Evaluation of Long-term Safety, Tolerability, and Efficacy of Subcutaneous Sibeprenlimab in Patients with Immunoglobulin A Nephropathy

The primary objective of this study is to evaluate the long-term **safety** and tolerability of sibeprenlimab in subjects with Immunoglobulin A Nephropathy (IgAN). This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use, which is crucial for managing a chronic condition like IgAN.

Secondary objectives include: - Evaluating the long-term efficacy of sibeprenlimab in subjects with IgAN, which is important for understanding the sustained therapeutic benefits of the treatment. - Assessing the immunoglobulin (Ig) response in subjects with IgAN, which can provide insights into the immune system's reaction to the treatment. - Evaluating immunogenicity in subjects with IgAN, which is essential for determining the potential for immune reactions against the treatment.

The clinical trial involves a total of **500 participants** diagnosed with **IgA nephropathy (IgAN)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their completion of previous trials (Trial 417-201-00007 or Trial VIS649-201) without safety concerns and their potential to benefit from treatment with sibeprenlimab. The trial includes individuals with an estimated glomerular filtration rate (eGFR) of at least 20 mL/min/1.73 m², calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The study population is characterized by a diverse range of health statuses, and the trial includes a vulnerable population. Participants are required to provide written, informed consent and demonstrate the ability to comply with all trial requirements. Lifestyle considerations such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the long-term safety, tolerability, and efficacy of **sibeprenlimab** administered subcutaneously in subjects with **Immunoglobulin A Nephropathy (IgAN)**. This is a Phase 2/3, multicenter, open-label trial. The trial is expected to commence recruitment on February 14, 2023, and is estimated to conclude by February 28, 2029. Participants will be involved in the study for a maximum treatment period of 100 weeks. The trial will include subjects who have completed previous related trials without safety concerns and meet specific inclusion criteria, such as having an estimated glomerular filtration rate (eGFR) of at least 20 mL/min/1.73 m².

The trial will consist of several study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Following the screening, participants will undergo regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments such as clinical laboratory tests, vital sign measurements, physical examinations, and evaluations of injection site reactions. The primary endpoint focuses on the incidence of treatment-emergent adverse events (TEAEs) graded by severity. Secondary endpoints include the slope of eGFR over 12 and 24 months, changes in urine protein-to-creatinine ratio (uPCR), and progression of chronic kidney disease.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the overall outcomes of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the long-term effects of sibeprenlimab in treating IgAN, contributing valuable insights into its potential therapeutic benefits.

The clinical trial involves the administration of **Sibeprenlimab**, a humanized IgG2 monoclonal antibody targeting TNFSF13, also known as APRIL. Sibeprenlimab is provided as a solution for injection in a pre-filled syringe. The route of administration is subcutaneous, with a maximum daily dose of 400 mg and a total maximum dose of 10,400 mg over a treatment period of 100 days. The pharmaceutical form is a solution for injection, and the product is classified as an orphan drug. Participant compliance is monitored through regular assessments of dosing adherence and response to treatment.

In addition to the experimental treatment, the trial includes several non-experimental treatments. These include combinations of small molecule drugs such as **Atorvastatin**, **Amlodipine**, and **Perindopril**, among others. These medications are provided in various pharmaceutical forms, including PHF00082MIG and PHF00006MIG, with unknown routes of administration. The maximum treatment period for these non-experimental treatments is also 100 days. The dosing schedules and participant compliance for these treatments are monitored through standard clinical trial procedures, ensuring adherence to the protocol and accurate assessment of treatment effects.

The efficacy of the clinical trial will be assessed using several secondary endpoints. These include the evaluation of the slope of estimated glomerular filtration rate (**eGFR**) over approximately 12 and 24 months, and the relative change from baseline in urine protein-to-creatinine ratio (**uPCR**) at the same time intervals, based on 24-hour urine collection. Additionally, the overall rate of clinical remission will be determined, defined as the proportion of subjects with total protein less than 1.0 g/day at 12 and 24 months. The progression of chronic kidney disease will be measured by the time to a doubling of serum creatinine, a 40% reduction in eGFR, eGFR less than 15 mL/min/1.73m², or the requirement for renal replacement therapy for at least 3 months. Furthermore, the proportion of subjects experiencing these outcomes over 24 months will be evaluated.

Pharmacodynamic assessments will include changes from baseline in total serum immunoglobulin A (**IgA**), immunoglobulin G (**IgG**), and immunoglobulin M (**IgM**) concentrations. Additionally, serum anti-drug antibody (**ADA**) levels will be evaluated. These efficacy parameters will be collected and analyzed at specified timepoints, including 12 and 24 months, to determine the long-term impact of the treatment on subjects with Immunoglobulin A Nephropathy (**IgAN**).