A Phase 2b, Randomized, Controlled Double-blind, Multicenter Study Comparing the Efficacy and Safety of Zetomipzomib (KZR-616) 30 mg or 60 mg with Placebo in Patients with Active Lupus Nephritis

The primary objective of this study is to evaluate the **efficacy** and **safety** of zetomipzomib in patients with active Class III or IV (with or without Class V; Class III/IV +/-V) lupus nephritis (LN) and for those with pure Class V LN. This is clinically relevant as lupus nephritis is a severe manifestation of systemic lupus erythematosus, and effective treatment options are crucial for managing disease progression and improving patient outcomes.

Secondary objectives include:

• To evaluate zetomipzomib compared with placebo in patients with active Class III/IV +/-V LN on background mycophenolate mofetil (MMF) or equivalent, and corticosteroids based upon current guideline-driven standard of care.

The clinical trial involves a total of **165 participants** diagnosed with an **autoimmune disease**. 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 body mass index of at least 18 kg/m² and an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m² or higher. Additionally, participants must have an unequivocally positive antinuclear antibody (ANA) test result and/or a positive anti-double-stranded DNA (anti-dsDNA) serum antibody test. The diagnosis of lupus nephritis (LN) must be confirmed by renal biopsy performed within 12 months prior to screening, according to the 2003 or 2018 ISN/RPS criteria. The trial includes individuals with active Class III or IV LN, with or without Class V, as well as those with pure Class V LN. Adequate hematologic, hepatic, and renal function are required for inclusion. The trial population also considers vulnerable populations, ensuring a comprehensive evaluation of the efficacy and safety of zetomipzomib in this demographic.

The clinical trial is a **randomized**, **controlled**, **double-blind** study designed to evaluate the efficacy and safety of **zetomipzomib** in patients with active lupus nephritis. The trial is categorized as a Phase 2b study and involves multiple centers. The primary objective is to assess the proportion of patients achieving complete renal response (CRR) at Week 37. Secondary endpoints include partial renal response (PRR) at various time points, changes in urine protein-to-creatinine ratio (UPCR), and other clinical measures. The trial is expected to conclude by April 2026, with recruitment starting in September 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as body mass index, renal function, and serological markers. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety. These visits will include assessments of renal function, laboratory tests, and clinical evaluations. The end-of-study visit will occur at Week 53, marking the completion of the participant's involvement in the trial.

The expected duration of participant involvement is approximately 52 weeks. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial will utilize a placebo control group to ensure the reliability of the results, with participants and investigators blinded to treatment assignments. The study will employ both oral and subcutaneous administration routes for the investigational product and comparator treatments.

The clinical trial involves the administration of **Zetomipzomib (KZR-616)**, a small-molecule inhibitor of the immunoproteasome, formulated as a solution for injection. Zetomipzomib is administered via **subcutaneous injection** with a maximum daily dose of 60 mg and a total dose of 3120 mg over a treatment period of up to 52 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Methylprednisolone** is used as an experimental medication in the trial, provided in the form of a powder for solution for injection. It is administered through **intravenous bolus injection or IV infusion**. The maximum daily dose is 3 grams, with a total dose of 3 grams over a treatment period of 1 day. This medication serves as an immunosuppressant in the study.

**Methylprednisolone sodium succinate** is another experimental medication, available as a solution for injection/infusion. It is administered via **intravenous bolus injection or IV infusion**. The dosing regimen includes a maximum daily dose of 3 grams, with a total dose of 3 grams over a 1-day treatment period. This medication also functions as an immunosuppressant.

**Myfenax 500 mg film-coated tablets**, containing the active substance **mycophenolate mofetil**, are used as a non-experimental treatment. These tablets are administered orally, with a maximum daily dose of 3 grams and a total dose of 1022 grams over a 52-week treatment period. Myfenax serves as an immunosuppressant medication in the study.

**Sterile Water For Injection**, provided in a prefilled syringe with a volume of 0.92 mL, is used as a solvent for parenteral use. It is administered via **subcutaneous injection**. The maximum daily and total dose is 0.92 mL, with a treatment period of up to 52 weeks. This sterile liquid is used as an auxiliary substance in the trial.

A **sterilized lyophilized powder with no active** ingredient is included in the study as a placebo. It is not associated with any specific pharmaceutical form or route of administration. This placebo is used to maintain the double-blind nature of the trial.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary efficacy endpoint is the proportion of patients achieving Complete Renal Response (CRR) at Week 37. Secondary efficacy endpoints include the proportion of patients achieving Partial Renal Response (PRR) at Weeks 25, 37, and 53, as well as CRR at Weeks 25 and 53. Additional secondary endpoints involve the percentage change from baseline in Urine Protein to Creatinine Ratio (UPCR) by visit, time to event (CRR, PRR, death, or renal event), and the proportion of patients achieving CRR with successful taper of prednisone or equivalent by Week 17. Other measures include the proportion of patients with UPCR ≤0.5 at Weeks 13, 25, 37, and 53, and changes from baseline in the clinical Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, excluding complement and anti-dsDNA components, as well as changes in EuroQol 5-Dimension 5-Level (EQ-5D-5L).