Efficacy and Safety of Oral BI 764198 in Adults and Adolescents with Primary or TRPC6-Variant Genetic Focal Segmental Glomerulosclerosis: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to demonstrate the superiority of BI 764198 regarding the mean relative change from baseline to Week 104 in the 24-hour urinary protein-to-creatinine ratio (UPCR) in participants with primary focal segmental glomerulosclerosis (pFSGS) or genetic focal segmental glomerulosclerosis related to TRPC6 gain-of-function mutations. This assessment is clinically significant for evaluating the reduction of proteinuria in patients, including those receiving background calcineurin inhibitor (CNI) therapy. 5

Secondary objectives include:

• Estimation of the difference between BI 764198 and placebo in the mean absolute change in estimated glomerular filtration rate based on serum cystatin C (eGFRcys) from baseline to Week 104.
• Demonstration of superiority regarding the proportion of responders or probability of treatment response, defined as a 24-hour UPCR <1000 mg/g at Week 104.
• Assessment of clinical endpoints related to kidney disease progression, such as sustained eGFRcys decline or end-stage kidney disease.
• Evaluation of the requirement for rescue therapy or intensification of co-medication resulting from treatment failure.
• Measurement of treatment effects on quality of life using patient-reported outcome measures, including KDQOL-36 and NS-SIMPRO to assess the burden of oedema in nephrotic syndrome.

This clinical trial involves 182 participants diagnosed with focal segmental glomerulosclerosis, specifically those with the primary form or those possessing gain-of-function mutations in the TRPC6 gene. The study population includes both males and females ranging from 12 years of age and older. Eligible participants must have a body weight of at least 40 kg and a body mass index of no more than 40 kg/m2. A key clinical requirement is a urinary protein-to-creatinine ratio of 1500 mg/g or greater. Additionally, participants must maintain a minimum estimated glomerular filtration rate of 25 mL/min/1.73 m2, calculated using age-appropriate formulas. Some subjects in this cohort receive background calcineurin inhibitor treatment.

This multicentre, randomised, double-blind, parallel group, placebo-controlled trial is designed to evaluate the efficacy and safety of the oral TRPC6 inhibitor BI 764198 in adult and adolescent participants diagnosed with focal segmental glomerulosclerosis (FSGS), specifically primary focal segmental glomerulosclerosis (pFSGS) or genetic FSGS associated with TRPC6 gene variants. The treatment period is scheduled for 104 weeks. The study begins with a screening visit to assess eligibility based on criteria such as age, weight, body mass index (BMI), and confirmed diagnosis. Key laboratory requirements at screening include a urinary protein-to-creatinine ratio (UPCR) of ≥1500 mg/g and a specific estimated glomerular filtration rate (eGFR). The primary objective is to demonstrate superiority of the test product compared to placebo regarding the mean relative change from baseline to Week 104 in the 24-hour UPCR. Secondary endpoints include changes in eGFR, treatment response, and complete remission. Participants will undergo regular follow-up visits throughout the 104-week period, concluding with an end-of-study visit.

The experimental medication is BI 764198, an oral TRPC6 inhibitor. This substance, chemically identified as [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-methoxypyridin-2-yl]methanone, is administered in a film-coated tablet pharmaceutical form via the oral route.

The placebo consists of a substance matching BI 764198 to maintain the double-blind design of the study. Participants may also receive background calcineurin inhibitor treatment as part of the management for primary focal segmental glomerulosclerosis or genetic FSGS related to TRPC6 gene variants.

The primary efficacy endpoint is the mean relative change from baseline to Week 104 in the 24-hour urinary protein-to-creatinine ratio (UPCR), measured in mg/g, in participants with primary focal segmental glomerulosclerosis (pFSGS) or those with TRPC6 gene gain-of-function mutations.

Secondary efficacy assessments include:

• Absolute change in eGFRcys in mL/min/1.73m2 from baseline to Week 104.
• Treatment response, defined as a 24-hour UPCR <1000 mg/g at Week 104.
• A multi-component treatment response, defined as a 24-hour UPCR <1000 mg/g and eGFRcys ≥85% versus baseline at Week 104 with no treatment failure between randomization and Week 104.
• Complete remission, defined as a 24-hour UPCR <300 mg/g at Week 104.
• Change from baseline in the NS-SIM-PRO clinical outcome assessment (COA) at Week 104.
• Change from baseline in the KDQOL-36 at Week 104.