Efficacy and Safety Evaluation of Frexalimab, SAR442970, and Rilzabrutinib in Primary Focal Segmental Glomerulosclerosis and Minimal Change Disease

The primary objective of this study is to evaluate the **efficacy** of frexalimab, SAR442970, and rilzabrutinib in reducing **proteinuria** compared to placebo in participants with primary focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Proteinuria is a critical marker of kidney damage, and its reduction is clinically significant as it may indicate improved kidney function and a potential slowing of disease progression.

Secondary objectives include:

• Evaluating the efficacy of frexalimab, SAR442970, and rilzabrutinib on the rate of partial remission compared to placebo in participants with primary FSGS/MCD.
• Assessing the efficacy of these agents on the rate of complete remission compared to placebo in the same participant group.
• Determining the safety and tolerability of frexalimab, SAR442970, or rilzabrutinib in participants with primary FSGS/MCD.
• Evaluating the pharmacokinetics (PK) of frexalimab, SAR442970, and rilzabrutinib.
• Assessing the potential for immunogenicity of frexalimab and SAR442970 in participants with primary FSGS/MCD.

The clinical trial involves a total of **67 participants** diagnosed with immune system diseases, specifically focusing on primary focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). The study population includes both **male and female subjects**, with an age range that encompasses both adults and adolescents. Participants were selected based on specific inclusion criteria, such as having a biopsy-proven diagnosis of primary FSGS or MCD, and meeting certain health parameters like a urine protein-to-creatinine ratio (UPCR) of at least 3 g/g at screening. The trial also considers lifestyle factors, requiring participants to be on a stable dose of renin-angiotensin-aldosterone system (RAAS) inhibitors and sodium-glucose co-transporter-2 (SGLT2) inhibitors, if applicable, for at least four weeks prior to screening. The study includes individuals with a body weight between 45 to 120 kg. Both vulnerable populations and those with a documented history of significant UPCR reduction in response to corticosteroid or other immunosuppressive therapy are included, provided they meet the criteria of stable medication use and health status.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **frexalimab**, **SAR442970**, and **rilzabrutinib** in participants aged 16 to 75 years with primary **focal segmental glomerulosclerosis** (FSGS) or **minimal change disease** (MCD). The trial is structured as a Phase 2a, multicenter, parallel-group treatment study. The primary objective is to assess the reduction in proteinuria compared to placebo in participants with primary FSGS/MCD. The trial is expected to commence recruitment on January 1, 2025, and conclude by February 28, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as biopsy-proven primary FSGS or MCD, UPCR ≥3 g/g, and eGFR ≥45 mL/min/1.73 m². Following randomization, participants will receive either the investigational product or placebo. The investigational products include frexalimab administered via **intravenous use**, SAR442970 via **subcutaneous use**, and rilzabrutinib in **tablet** form for **oral use**. The maximum treatment periods for these products are 20, 22, and 24 weeks, respectively.

Study visits will include regular follow-up assessments to monitor efficacy and safety endpoints, such as the percent reduction in urine protein to creatinine ratio (UPCR) and the incidence of treatment-emergent adverse events. Plasma and serum concentrations of the investigational products, as well as the occurrence of anti-drug antibodies, will also be evaluated. The end-of-study visit will mark the completion of the participant's involvement in the trial.

Participants are expected to be involved in the study for the duration of the treatment period, with conditions for early termination including significant adverse events or non-compliance with the study protocol. The trial aims to provide valuable insights into the treatment of immune system diseases, specifically targeting FSGS and MCD, with the potential to improve therapeutic outcomes for affected individuals.

**Frexalimab** is an experimental medication used in this clinical trial. It is formulated as a **solution for injection** and is administered via **intravenous use**. The maximum daily dose is 1800 mg, with a total maximum dose of 7800 mg over a treatment period of 20 days. Frexalimab is a protein-based substance developed by Sanofi Aventis Recherche et Développement (SAR). Participant compliance with the dosing schedule will be monitored throughout the trial.

**SAR442970** is another investigational drug in the study, also presented as a **solution for injection**. It is administered through **subcutaneous use**. The maximum daily dose is 300 mg, with a total maximum dose of 1950 mg over a 22-day treatment period. SAR442970 is a protein-based substance, also developed by Sanofi Aventis Recherche et Développement (SAR). Compliance with the administration schedule will be closely monitored.

**Rilzabrutinib** is included in the trial as a **tablet** for **oral use**. The maximum daily dose is 800 mg, with a total maximum dose of 134,000 mg over a 24-day treatment period. Rilzabrutinib is a chemically synthesized substance provided by Principia Biopharma, Inc. Participant adherence to the oral dosing regimen will be assessed regularly.

The trial also includes several **placebo** treatments to serve as controls. These include the **SAR444671 Placebo**, **SAR441344 Placebo**, and **SAR442970 Placebo**. These placebos are matched to their respective test products to ensure blinding and are administered in the same manner as the active treatments. The placebo formulations are designed to mimic the excipients of the test products, ensuring that participants and investigators remain blinded to the treatment assignments.

The efficacy of the investigational products in the clinical trial will be assessed primarily through the **percent reduction in urine protein to creatinine ratio (UPCR)**. This primary endpoint is designed to evaluate the effectiveness of frexalimab, SAR442970, and rilzabrutinib in reducing proteinuria in participants with primary focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Secondary endpoints include the percentage of participants achieving FSGS partial remission, the percentage achieving complete remission (CR), and the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) leading to investigational medicinal product (IMP) discontinuation. Additionally, plasma concentrations of frexalimab and rilzabrutinib, serum concentrations of SAR442970, and the occurrence of anti-drug antibodies (ADAs) against frexalimab and SAR442970 will be measured.