Heejae Won 1, Jieon Lee 1, Seong Bok Jang 1
1 Yuhan Corporation (Seoul, Republic of Korea)
Objectives
Lesigercept (YH35324) is a long-acting IgETrap-Fc fusion protein with a dual mechanism of action, binding circulating free immunoglobulin E (IgE) with high affinity while also targeting FcεRIα-related IgE signaling pathways, thereby suppressing IgE-driven allergic inflammation. Chronic spontaneous urticaria (CSU) is characterized by IgE-mediated mast cell activation, where achieving sustained suppression of free IgE is key to clinical efficacy. The objectives of this analysis were to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to characterize the lesigercept PK and IgE target engagement, identify clinically relevant covariates, and use model-based simulations to inform dose selection in patients with CSU.
Methods
The population PK/PD analysis was based on a dataset containing serum lesigercept concentrations and free IgE levels from three phase 1 clinical studies (YH35324-101 [NCT05061524], YH35324-102 [NCT05564221], and YH35324-103 [NCT05960708]). The integrated dataset included subjects with mild allergic disease, as well as patients with CSU and chronic inducible urticaria, who received lesigercept as single subcutaneous (SC) doses of 0.3–9 mg/kg or multiple SC doses of 0.75 mg/kg every 2 weeks, 3 mg/kg every 4 weeks (Q4W), and 6 mg/kg Q4W or every 8 weeks. A simultaneous mechanism-based PK/PD model was developed to characterize the relationship between lesigercept PK and its effect on free IgE levels. The influence of potential covariates was evaluated on PK and PD parameters using the stepwise covariate model building procedure with adaptive scope reduction and physiological characteristics. Model performance was evaluated using standard goodness-of-fit plots and visual predictive checks. PK/PD simulations were performed to suggest alternative fixed-dose regimens and to predict the duration of free IgE suppression below a target concentration of 25 ng/mL at steady state in a moderate-severe CSU population. The distributions of significant covariates included in the final PK/PD model were simulated (N = 1,000) based on the demographic information reported in the Phase 3 ligelizumab studies [1]. All modeling and simulations were performed with NONMEM® version 7.6.0.
Results
A total of 1,803 observations (1,009 for lesigercept concentrations and 794 for free IgE level measurements) from 92 subjects were included in model development. In the overall study population, the median body weight was 66.8 kg, and the median baseline total IgE level was 196 IU/mL. Lesigercept PK was adequately described by a two-compartment model with first-order absorption and elimination, while free IgE suppression was characterized using target-mediated drug disposition model with quasi-steady state [2]. The final model adequately described observed concentration-time profiles of lesigercept and free IgE dynamics across studies. Body weight and baseline total IgE level were identified as significant covariates influencing lesigercept exposure and IgE suppression. Simulation results demonstrated that lesigercept doses ≥250 mg Q4W maintained free IgE levels below 25 ng/mL for 28 days in more than 50% of patients and for at least 21 days in over 75% of patients. Considering SC injection volume constraints, doses in 150-mg increments were evaluated. The 450 mg Q4W regimen, corresponding to the currently maximum tested dose of lesigercept, demonstrated a longer duration of free IgE suppression and greater consistency across the simulated CSU population compared with lower-dose regimens.
Conclusions
The population PK/PD model successfully described lesigercept PK and free IgE suppression while accounting for drug-IgE binding and patient-specific covariates. Model-informed simulations supported selection of a fixed-dose regimen for Phase 2 [NCT07415551], with 450 mg Q4W identified as the most appropriate regimen for achieving sustained suppression of free IgE in patients with CSU.
References:
[1] Maurer M, Ensina LF, Gimenez-Arnau AM, et al. Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials. Lancet. 2024;403(10422):147-159. doi:10.1016/S0140-6736(23)01684-7
[2] Dua P, Hawkins E, van der Graaf PH. A Tutorial on Target-Mediated Drug Disposition (TMDD) Models. CPT Pharmacometrics Syst Pharmacol. 2015;4(6):324-337. doi:10.1002/psp4.41
Reference: PAGE 34 (2026) Abstr 12025 [www.page-meeting.org/?abstract=12025]
Poster: Drug/Disease Modelling - Other Topics