A Phase I Study of YK012 in Primary Membranous Nephropathy

Official title

A Phase I Study of YK012, a Humanized CD19 × CD3 Bispecific Antibody, in Participants With Very High-Risk, Refractory Primary Membranous Nephropathy

Overview

The goal of this clinical trial is to evaluate the safety, tolerability, pharmacokinetics(PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy of YK012 in participants with primary membranous nephropathy (pMN).

Interventions

• Drug YK012
  YK012 is a bispecific antibody targeting CD19 on B cells and CD3 on T cells leading to T cell-mediated cytotoxicity of malignant B cells

Primary outcome measures

• Ia: Dose-Limiting Toxicity (DLT) [Time frame: up to 28 days after the first dose]
• Adverse Event (AE) [Time frame: From the first induction to the end of the trial at 53 weeks]
• Severe Adverse Event [Time frame: From the first induction to the end of the trial at 53 weeks]

Secondary outcome measures (12)

• Area under the concentration-time curve (AUC0-t) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Area under the concentration-time curve from time 0 to ∞ (AUC0-∞) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Maximum plasma concentration (Cmax) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Time to reach maximum concentration (Tmax) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Half-life (t1/2) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Apparent clearance (CL) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• apparent volume of distribution (Vd) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Minimum plasma concentration (Cmin) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Time to onset and duration of peripheral blood B-cell and B-cell subset depletion [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Changes in peripheral blood Natural Killer (NK) cells [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• Changes in peripheral blood T cells and T cell subsets (CD4+ T cells, CD8+ T cells) [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]
• The profile of cytokine changes [Time frame: From 1 hour before the first infusion of YK012 to the end of trial at 53 or 77 weeks]

Eligibility criteria

Inclusion criteria

• Age 18-80 (inclusive), both gender.
• Diagnosed with primary (idiopathic) membranous nephropathy by renal biopsy within 10 years.
• Participants who meet the criteria of very high-risk primary (idiopathic) membranous nephropathy based on 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases and who have failed available therapies for the treatment of pMN.
• eGFR estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula is ≥45 mL/min/1.73 m².
• If taking angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), or Sodium-Glucose Co-Transporter 2 (SGLT-2) inhibitor, the medication dosage must have been stable (≤50% change in dose) for at least 4 weeks prior to screening and continue being stable prior to the initiation of the investigational product.
• Laboratory tests within 7 days prior to enrollment meet the pre-defined criteria.
• Be able to understand and voluntarily participate in this clinical trial with written signed informed consent and available for scheduled visits, treatments, examinations, and other study procedures.

Exclusion criteria

• Diagnosed with secondary membranous nephropathy.
• Any prior receipt of protocol-specified pharmacological treatment for membranous nephropathy.
• History of malignant tumor within 5 years prior to screening.
• Poorly controlled hypertension.
• Participants with severe renal insufficiency who have received or require dialysis or kidney transplantation within 6 months prior to the initiation of the investigational product.
• History of diabetic nephropathy confirmed by renal biopsy.
• History of severe or chronic infections within 6 months prior to screening or currently infection requiring systemic antibiotic or antiviral therapy.
• History of cardiovascular event leading to hospitalization within 6 months prior to screening.
• Other severe or poorly controlled diseases that may affect the protocol compliance or efficacy assessments.
• Have active tuberculosis with clear evidence of infection.
• History of substantial organ or bone marrow transplantation.
• Received live vaccination, underwent major surgery, or participated in other clinical trials and applied any other study drugs within 28 days prior to the initiation of the investigational product.
• Hepatitis B surface antigen (HBsAg) positive, or hepatitis B core antibody (HBcAb) positive with hepatitis B virus (HBV) DNA quantification ≥ 1×103 copies/L or ≥ 50 IU/L (HBcAb positive participants require regular HBV DNA testing); Hepatitis C virus (HCV) antibody positive; Human immunodeficiency virus (HIV) seropositive; Syphilis helical antibody positive.
• Peripheral blood CD4+ T-lymphocyte count < 200 cells/μL.
• The peripheral blood B-cell count is below the lower limit of normal.
• Known hypersensitivity to any of the ingredients of YK012.
• Female participants who are pregnant or breastfeeding, or women of childbearing potential (WOCBP) who have a positive pregnancy test result at screening; or those who plan to have children during the trial period and for 12 months after the end of the trial, and those who are unwilling to use one or more physical contraceptive methods during the trial period and for 12 months after the end of the trial.
• Other conditions that the investigator considers inappropriate for participation in this trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07234474 · YK012-3-FDA

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗