A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of RO7434656, an Antisense Inhibitor of Complement Factor B, in Patients with Primary IgA Nephropathy at High Risk of Progression

The primary objective of this Phase III, multicenter, randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of RO7434656, an antisense inhibitor of Complement Factor B, in patients with Primary Immunoglobulin A (IgA) Nephropathy at high risk of progression. This will be assessed by measuring the change in **proteinuria**, specifically the urine protein-to-creatinine ratio (UPCR) at Week 37 from baseline, using a 24-hour urine collection. This objective is clinically relevant as proteinuria is a key marker of kidney damage and progression in IgA nephropathy, and reducing proteinuria is associated with improved renal outcomes.

Secondary objectives include:

• Evaluating the efficacy of RO7434656 compared with placebo based on the estimated glomerular filtration rate (eGFR) slope at Week 105 from baseline, calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation.
• Assessing the efficacy of RO7434656 compared with placebo on the basis of time to the composite kidney failure endpoint.
• Evaluating the level of fatigue in participants treated with RO7434656 compared with placebo.
• Assessing the safety of RO7434656 compared with placebo.
• Characterizing the pharmacokinetic (PK) profile of RO7434656.

The clinical trial involves a total of **341 participants** diagnosed with **Primary Immunoglobulin A (IgA) Nephropathy**. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on specific criteria, including a confirmed diagnosis of Primary IgA Nephropathy through a kidney biopsy conducted within the last ten years, and treatment with maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The trial population is characterized by a requirement for a urine protein-to-creatinine ratio of at least 1 g/g or urine protein excretion of at least 1 g/day, as measured from a 24-hour urine collection during screening. Additionally, participants must have an estimated glomerular filtration rate of at least 20 mL/min/1.73 m². Vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae is required according to national guidelines. The study includes a vulnerable population, and both genders are represented without specific lifestyle considerations such as diet or physical activity being highlighted.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of RO7434656, an antisense inhibitor of complement factor B, in patients with **Primary Immunoglobulin A (IgA) Nephropathy** at high risk of progression. The trial aims to assess the change in proteinuria, as measured by the urine protein-to-creatinine ratio (UPCR) change at Week 37 from baseline, using a 24-hour urine collection. The study is expected to run until September 2030, with recruitment starting in October 2023.

Participants will be involved in the study for a maximum treatment period of 84 weeks. The trial includes several key visits: an initial **screening visit** to confirm eligibility based on criteria such as a kidney biopsy within the last 10 years, treatment with ACE inhibitors or ARBs, and specific UPCR and eGFR levels. Following the screening, participants will undergo regular follow-up visits to monitor efficacy and safety endpoints, including the primary endpoint at Week 37 and secondary endpoints at Week 105. The **end-of-study visit** will conclude the participant's involvement, assessing long-term outcomes and any adverse events.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial will utilize a placebo group to ensure the reliability of the results, with participants receiving either the active treatment or a placebo via **subcutaneous** injection. The study's design and methodology are structured to provide robust data on the potential benefits and risks of RO7434656 in treating high-risk IgA nephropathy patients.

The clinical trial involves the administration of **ASO FACTOR B**, an experimental medication formulated as a **solution for injection**. The active substance in ASO FACTOR B is **ISIS 696844**, a nucleic acid-based antisense oligonucleotide. The medication is administered via the **subcutaneous** route. The maximum daily dose is 70 mg, with a total maximum dose of 5950 mg over a treatment period of 84 days. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the study includes the use of **ASO FACTOR B PLACEBO**. This placebo is utilized to maintain the double-blind nature of the trial, ensuring unbiased assessment of the experimental treatment's efficacy. The placebo is administered in a manner consistent with the experimental drug, although specific details regarding its pharmaceutical form and administration route are not provided.

Furthermore, the trial incorporates the use of **PNEUMOCOCCUS, PURIFIED POLYSACCHARIDES ANTIGEN** as an auxiliary treatment. This antigen is administered intramuscularly, with a maximum daily dose of 400 mg and a total maximum dose of 355600 mg over a treatment period of 131 days. The pharmaceutical form is designated as PHF00231MIG.

Additionally, the study includes the use of a **MENINGOCOCCAL VACCINE** as another auxiliary treatment. This vaccine is also administered intramuscularly, with a maximum daily dose of 0.5 ml and a total maximum dose of 2 ml over a treatment period of 87 days. The pharmaceutical form is designated as PHF00243MIG.

The efficacy of the investigational product RO7434656, an antisense inhibitor of complement factor B, will be assessed in patients with **Primary IgA Nephropathy** at high risk of progression. The primary endpoint for evaluating efficacy is the change in proteinuria, specifically measured by the urine protein-to-creatinine ratio (UPCR) change at Week 37 from baseline, using a 24-hour urine collection. This measurement will provide a quantitative assessment of the reduction in proteinuria, which is a critical indicator of disease progression in IgA nephropathy.

Secondary endpoints include the estimated eGFR slope at Week 105 from baseline, calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. Additionally, the time to the composite kidney failure endpoint will be evaluated, which includes criteria such as the need for kidney transplantation, kidney replacement therapy, or a sustained decline in eGFR. Changes in fatigue levels will also be assessed at Week 105 compared with baseline, utilizing the Functional Assessment of Chronic Illness Therapy–Fatigue Scale. The incidence and severity of treatment-emergent adverse events will be monitored, with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. Plasma concentrations of RO7434656, both conjugated and unconjugated, will be measured at specified timepoints to further evaluate the pharmacokinetics of the treatment.