Phase III Randomized, Double-Blind, Placebo-Controlled Study Evaluating Efficacy and Safety of Iptacopan in Patients with Primary IgA Nephropathy

The primary objective of this study is to demonstrate the **superiority** of LNP023 compared to placebo in the reduction of proteinuria at 9 months, as measured by the urine protein-to-creatinine ratio (UPCR) from a 24-hour urine collection. This is clinically relevant as proteinuria is a key marker of kidney damage in patients with **IgA Nephropathy** (IgAN), and its reduction is associated with improved renal outcomes.

Secondary objectives include: - Evaluating the effect of LNP023 versus placebo on slowing the estimated glomerular filtration rate (eGFR) decrease, which is crucial for assessing kidney function over time. - Assessing the proportion of participants achieving proteinuria below 1g/g of UPCR, indicating a significant reduction in proteinuria. - Evaluating the effect on IgAN progression by measuring the annualized total slope of eGFR decline over one year. - Assessing changes in fatigue levels using the FACIT-Fatigue questionnaire, which is important for understanding the impact on patient quality of life. - Evaluating the safety and tolerability of LNP023 compared to placebo, ensuring the treatment's risk-benefit profile is acceptable. - Demonstrating the superiority of LNP023 in delaying the time to the first occurrence of a composite kidney failure endpoint, which is critical for long-term renal health. - Demonstrating the superiority of LNP023 in reducing proteinuria at 9 months and in the proportion of participants reaching proteinuria below 1g/g of UPCR at 9 months. - Demonstrating the superiority of LNP023 in the change from baseline to 9 months in the fatigue scale measured by the FACIT-Fatigue Questionnaire.

The clinical trial involves a total of **412 participants** diagnosed with **IgA Nephropathy**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific health criteria, including an estimated glomerular filtration rate (eGFR) and biopsy-confirmed IgA nephropathy. The trial population is required to have been on a stable dose regimen of ACE inhibitors or angiotensin receptor blockers for approximately 90 days prior to the study. Additionally, participants must have received vaccinations against Neisseria meningitidis, Streptococcus pneumoniae, and, if available, Haemophilus influenzae infections before the commencement of the study treatment. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants meet the necessary health requirements to assess the efficacy of the investigational treatment in reducing proteinuria and slowing the progression of IgA Nephropathy.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled**, parallel group, phase III study designed to evaluate the efficacy and safety of **Iptacopan** in patients with **IgA nephropathy**. The trial aims to demonstrate the superiority of Iptacopan over placebo in reducing proteinuria at 9 months and in slowing the progression of IgA nephropathy over 24 months. The study is expected to run from December 2020 to September 2025, with a total duration of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, eGFR levels, and biopsy-confirmed IgA nephropathy. Following successful screening, participants will be randomized to receive either Iptacopan or placebo in the form of hard gelatin capsules, administered orally. The study includes interim and final analyses, with primary endpoints focusing on the reduction of proteinuria and the annualized total slope of eGFR decline.

Study visits will occur at regular intervals to monitor safety and efficacy, including assessments of proteinuria, eGFR, and other health parameters. Participants will be required to maintain stable doses of supportive care medications, such as ACE inhibitors or ARBs, for approximately 90 days prior to the first administration of the study drug. Vaccinations against specific infections are mandatory before starting the study treatment.

The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events, non-compliance with study procedures, or withdrawal of consent. The study will conclude with an end-of-study visit to assess final outcomes and ensure participant safety. Throughout the trial, safety endpoints, including adverse events and laboratory parameters, will be closely monitored to ensure participant well-being.

The clinical trial involves the administration of **IPTACOPAN**, a chemical compound, as the experimental medication. IPTACOPAN is provided in the form of hard gelatin capsules, with each capsule containing the active substance. The pharmaceutical form is specifically designed for oral administration. Participants in the trial will receive a maximum daily dose of 400 mg, with the total dose not exceeding 400 mg per day. The treatment period is set for a maximum of 24 months. The primary objective is to evaluate the efficacy and safety of IPTACOPAN in patients with primary IgA nephropathy, focusing on the reduction of proteinuria and the slowing of disease progression. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is formulated as a 0 mg hard gelatin capsule, size 0, and is designed to match the appearance of the IPTACOPAN capsules. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain the study's blinding integrity. The use of a placebo allows for the assessment of IPTACOPAN's efficacy by comparing outcomes between the treatment and control groups. Participant compliance with the placebo administration will be similarly monitored to ensure the validity of the trial results.

The efficacy of the investigational product, **Iptacopan**, in the treatment of primary IgA nephropathy will be assessed through a series of predefined endpoints. The primary endpoint for the interim analysis is the log-transformed ratio to baseline in the urine protein-to-creatinine ratio (UPCR) sampled from a 24-hour urine collection at 9 months. For the final analysis, the primary endpoint is the annualized total slope of estimated glomerular filtration rate (eGFR) decline over 24 months. Secondary endpoints for the interim analysis include changes from baseline in eGFR at 9 months, the proportion of participants achieving a UPCR of less than 1 g/g at 9 months without receiving corticosteroids/immunosuppressants or initiating new therapies, and changes in fatigue as measured by the FACIT-Fatigue questionnaire. Safety endpoints, including adverse events and laboratory parameters, will also be monitored from baseline to 9 months.

For the final analysis, secondary endpoints will include the time from randomization to the first occurrence of a composite kidney failure event, changes in UPCR, and fatigue scale changes measured by the FACIT-Fatigue questionnaire. Safety endpoints will be collected from baseline to the end of the study. Efficacy assessments will be conducted at specified time points, with UPCR and eGFR being key parameters measured through validated laboratory tests and patient-reported outcomes. The study aims to demonstrate the superiority of Iptacopan over placebo in reducing proteinuria and slowing the progression of IgA nephropathy.