An open-label Phase II trial of VDJ-001, a high-affinity IL-6R antagonist antibody, for the treatment of patients with idiopathic multicentric castleman disease

Abstract

Abstract Interleukin-6 (IL-6) targeted therapy has been recommended as the most important treatment option for idiopathic Multicentric Castleman Disease (iMCD). Although siltuximab has been approved in many countries, this first IL-6 blocking antibody only revealed a beneficial effect for 34% of patients with iMCD. To explore more effective therapy, a novel IL-6R antagonizing antibody (VDJ-001) with high-affinity and potent activities has been assessed for safety and efficacy in this open-label phase II trial. A total of 25 Chinese iMCD patients with active disease were enrolled in this open-label, multi-center, dose-escalation and regimen study from April 2022 to September 2024; and their treatment responses and safety profiles after VDJ-001 treatment were monitored up to June 18th, 2025 (last follow-up date). A first batch of 9 patients received VDJ-001 infusion in three dose groups (4 mg/kg, n=3; 6 mg/kg, n=3; 8 mg/kg, n=3) every 2 weeks (q2w, each infusion was considered as a cycle) for 22 cycles which were then adjusted to a single dose of 4 mg/kg to all 9 patients till Cycle 52 (W104). From Cycle 53 (W105), the regimen was extended to every 3 weeks (q3w). A second batch of 16 patients were given VDJ-001 infusion in two dose groups (4 mg/kg, n=8; 6 mg/kg, n=8) every 3 weeks for 16 cycles (NCT05345522, ChiCTR2200058864). The safety profiles were recorded according to CTCAE v5.0; the treatment responses were evaluated with Castleman Disease Collaborative Network (CDCN) criteria proposed in 2018. Treatment responses (biochemical, lymph node, symptomatic and overall responses) were defined as ≥ partial responses. The median age of the 25 Chinese patients at the time of enrollment was 42 (28-59) years old, and the male to female ratio was 2:1. Four (16.0%) were newly diagnosed patients. By June 18th, 2025, a median of 64 & 15 cycles (140 & 45 weeks) (range: 40-69 & 13-17 cycles) of treatment were given to the first and second batches of patients, respectively. All three doses of VDJ-001 were safe and well-tolerated, even during the Covid-19 pandemic. While most of the patients revealed low Grade 1-2 of adverse events (AEs), six patients experienced G3 level of adverse reaction (ADR) without obvious dose-dependency: two patients (4 & 6 mg/kg group each) with neutropenia/lymphopenia; two patients (4 & 6 mg/kg group each) with hypertriglyceridemia; one patient (8 mg/kg group) with eosinophilia; and one patient (6 mg/kg group) had hypofibrinogenemia. All G3 ADRs were resolved/alleviated before Cycle 9. None of these ADRs led to discontinuation of the study drug. For the first batch trial, there was a time-dependent overall response to VDJ-001 administration including 22 cycles of 3-seperate doses and 30 cycles of a dose-unification to 4 mg/kg from Cycle 23. The overall response rate was 55.6%, 77.8% and 88.9% by week 8, 20 and 32 respectively. The maximal overall response rate of 88.9% was observed between 32-104 weeks. Symptomatic and biochemical responses occurred rapidly, with median response time of 3 weeks (0-4) and 2 weeks (1-20) respectively; while the median response time of lymph node obtained at 8 weeks after the first infusion of this investigative drug. The optimal biochemical response rate sustained at 88.9% from week 20 throughout week 104. The pharmacokinetic (PK) and pharmacodynamic (PD) analysis revealed a non-liner correlation between VDJ-001 exposure (Cmin) and disease biomarkers; and all 3 doses on the q2w regimen were exceeded the steady-state requirement of minimal concentration (Cmin) at 5μg/ml for biochemical normalization/efficacy exhibition. No obvious dose-dependent responses were observed for the overall nor 3 individual parameters in this 9-patient q2w small trial. For the second batch, even though the follow-up was relatively short, good efficacy profiles were also observed. All patients achieved symptomatic response and biochemical response by the last follow-up. The overall response rate was 68.75% by June 18th, 2025. The PK analysis indicated a different Cmin profile between two doses, [i.e., the median (range) of Cmin by Cycle 4 was 3.04 μg/mL (undetectable~14.4) for 4mg/kg group and 9.66 μg/mL (5.05~16.7) for 6mg/kg group respectively,] and only 6 mg/kg dose met/exceeded the steady-state requirement of minimal concentration (Cmin) at 5μg/ml. In conclusion, VDJ-001exhibited good safety and efficacy profiles in patients with iMCD.