Annabelle Walz 1, Christian Toensing 1, Anne Kümmel 1, Petra Jauslin 1, Nikunjkumar Patel 2, Itay Perlstein 3, Avia Merenlender-Wagner 4, Tamar Bar-Nur 4, Anna Elgart 4, Rajendra Singh 2
1 IntiQuan AG (Basel, Switzerland), 2 Teva Branded Pharmaceutical Products R&D, Inc. (West Chester, USA), 3 Magic Wand Research LLC (Philadelphia, USA), 4 Teva Pharmaceutical Industries Ltd (Netanya, Israel)
Introduction/Objectives:
Olanzapine is a second-generation antipsychotic drug available in oral, intramuscular (IM) immediate release, and IM long-acting injectable (LAI) formulations. Long-acting antipsychotics are associated with improved long-term adherence, as well as improved outcomes. However, IM LAI olanzapine use is limited due to the risk of post-injection delirium/sedation syndrome (PDSS) and associated risk evaluation and mitigation strategy requirements. TV-44749 is an innovative, once-monthly, subcutaneous, LAI olanzapine formulation designed to avoid the risk of PDSS and provide sustained efficacy. Its efficacy, safety, and tolerability in adults with schizophrenia was assessed in the Phase 3 study SOLARIS (NCT05693935) with the Clinical Global Impression-Severity (CGI-S) scale as a key secondary efficacy endpoint. CGI-S is a 7-point ordered categorical scale where lower scores indicate improvement. The objective of this analysis was to characterize the exposure-response (ER) relationship between TV-44749 exposure and the CGI-S score.
Methods:
Exposure parameters (average concentration [Cavg] and trough concentration [Ctrough]) were simulated using a previously developed population pharmacokinetic model [1] developed on data from 3 completed studies: two Phase 1 and one Phase 3 study (SOLARIS). The current analysis included participants on active treatment (monthly injections of TV-44749 318 mg, 425 mg, and 531 mg) or placebo from the SOLARIS trial. SOLARIS included an 8-week double-blind placebo-controlled treatment period (Period 1) and an open-label safety period of up to 48 weeks (Period 2). in Period 1, participants with acute exacerbation of schizophrenia were randomized in a 1:1:1:1 ratio to active treatment or placebo. Participants on placebo in Period 1 were rerandomized in a 1:1:1 ratio to one of the active treatments in Period 2. Change from baseline to week 8 in CGI-S score was one of the key secondary efficacy endpoints.
The relationship between exposure metrics and CGI-S scores was initially investigated graphically and subsequently using a longitudinal non-linear mixed-effect model. The model was based on a proportional odds model by Darwish et al. [2] and incorporated an additive placebo and treatment effect. Both effect components were time-dependent. The treatment effect was described by a saturable maximum effect (Emax) relationship, and the placebo effect was similarly described as reaching a maximum effect (Pmax). Covariate analysis assessed the impact of baseline CGI-S score, smoking status, and demographics. Simulations were performed using either individual participant dosing history, post hoc parameters and covariates, or a general patient population and nominal dosing to further characterize TV-44749’s efficacy.
Results:
Overall, 665 participants were included in the analyses (7808 CGI-S observations). Exploration of SOLARIS data revealed rapid improvement in CGI-S score following initiation of TV-44749 treatment, with a more pronounced effect than placebo during Period 1. In Period 2, participants who retained their active treatment experienced further improvement in CGI-S score. Participants who switched from placebo to active treatment experienced greater improvement than participants who retained their active treatment due to higher Period 2 baseline severity and ultimately reached a similar CGI-S score to those who had been on active treatment from the start.
The diagnostics and visual predictive checks of the model indicated an adequate model fit. Graphical exploration of Cavg and Ctrough showed that the ER relationship for CGI-S scores was flat over the exposure range obtained from the three TV-44749 doses, indicating that these doses lead to drug concentrations close to the Emax of the ER curve; thus, the concentration at half the maximal drug-effect (EC50) could not be reliably estimated. Cavg provided a slightly better fit than Ctrough; however, results were consistent overall. Covariate analysis showed that baseline CGI-S scores positively correlated with maximal placebo and treatment responses (i.e., larger effect when starting from a higher baseline) but negatively correlated with the probability of achieving a CGI-S score of ≤2 during treatment. Simulations of CGI-S over time showed clear differentiation between TV-44749 and placebo, but little difference between dose groups or exposure quartiles for both SOLARIS participants and the larger population simulations.
Conclusion:
Treatment with TV-44749 led to significant improvement in CGI-S compared to placebo, with all tested doses achieving near-maximal effect. No clear dose-response relationship was observed, and both evaluated exposure metrics showed similar predictive performance. Higher baseline CGI-S correlated with larger TV-44749 treatment response. This analysis supports TV-44749 as an effective subcutaneous LAI treatment for schizophrenia.
References:
[1] Jauslin P, Schmidt H, Schweinoch D, Patel N, Perlstein I, Merenlender-Wagner A, Singh R. Population Pharmacokinetic Analysis of Oral, Intramuscular, and Subcutaneous Long-Acting Injectable Olanzapine Using Phase 1 and Phase 3 Data. Abstract PAGE 2026.
[2] Darwish M, Bugarski-Kirola D, Passarell J, Owen J, Jaworowicz D, DeKarske D, Stankovic S. Pimavanserin Exposure-Response Analyses in Patients With Schizophrenia: Results From the Phase 2 ADVANCE Study. J Clin Psychopharmacol. 2022 Nov-Dec 01;42(6):544-551.
Reference: PAGE 34 (2026) Abstr 12218 [www.page-meeting.org/?abstract=12218]
Poster: Drug/Disease Modelling - CNS