Clinical Benefit and Risk Profile of TV-46000 for Patients with Schizophrenia as Assessed by Number Needed to Treat and Number Needed to Harm

Purpose: Long-acting injectable antipsychotics (LAIs) are underused, despite advantages in terms of patient outcomes. The Phase 3 RIsperidone Subcutaneous Extended-release (RISE) study evaluated the efficacy and safety of TV-46000, a subcutaneously administered long-acting formulation of risperidone, administered monthly (q1m) and once every 2 months (q2m), in patients with schizophrenia. During the relapse-prevention phase, TV-46000 significantly prolonged time to impending relapse versus placebo, with a safety profile comparable to other risperidone formulations. This post hoc study examined the number needed to treat (NNT) and the number needed to harm (NNH) using RISE data. Patients and Methods: NNT estimates versus placebo were calculated for patients who were free of impending relapse (ie, worsening symptom scores, psychiatric hospitalization, aggressive/violent behavior, suicidality), maintained stability, and achieved remission as well as all-cause discontinuation (an acceptability proxy). NNH estimates were calculated for safety and tolerability outcomes. Results: TV-46000 NNT estimates (95% CI) versus placebo were 5 (4– 7) for q1m and 7 (5– 13) for q2m for avoidance of impending relapse, and 4 (3– 6) and 6 (4– 11) for maintenance of stability. Remission rates ranged from 16.6– 23.5% and did not differ between TV-46000 and placebo (TV-46000 NNT estimates: q1m, 22; q2m, 15). For all groups, adverse event (AE)–related discontinuation rates were low (1.7– 3.9%), and NNH estimates for TV-46000 q1m and q2m versus placebo were 190 and 45, respectively, and not statistically significant. For AEs common to many second-generation antipsychotics (eg, akathisia, restlessness, somnolence, sedation) and ≥ 7% weight increase from baseline, NNH estimates for TV-46000 versus placebo were ≥ 10 and not statistically significant, indicating favorable safety and tolerability. Conclusion: Robust, single-digit NNT estimates for avoiding impending relapse and maintaining symptomatic stability support TV-46000 q1m and q2m efficacy, and high NNH estimates for safety and tolerability endpoints suggest TV-46000 is well tolerated regardless of dosing frequency. These findings provide clinically intuitive data supporting a favorable benefit–risk profile of TV-46000 for relapse prevention. Keywords: schizophrenia, TV-46000, long-acting injectable antipsychotic, number needed to treat, number needed to harm, likelihood to be helped or harmed