A Phase 1 Open-Label Study Assessing the Safety and Pharmacokinetics of TV-46000, an Extended-Release Injectable...

TV-46000 (Uzedy^®) is a long-acting injectable antipsychotic for subcutaneous use that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that was approved as a treatment for schizophrenia and bipolar I disorder by the US Food and Drug Administration (FDA) in April 2023 and October 2025, respectively. It is a risperidone injectable that can be administered once monthly or once every 2 months. As part of the clinical development of TV-46000, a Phase 1 open-label dose escalation study (TV46000-SAD-10055) was conducted to evaluate the safety and pharmacokinetics (PK) of TV-46000 in participants with schizophrenia or schizoaffective disorder.

Individuals diagnosed with schizophrenia or schizoaffective disorder were assigned to 1 of 8 cohorts, which consisted of single escalating doses (50 to 225 mg) or 3 multiple doses (75 mg or 150 mg) administered every month for 3 months. Every cohort was preceded by a run-in period of 7 days with daily oral risperidone (2-6 mg) followed by a 7-day washout period before the TV-46000 injection. TV-46000 was administered in the abdomen in all but one cohort, where 225 mg was administered in the upper arm, to assess interchangeability between injection sites. Outcome measures reported were adverse events (AEs), local tolerability, changes in neurological and clinical assessments, and PK measures (determined by risperidone and 9-OH risperidone total active moiety [TAM] concentrations).

Of the 194 participants screened, 99 were included in the study. Of the 99 participants, 13 discontinued the study, but none of the discontinuations were related to the treatment. Most participants were Black or African American men, with a mean age of 44.2 years and a mean body mass index of 28.53 kg/m². Treatment-emergent AEs after TV-46000 administration included injection-site reactions, increased blood creatine phosphokinase, and weight gain. There were two serious AEs; one death due to suicide and one exacerbation of schizophrenia requiring hospitalization that were both unrelated to TV-46000. After a single dose injection of TV-46000 50 to 225 mg, TAM concentrations reached clinically relevant plasma concentrations of 10 ng/mL within 24 hours for all doses and remained within therapeutic range for 28-56 days, depending on dose. The systemic exposure parameters (maximum, minimum, and average plasma concentration) after the third monthly TV-46000 injections of 75 and 150 mg were comparable with the corresponding steady-state exposure of 3-5-mg/day oral risperidone.

Overall, TV-46000 was well tolerated with no new safety signals detected compared with other formulations of risperidone. The PK profile of TV-46000 exhibited favorable characteristics of an extended-release formulation, including rapid initial release for fast onset of action and prolonged systemic exposure adequate for monthly administration.