A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Sibeprenlimab Administered Subcutaneously in Subjects with Immunoglobulin A Nephropathy

The primary objective of this study is to compare the relative change from baseline in urinary protein-to-creatinine ratio (**uPCR**) achieved with **sibeprenlimab** versus placebo added to standard of care (SOC), after 9 months of subcutaneous administration. This is clinically relevant as it aims to assess the efficacy of sibeprenlimab in reducing proteinuria, a key marker of disease progression in patients with **IgA Nephropathy**.

Secondary objectives include:

• Comparing the annual rate of change from baseline (slope) of estimated glomerular filtration rate (**eGFR**) achieved with sibeprenlimab versus placebo added to SOC, after approximately 24 months of subcutaneous administration.
• Evaluating the treatment effect of sibeprenlimab on eGFR versus placebo added to SOC.
• Comparing the treatment effects on the progression to chronic kidney failure (**CKF**) endpoint achieved with sibeprenlimab versus placebo added to SOC.
• Evaluating the effect of sibeprenlimab on total immunoglobulin A (**IgA**), immunoglobulin G (**IgG**), and immunoglobulin M (**IgM**).
• Evaluating the safety and tolerability of sibeprenlimab versus placebo added to SOC.
• Evaluating the immunogenicity of sibeprenlimab.

The clinical trial involves a total of **431 participants** diagnosed with **IgA Nephropathy**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults. Participants were selected based on specific inclusion criteria, including a source-verified biopsy confirming IgA Nephropathy and stable treatment with authorized angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) for at least three months prior to screening. Additionally, subjects on a stable dose of SGLT2i therapy for IgA Nephropathy, in conjunction with ACEIs and/or ARBs, were eligible if treatment commenced at least three months before screening. The trial population is characterized by a requirement for a urine protein-to-creatinine ratio (uPCR) of ≥ 0.75 g/g or urine protein ≥ 1.0 g/day, and an estimated glomerular filtration rate (eGFR) of ≥ 30 mL/min/1.73 m². The study also includes a vulnerable population, ensuring a comprehensive assessment of the investigational treatment's efficacy and safety across diverse patient profiles.

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **Sibeprenlimab** administered subcutaneously in subjects with **Immunoglobulin A Nephropathy** (IgAN). The trial aims to compare the relative change from baseline in urine protein-to-creatinine ratio (uPCR) achieved with Sibeprenlimab versus placebo, added to standard of care (SOC), after 9 months of subcutaneous administration. The trial is expected to conclude by December 2026, with recruitment having commenced in September 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as biopsy-confirmed IgAN and stable treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). The screening will also assess uPCR and estimated glomerular filtration rate (eGFR) levels. Following randomization, participants will receive either Sibeprenlimab or a matching placebo, administered subcutaneously. The primary endpoint is the ratio of uPCR at 9 months compared with baseline, while secondary endpoints include the annualized slope of eGFR over approximately 24 months and progression to chronic kidney failure (CKF).

Study visits will include regular follow-up assessments to monitor efficacy and safety, including clinical laboratory tests, vital sign measurements, and physical examinations. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted. Participant involvement is expected to last up to 24 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will also evaluate pharmacodynamics and safety, including the incidence of treatment-emergent adverse events (TEAEs) and changes in serum immunoglobulin levels.

The clinical trial involves the administration of **Sibeprenlimab**, a humanised IgG2 monoclonal antibody targeting TNFSF13, also known as APRIL or Proliferation Inducing Ligand. **Sibeprenlimab** is provided as a **solution for injection in a pre-filled syringe** and is administered via the **subcutaneous** route. The maximum daily dose is 400 mg, with a total maximum dose of 10,400 mg over a treatment period of 100 days. The pharmaceutical form is specifically designed for ease of administration and to ensure accurate dosing. The product is developed by Otsuka Pharmaceutical Development & Commercialization, Inc., and is identified by the sponsor product code VIS649.

In addition to the experimental treatment, a **Sibeprenlimab-matching placebo** is utilized in the study. The placebo is designed to mimic the appearance and administration method of the active treatment, ensuring the double-blind nature of the trial. The placebo is administered subcutaneously, similar to the active treatment, to maintain consistency in the administration process. The use of a placebo allows for a controlled comparison to evaluate the efficacy and safety of **Sibeprenlimab** in subjects with Immunoglobulin A Nephropathy.

The efficacy of the clinical trial evaluating **Sibeprenlimab** in subjects with Immunoglobulin A Nephropathy (IgAN) will be assessed using several parameters. The primary efficacy endpoint is the ratio of urine protein-to-creatinine ratio (uPCR) at 9 months compared with baseline, based on 24-hour urine collection. This measurement will provide insight into the drug's impact on proteinuria, a key indicator of kidney function in IgAN patients.

Secondary efficacy endpoints include the annualized slope of estimated glomerular filtration rate (eGFR) over approximately 24 months, mean change of eGFR from baseline at 24 months, and progression to chronic kidney failure (CKF). The progression to CKF will be assessed by the time to progression from the randomization date to the first occurrence of CKF and the proportion of subjects experiencing this progression. Additionally, changes from baseline in total serum immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) concentrations will be evaluated to understand the pharmacodynamics of the treatment.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, ensuring a comprehensive assessment of the treatment's impact on disease progression and patient outcomes. The trial is designed to provide robust data on the efficacy of Sibeprenlimab in managing IgAN, contributing to the understanding of its therapeutic potential.