#130 Novel Bruton's tyrosine kinase inhibitor EVER001 in Chinese patients with primary membranous nephropathy: preliminary results from a phase 1b/2a study

Abstract Background and Aims Primary membranous nephropathy (pMN) is an autoantibody-driven glomerular disease. Bruton's tyrosine kinase (BTK) is a key mediator of B-cell receptor signaling and a promising therapeutic target for autoimmune diseases. EVER001, a highly selective, reversible, covalent BTK inhibitor, is being developed for the treatment of proteinuric autoimmune glomerular diseases. This phase 1b/2a study aims to evaluate the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of EVER001 in patients with pMN (NCT05800873). Methods This ongoing, open-label, single-arm study enrolled patients with anti-phospholipase A2 receptor (anti-PLA2R)–positive, biopsy-proven pMN, and nephrotic-range proteinuria (≥8 weeks) on top of supportive care. The total study duration includes a treatment period of 36 weeks and a follow-up period of up to 68 weeks. Patients were enrolled in two cohorts: patients in cohort 1 received EVER001 100 mg once daily for 4 weeks, escalating to 100 mg twice daily for 32 weeks, while patients in cohort 2 received EVER001 200 mg twice daily for 36 weeks. The primary endpoints were safety and tolerability. Secondary endpoints included changes in anti-PLA2R autoantibodies and proteinuria, percentage of patients with immunological complete remission (ICR) (anti-PLA2R <20 RU/mL), percentage of patients with complete remission (CR) (proteinuria <0.3 g/24 h) or partial remission (PR) (proteinuria ≥0.3 g/24 h but <3.5 g/24 h and a decrease of >50%), and PK/PD analyses. Results Thirty-one patients (13 in cohort 1 and 18 in cohort 2) were enrolled at 19 sites in China. By December 17, 2024, the median durations of exposure in cohorts 1 and 2 were 253 days and 190 days, respectively; 11 patients in cohort 1 completed 36 weeks of treatment, with 10 of these patients followed to 52 weeks; in cohort 2, 17 and 10 patients completed 12 and 24 weeks of treatment, respectively. Four patients discontinued early. The median age was 44.5 years and 63.3% were male. At baseline, the median (range) values were: anti-PLA2R autoantibodies 85.4 (18.3–296.8) RU/mL; proteinuria 5.2 (2.4–10.8) g/24 h; serum albumin 31.2 (21.6–37.7) g/L; and estimated glomerular filtration rate 93.8 (62.5–135.9) mL/min/1.73 m2. In the safety‑evaluable population (n = 31), treatment-related adverse events (TRAEs) occurred in 76.9% (10/13) of patients in cohort 1 and in 44.4% (8/18) of patients in cohort 2. Four patients had Grade 3 TRAEs whereas the others all experienced Grade 1–2 TRAEs. Serious TRAEs occurred in 15.4% (2/13) and 11.1% (2/18) of patients in cohorts 1 and 2, respectively. The most common TRAEs (≥2 patients) in all patients were anemia (12.9%), dizziness (9.7%), upper respiratory tract infection (6.5%), decreased B-cell count (6.5%), hyperkalemia (6.5%), palpitations (6.5%), nausea (6.5%), and vomiting (6.5%). In the efficacy-evaluable population (n = 30), anti-PLA2R autoantibody levels in cohorts 1 and 2 decreased by 62.1% and 87.3% at Week 12, and by 93.2% and 93.9% at Week 24, respectively (Fig. 1). At Week 12, 38.5% (5/13) of patients in cohort 1 and 64.7% (11/17) of patients in cohort 2 achieved ICR; at Week 24, the percentages increased to 76.9% (10/13) and 81.8% (9/11), respectively. In cohort 1, proteinuria decreased by 78.0% and 79.5% at Weeks 36 and 52, respectively, while a 70.1% reduction at Week 24 was observed in cohort 2 (Fig. 2). CR or PR was achieved in 69.2% (9/13) and 54.5% (6/11) of patients in cohort 1 at Weeks 36 and 52, respectively, while CR or PR occurred in 80.0% (8/10) of patients in cohort 2 at Week 24. Early PK data suggest a correlation between dose and receptor occupancy (RO), with a median RO at trough of >95%. Conclusions Preliminary results showed that EVER001 was well tolerated and effective in patients with pMN, supporting its potential as a treatment for proteinuric autoimmune glomerular diseases.