Min Li 1, Jiayu Chen 1, Bei Wang 2, Luandi Yao 2, Jennifer Yang 3, Sandra Zeng 2, Kehua Wu 3, Xiao Zhu 1
1 Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University (Shanghai, China), 2 R & D/Drug Development, Everest Medicines (Shanghai, China), 3 R & D/Discovery & Translational Research, Everest Medicines (Shanghai, China)
Introduction:
Primary membranous nephropathy (pMN) is an autoimmune disease caused by specific autoantibodies produced by B cells that attack the glomerular filtration barrier [1]. Bruton’s tyrosine kinase (BTK) inhibitors suppress B cell activation, proliferation, and survival, showing promise in treating B cell-related autoimmune diseases [2]. EVER001(also named SN1011, XNW1011) is a highly selective, reversible, covalent BTK inhibitor that binds to the Cys481 residue in the BTK active site, resulting in potent kinase inhibition along with a favorable safety profile, indicating its therapeutic potential for pMN [3]. However, its clinical dose remains to be determined for EVER001
Objectives:
This study aimed to propose dose of EVER001 for Phase 1b/2a trial in patients by (1) establishing a population pharmacokinetic (PopPK)–receptor occupancy (RO) model and (2) guide clinical dose selection based on modeling & simulation.
Methods:
The plasma concentration and plasma BTK RO data of EVER001were extracted from a Phase I clinical trial in healthy volunteers[3]. One- and two-compartment models, along with several candidate absorption models (first-order with/without lag time, and transit compartment model), were tested for base PopPK model development. Continuous (age, height, body weight, body mass index (BMI)) and categorical covariates (sex and food) were screened via stepwise covariate modeling (forward inclusion: p<0.05; backward elimination: p<0.01). Subsequently, several pharmacodynamic (PD) candidate models (e.g., Emax, Hill equation, logit, and effect compartment models) were explored for the relationship between exposure and RO. The nonlinear mixed-effects modeling software NONMEM (version 7.5) and Perl-speaks-NONMEM (PsN, version 5.2.6) were used for model development. Statistical analysis, data visualization, and exploratory analysis were conducted in R (version 4.4.1). Model evaluation was based on goodness of fitting (GOF) and visual predictive checks (VPCs). Monte Carlo simulations were conducted in following doses levels: 100–600 mg QD and 100–300 mg BID. The Phase 1b/2a dose was selected based on the following criteria: 1) plasma EVER001 concentrations were below the maximum exposure tested in the phase I study to ensure safety; 2) plasma BTK RO was saturated for effectiveness .
Results:
A total of 1,476 plasma concentrations and 148 BTK RO observations were analyzed, including single doses (100-800 mg, fasted), multiple doses (200-600 mg once daily, fasted), and 600 mg (fed). The PK behavior of EVER001 was characterized by a two-compartment PK model with first-order elimination and transit compartment absorption, yielding a mean transit time (MTT) of 0.647 h, which well described the relatively slow and delayed absorption. Other PK parameters (estimate, RSE%) were precisely estimated: apparent clearance (32.4L/h, 6.1%), apparent volume of distribution of central compartment (574L, 7.5%), apparent volume of distribution of peripheral compartment (257L, 14.4%) and inter-compartment clearance (42.9L/h,15.2%). The relationship between drug plasma concentration and RO was well described by an direct Emax model, with an estimated maximum occupancy (Emax) of 92% and half-maximal effect plasma concentration (EC₅₀) of 24.4 ng/mL. Monte Carlo simulation results suggested 100 mg BID as the lower dose and 200 mg twice daily as the efficacious dose. The clinical effectiveness of proposed dose has been elicited in the Phase 1b/2a trial [4].
Conclusion:
The developed PopPK-RO model well described relationship across dose, PK as well as RO from Phase I clinical trial, and was used to guide the dose selection in subsequent Phase 1b/2a trial. The favorable clinical efficacy observed in Phase 1b demonstrated the viability of this approach in dose selection [4].
References:
[1] Hoxha E et al., Nat Rev Nephrol. 2022 Jul;18(7):466-478.
[2] McDonald C et al. Immunology. 2021 Dec;164(4):722-736.
[3] Zhu LL et al., Clin Transl Sci. 2023 Oct;16(10):1982-1996.
[4] Cui Zhao et al., NEPHROL DIAL TRANSPL. 2025 Oct;40(S3):565-566.
Reference: PAGE 34 (2026) Abstr 12236 [www.page-meeting.org/?abstract=12236]
Poster: Drug/Disease Modelling - Other Topics