To Assess the Efficacy and Safety of Utilizing Galactose-deficient IgA1 Biomarker Changes to Guide Pathogenic IgA-targeted Therapeutic Strategies

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of end-stage renal disease (ESRD) in young adults. Even with standard supportive care, many patients still experience worsening renal function and eventually develop ESRD.

The widely accepted multi-hit pathogenesis of IgAN recognizes the production of galactose-deficient IgA1 (Gd-IgA1) as the key step. Pathogenic Gd-IgA1 forms immune complexes that deposit in the kidney, triggering inflammation and renal damage, which serves as a target for new regimens.

Two novel targeted therapies have shown positive clinical effects for IgAN:

• Budesonide Enteric Capsules (Nefecon): A gut-targeted oral preparation that releases drugs in the ileocecal region, reducing Gd-IgA1 production and renal immune deposition to protect renal function.
• Telitacicept: A dual Blys/APRIL inhibitor that blocks the proliferation of B cells to reduce pathogenic Gd-IgA1 production.

However, the clinical effects of these novel therapies usually take time to appear (e.g., a significant drop in urinary protein with Nefecon is often seen 3 to 6 months after treatment). Early, sensitive indicators reflecting therapeutic effects are needed to enable timely adjustment of treatment plans.

Biomarkers (e.g., Gd-IgA1) decline earlier than urinary protein, which is highly significant for monitoring early treatment efficacy and optimizing personalized treatment decisions.

Inclusion criteria

• Male or female, between 18 and 75 years age;
• Biopsy confirmed diagnosis of primary IgA nephropathy or IgA Vasculitis-Associated Nephritis;
• Persistent proteinuria, defined as: two separate measurements (with an interval of ≥ 4 weeks) of 24-hour urinary protein excretion (24hUTP) ≥ 0.5 g/day, or urine protein-to-creatinine ratio (UPCR) ≥ 0.44 g/g;
• Estimated glomerular filtration rate (eGFR) (CKD-EPI) ≥ 30 ml/min per 1.73m^2;
• Have received the angiotensin converting enzyme Inhibitors(ACEI) / angiotensin receptor blocker(ARB) standard treatment for 4 weeks prior to randomization;
• Intending to receive or having received Nefecon or telitacicept treatment for ≤ 2 weeks at the time of screening.

Exclusion criteria

• Secondary IgA nephropathy (excluding IgA vasculitis) caused by ankylosing spondylitis, systemic lupus erythematosus, viral hepatitis, liver cirrhosis, etc.;
• With a known history or clinical evidence of concurrent renal diseases other than IgA nephropathy;
• Treating with systemic corticosteroids or immunosuppressants including cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, rituximab, etc. within 3 months prior to randomizing;
• Have initiated or had a dose adjustment of leflunomide, tripterygium wilfordii or hydroxychloroquine within 3 months prior to randomizing;
• Active tuberculosis or latent carrier without treatment;
• Herpes zoster infected patients or patients with positive HIV antibody, positive HCV antibody or HBV infection (According to the HBV screening test, a) the HBsAg-positive; b) HBsAg-negative and HBcAb-positive, the HBV-DNA should be tested to determine the situation: the HBV-DNA positive subjects should be excluded, while the HBV-DNA negative subjects can participated in.)
• Suffering from following gastrointestinal diseases: gastric ulcer bleeding within the past 6 months, active inflammatory bowel disease, a history of major gastrointestinal surgery (e.g., gastrectomy, gastroenterostomy, or bowel resection), or pancreatic injury/pancreatitis within the past 6 months;
• A confirmed history of osteoporosis or osteonecrosis of the femoral head;
• Type 1 or type 2 diabetes with poor glycemic control (HbA1c > 8%);
• Body mass index (BMI) < 18.5 kg/m².;
• Systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg;
• Decreased lymphocyte count (absolute value < 1.1 × 10⁹/L) or decreased immunoglobulin G (IgG < 6 g/L).
• Hepatic dysfunction, meeting any of the following: a) Child-Pugh Class C liver dysfunction; b) ALT or AST > 2 × upper limit of normal (ULN), or total bilirubin > 2 × ULN at screening; c) history of hepatic encephalopathy, esophageal varices, or portosystemic shunt surgery;
• Evidence of urinary tract obstruction or dysuria.
• A history of solid organ transplantation, hematopoietic stem cell/cell/bone marrow transplantation, or kidney transplantation.
• Pregnancy, lactation, female participants with childbearing plans during the trial or within 6 months of its completion, and male participants planning to conceive or donate sperm during the trial or within 3 months of its completion;
• With a history of malignant tumors within the past 5 years (excluding cutaneous squamous cell carcinoma or basal cell carcinoma);
• Allergy to human-derived biologics;
• Nephrotoxic drugs is unavoidable during the study period;
• Not suitable for the study judged by investigator.