A Phase Ib/ Ⅱ Clinical Study of MIL62 in Primary Membranous Nephropathy

Beijing Mabworks Biotech Co., Ltd.94 enrolled

Overview

This study was divided into two stages. In the first stage (Phase Ib), 30 subjects were randomly divided into MIL62 600mg, MIL62 1000mg and cyclosporine groups at a ratio of 1:1:1, with 10 subjects in each group. Tolerance to MIL62 was evaluated within 4 weeks after the first administration. If the overall safety is determined by the investigator and sponsor to be tolerable to MIL62, phase II enrollment will be initiated. The second stage(Phase II) was also randomly divided into MIL62 600mg, MIL62 1000mg and cyclosporine groups according to the ratio of 1:1:1, 20 subjects in each group, to evaluate the efficacy of MIL62 and cyclosporine in the treatment of primary membranous nephropathy. Eligible subjects in both phases received treatment and follow-up for a total of 104 weeks. The primary efficacy endpoints were the 12-week immune remission rate and the 24-week overall remission rate.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Primary Membranous Nephropathy

Interventions

A 600 mg intravenous (IV) infusion of MIL62 will be administered on Week 1 Day 1 and Week 3 Day 1. If treatment response is observed, additional doses will be administered on Week 25 Day 1 and Week 27 Day 1. According to the protocol amendment in June 2023, some patients also received MIL62 treatment on Week 53 Day 1.

CyclosporineDRUG

Participants will receive Cyclosporine at a starting oral dose 3.5 mg/kg/d, divided into 2 doses, try to give every 12 hours. The dose was adjusted according to the blood concentration of cyclosporine monitored every 2 weeks ±3 days until the target blood concentration of 125\~175 ng/ mL was reached. Optimized cyclosporine dose will be maintained for a maximum 52 weeks dependent on response and then tapered over 8 weeks.

MIL62DRUG

A 1000 mg intravenous (IV) infusion of MIL62 will be administered on Week 1 Day 1 and Week 3 Day 1. If treatment response is observed, additional doses will be administered on Week 25 Day 1 and Week 27 Day 1. According to the protocol amendment in June 2023, some patients also received MIL62 treatment on Week 53 Day 1.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult patients, ≥18 years of age; 2. Diagnosis of primary membranous nephropathy (pMN) according to renal biopsy prior to or during screening； 3. Screening 24-hour urinary protein \>= 5 g after best supportive care for \>= 3 months prior to screening or screening 24-hour urinary protein \> 3.5 g after best supportive care for \>= 6 months prior to screening, or Screening 24-hour urinary protein \> 3.5 g with at least one high-risk factor defined by the protocol; 4. Estimated glomerular filtration rate (eGFR ) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula ≥40 mL/min/1.73 m\^2； 5. Sufficient organ function; 6. Able and willing to provide written informed consent and to comply with the study protocol. Exclusion Criteria: 1. Participants with a secondary cause of MN 2. Cyclosporine resistance 3. Urine protein decreased by \> 50% within 6 months before screening 4. Received treatment drugs for membranous nephropathy 5. Concomitant with other serious diseases 6. Received live vaccination, major surgery (excluding diagnostic procedures), and participated in other clinical trials within 28 days prior to receiving the first study drug 7. Patients who are positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb), with HBV DNA levels above the normal range (HBsAg and/or HBcAb-positive patients require regular HBV DNA testing); patients positive for hepatitis C virus (HCV) antibodies; or patients with a positive human immunodeficiency virus (HIV) serology 8. Participants with CD4+ T lymphocyte count \< 300 cells/μL 9. Those who have a clear history of tuberculosis or have received anti- tuberculosis treatment 10. Participants with known history of severe allergic reactions to humanized monoclonal antibodies, MIL62, or Cyclosporine 11. Breastfeeding or pregnant women 12. Childbearing potential and unwillingness or impossibility to comply with a scientifically acceptable birth-control method 13. Other conditions unsuitable for participation in this study determined by the Investigator

Outcomes

Primary Outcomes

Stage 1: The Tolerability and Safety of MIL62 in Participants with Primary Membranous Nephropathy

Evaluation of the Tolerability and Safety of MIL62 in Participants with pMN.The tolerance is defined as the occurrence of CTCAE 5.0 Grade ≥3 adverse events within 28 days after the first dose of MIL62.Safety assessments included adverse events, vital signs, physical examinations, laboratory tests, Eastern Cooperative Oncology Group (ECOG) performance status and 12-lead electrocardiograms (ECG) during the study period.

Time frame: up to 2 year after enrollment

Stage 1 and Stage 2: The 12-week immune remission rate in the anti-PLA2R antibody-positive population.

The proportion of participants who achieved immune remission(Anti-PLA2R antibody\<14RU/mL) at week 12.

Time frame: Week 12

Stage 1 and Stage 2:The 24-week overall remission rate (ORR)

The proportion of participants who achieved overall remission (complete and partial remission) at week 24.

Time frame: week 24

Secondary Outcomes

Stage 2: The immune remission rate at week 24, 52, 76, and 104.

The proportion of participants who achieved immune remissionat week 24, 52, 76, 104.

Time frame: Week 24, 52, 76 and 104

Stage 2: The complete remission rate (CRR) and partial remission rate (PRR) at week 24.

The proportion of participants who achieved complete remission (CR) and partial remission (PR) at week 24.

Time frame: Week 24

Stage 2:The CRR, PRR and ORR at week 52, 76, 104.

The proportion of participants who achieved CR、PR and overall remission (OR) at week 52,76,104.

Time frame: Week 52, 76, 104

Stage 2: Time to CR and OR

Time frame: up to 104 weeks

Stage 2:The duration of CR and OR

Time frame: up to 104 weeks

Stage 2: Change in anti-PLA2R antibody

Time frame: up to 104 weeks

Stage 2: Change in eGFR

Time frame: up to 104 weeks

Stage 2: Change in 24-hour urine protein

Time frame: up to 104 weeks

Stage 2: Percentage of Participants with Adverse Events (AEs)

Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

Time frame: up to 104 weeks

Stage 2: Percentage of participants with AEs of Special Interest (AESIs)

Time frame: up to 104 weeks

Stage 2: Peripheral B-cell Counts at Specified Timepoints.

Time frame: up to 104 weeks

Stage 2: Incidence of ADAs during the study

Time frame: up to 104 weeks

Stage 2: Pharmacokinetic(PK) Parameters during the study: Area Under the Curve(AUC)

Time frame: up to 104 weeks

Stage 2: Pharmacokinetic(PK) Parameters during the study:Maximum Concentration(Cmax)

Time frame: up to 104 weeks

Stage 2: Pharmacokinetic(PK) Parameters during the study: t1/2

Time frame: up to 104 weeks

Stage 2: Pharmacokinetic(PK) Parameters during the study: Volume of Distribution (Vd)

Time frame: up to 104 weeks

Stage 2: Pharmacokinetic(PK) Parameters during the study: Clearance(CL)

Time frame: up to 104 weeks

A Phase Ib/ Ⅱ Clinical Study of MIL62 in Primary Membranous Nephropathy

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes