#3776 THE TYPE Ⅱ ANTI-CD20 MONOCLONAL ANTIBODY MIL62 OR CYCLOSPORINE IN CHINESE PRIMARY MEMBRANOUS NEPHROPATHY: PRELIMINARY RESULTS OF A PHASE ⅠB/Ⅱ TRIAL
Authors: Cui Zhao , Zhang Yimiao , LI Heng , Zhou Hua , Lin Hongli , Xing Guangqun , Chen Wei , Liang Wei , Luo Ping , Chen Xiaolan , Xu Hui , Zha Yan , Wang Yue , Chen Xing , Ni Zhaohui , Zhang Junjun , Lu Wanhong , Zhang Haitao , Long Haibo , Sun Dong , Cao Yu , Zhao Minghui , Meng Song , Wei Min 
Published: June 2023

Abstract

Background and Aims
Anti-CD20 monoclonal antibody has become one of the first-line therapies for the treatment of moderate and high-risk primary membranous nephropathy (pMN). A novel glycoengineered type Ⅱ anti-CD20 antibody, MIL62 with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of MIL62 in pMN, we conducted a multicenter, randomized, controlled, open-label, phase Ib/Ⅱ study (NCT05398653).

Method
This study aims to investigated MIL62 or Cyclosporine for the treatment of Chinese pMN. Eligible patients with pMN diagnosed by kidney biopsy, proteinuria of at least 3.5 g per 24 hours received intravenous MIL62 (two infusions, 600 or 1000 mg each, administered 14 days apart; repeated at 6 months) or Cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed up for up to 104 weeks. The primary outcome was a composite of complete or partial remission of proteinuria and stable eGFR at 76 weeks. Laboratory variables and safety were also assessed.

Results
From February 23th, 2022 to December 21th, 2022, 85 patients were randomly enrolled from 19 centers in China, and received at least one dose of MIL62 or Cyclosporine. At the data cut-off date (January 30th, 2023), 60 patients were followed up for at least 12 weeks, 24/40 (60%) patients in the MIL62 group and 7/20 (35%) patients in the Cyclosporine group achieved complete or partial remission; 26 patients were followed up for at least 24 weeks, 11/18 (61.1%) patients in the MIL62 group and 2/8 (25%) patients in the Cyclosporine group achieved partial remission. In the 56 patients who were positive for anti-PLA2R antibodies (≥14RU/mL) at baseline and followed up for at least 12 weeks, 29/38 (76.3%) patients in the MIL62 group achieved immunological remission (PLA2R Abs&lt;14RU/mL), which was superior to the Cyclosporine group where 8/18 (44.4%) patients achieved immunological remission (P&lt; 0.05). The remission to MIL62 in our study was rapid because 61.1% of patients achieved complete or partial remission at 24 weeks compared with the 35% 6-month response rate reported in the Membranous Nephropathy Trial of Rituximab study [1]. Among the 85 safety-evaluable patients, treatment emergent adverse events (TEAEs) occurred in 23/30 (76.7%) patients in the MIL62 600 mg group, 26/30 (86.7%) patients in the MIL62 1000 mg group and 24/25 (96.0%) patients in the Cyclosporine group; treatment-related AEs (TRAEs) occurred in 21/30 (70.0%), 23/30 (76.7%) and 18/25 (72.0%) in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively; Grade 3 or above TEAEs were observed in 5 (16.7%), 1 (3.3%) and 2 (8.0%) patients in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively; Serious adverse events (SAEs) occurred in 5 (16.7%), 0 (0.0%) and 2 (8.0%) patients in the MIL62 600 mg, MIL62 1000 mg and Cyclosporine group respectively. Only one patient in the MIL62 600 mg group experienced serious treatment-related thrombocytopenia and has recovered so far; Other SAEs are not related to treatment. B cell depletion occurred within 24 hours after MIL62 infusion and could last for 24 weeks.

Conclusion
The 12-week immunological remission rate in the MIL62 group was significantly higher than the Cyclosporine group. MIL62 had a manageable safety profile. This phase Ib/II preliminary data warrant further phase III clinical trials of MIL62 in pMN.