2026 ECNP Congress

PS02-2246

Exposure–response efficacy and safety analysis of subcutaneous LAI olanzapine (TV-44749): clinical application for dosing and switching strategies

Avia Merenlender Wagner — N. Patel, A. Walz, I. Perlstein, H. Knebel, A. Elgart, R. Singh · Teva Pharmaceutical Industries Ltd., Clinical Pharmacology & Pharmacometrics- Specialty Clinical Development, Netanya, Israel

2026 ECNP Congress

Background

Olanzapine (OLZ) is a second-generation antipsychotic available in oral, intramuscular (IM) immediate-release (IR), and IM long-acting injectable (LAI) formulations. For schizophrenia, LAIs mitigate nonadherence to oral antipsychotics. However, IM LAI OLZ pamoate clinical use is limited by post-injection syndrome risk and post-injection monitoring requirements. TV-44749 is an innovative, subcutaneous (SC) LAI OLZ designed to provide sustained efficacy over a monthly dosing interval and avoid post-injection syndrome risk. This analysis characterised the exposure–response (ER) relationship of TV-44749 with efficacy and safety outcomes using data from SOLARIS (NCT05693935), a Phase 3 trial in adults with acute exacerbation of schizophrenia.

Methods

Exposure parameters were derived from a previously developed population pharmacokinetics model from 3 trials (Phase 1 SAD-10154 and NPC-10205; SOLARIS). SOLARIS had an 8-week placebo (PBO)-controlled period (P1) followed by a 48-week open-label period (P2). Participants received TV-44749 318, 425, or 531 mg. Participants treated with PBO in P1 were re-randomised to active treatment in P2. The efficacy ER relationship for Positive and Negative Syndrome Scale (PANSS) total score (TS) was evaluated graphically and using nonlinear mixed-effects modelling to characterise the relationship between PANSS TS and simulated olanzapine plasma average concentration (Cavg) or trough concentration (Ctrough) within a TV-44749 dosing interval. Safety ER analyses included selected treatment-emergent adverse events (AEs; somnolence, extrapyramidal syndrome, and metabolic symptoms) and body weight change from baseline.

Results

Analyses included 665 and 661 participants in the PANSS ER (7811 observations) and safety ER datasets, respectively. Baseline PANSS TS (SD) was 95.8 (8.62), mean (SD) age was 44.3 (11.4) years, and 75.2% were male. The final model included PBO/treatment effect, maximal PBO effect (Pmax), and maximal drug effect (Emax), with good predictive performance. Rapid decreases in PANSS TS were observed in P1, with greater reductions for TV-44749 versus PBO. Further reductions occurred in P2, and end-of-P2 PANSS TSs were comparable across P1 treatment groups. The EC50 was ~4.97 ng/mL, indicating that exposures achieved with all doses were near the efficacy plateau. Cavg provided a superior fit with efficacy parameters compared with Ctrough. Higher baseline PANSS TSs were associated with greater reductions. Simulations indicated that delayed or missed dosing at steady state did not lead to substantial worsening of PANSS TS (<1 point). No clear ER relationships were observed for assessed AEs across exposure metrics. Body weight increases occurred with both PBO and TV-44749, with greater increases for TV-44749 during P1 but no dose-related difference.

Conclusions

Simulation of PANSS TS over time showed a clear treatment effect, with greater reduction for TV-44749 versus PBO in P1. Further reduction in PANSS TS was observed in P2 regardless of treatment allocation in P1, indicating that improvements were maintained over the duration of P2. For AEs assessed, there was no apparent ER relationship; further, extent of body weight increase was not dose or exposure dependent. Findings suggest that missed/delayed doses or switches between TV-44749 and oral OLZ would not likely impact efficacy. Data support TV-44749 as an SC LAI OLZ option for schizophrenia designed to avoid post-injection syndrome risk.

References

No references