower risk of psychiatric-related discontinuation (RD, -90; 95% CI: -155, -37) and nonresponse to treatment (RD, -215; 95% CI: -329, -95), and higher risks of hyperprolactinemia (RD, 284; 95% CI: 179, 390), clinically significant (≥7%) weight gain (RD, 213; 95% CI: 136, 299), sedation (RD, 97; 95% CI: 39, 166), worsening of fasting triglycerides (RD, 140; 95% CI: 60, 228), and glucose (RD, 56; 95% CI: 25, 110). No statistical differences were noted for fasting total and LDL cholesterol, neutropenia, orthostatic hypotension, and movement disorders. In ENLIGHTEN-2, compared with OLZ, OLZ/SAM had reduced risks of weight gain (RD, -159; 95% CI: -253, -65) and waist circumference increases (RD, -171; 95% CI: -263, -78). No statistical differences were noted for relapse and psychiatric-related discontinuation or for risks of metabolic abnormalities, neutropenia, hyperprolactinemia, orthostatic hypotension, sedation, and movement disorders.

Conclusions: In this assessment, OLZ/SAM treatment was more efficacious than PBO and had similar antipsychotic efficacy to OLZ. OLZ/SAM had a consistent safety profile relative to OLZ, with reduced risks of weight gain and waist circumference increases. This analysis supports a favorable benefit-risk profile of OLZ/SAM.