(#45) Olanzapine for Extended-Release Injectable Suspension (TV-44749) for Subcutaneous Use Is Designed for Sustained Efficacy and to Eliminate the Risk of Post-injection Delirium/Sedation Syndrome: In Vitro and Clinical Data

Abstract: Use of intramuscular (IM) long-acting injectable (LAI) olanzapine is limited due to a boxed warning for post-injection delirium/sedation syndrome (PDSS) and the associated Risk Evaluation and Mitigation Strategy (REMS). PDSS, which presents with symptoms consistent with olanzapine overdose, may arise from vessel injury during IM injection and rapid dissolution of olanzapine, causing significant increases in plasma concentration. TV-44749 is a once-monthly, subcutaneous, extended-release injectable olanzapine utilizing an innovative copolymer drug delivery technology to ensure controlled olanzapine release over a 1-month period. TV-44749ís subcutaneous administration and formulation were designed to provide sustained efficacy over the dosing interval and to eliminate the risk of PDSS. TV-44749 copolymers precipitate instantly following subcutaneous injection, forming an insoluble depot, entrapping olanzapine particles and preventing uncontrolled dissolution. In addition, subcutaneous tissue is less vascular than muscle tissue; therefore, inadvertent intravascular injury is less likely. Solubility and in vitro release studies in human plasma explored the risk of PDSS following TV-44749 injection versus the currently marketed IM olanzapine LAI. The phase 1 study evaluated TV-44749ís pharmacokinetic characteristics. In the in vitro, and the phase 1 study, TV-44749 maintained extended-release properties without any burst or uncontrolled release in olanzapine concentrations in plasma. The benefit of TV-44749 was observed in the 8-week acute treatment period of SOLARIS (phase 3 study), where there was robust efficacy and no suspected or confirmed PDSS events. Additionally, TV-44749 was well tolerated with a systemic safety profile consistent with approved olanzapine formulations.Short Description: TV-44749 is an investigational, once-monthly, subcutaneous, extended-release injectable olanzapine for treatment of schizophrenia, designed to eliminate the risk of post-injection delirium/sedation syndrome (PDSS). In vitro and phase 1 data confirm that TV-44749ís route of administration and formulation are associated with decreased PDSS risk. Results from the 8-week acute treatment period of SOLARIS (phase 3 trial) showed robust efficacy and a systemic safety profile consistent with approved olanzapine formulations, with no suspected or confirmed PDSS events.Name of Sponsoring Organization(s): Teva Branded Pharmaceutical Products R&D LLC