Evaluation of Obinutuzumab on Anti-PLA2R Antibody Kinetics in Primary Membranous Nephropathy Patients: A Pilot Study

The primary objective of this study is to calculate the **disappearance rate (half-life)** of anti-PLA2R antibodies in patients with primary membranous nephropathy. This is clinically relevant as it provides insights into the pharmacokinetics of obinutuzumab, potentially informing treatment regimens and improving therapeutic outcomes for patients with this condition.

Secondary objectives include:

• Assessing **immunological remission**, defined as a negative result in the anti-PLA2R antibody immunofluorescence test (IFT).
• Evaluating the efficacy of obinutuzumab on disease activity, determined by complete or partial remission at 12 months.
• Assessing adverse events associated with obinutuzumab treatment, categorized as serious adverse events (SAE) or non-serious adverse events of special interest (NSAESI), up to 12 months.
• Determining the quality of life using the 'Kidney Disease Quality of Life-36' questionnaire, with scores averaged at baseline and at weeks 12, 24, 37, and 52, or until study exit.

The clinical trial involves participants diagnosed with **primary membranous nephropathy**, confirmed either through a kidney biopsy or a positive serum anti-PLA2R antibody test. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a serum anti-PLA2R antibody titer greater than 80 RU/ml and proteinuria of at least 3.5 g/24h, despite receiving supportive treatment for a minimum of six months with the maximum tolerated and stable dose of ACE-inhibitor or ARB. Additionally, serum albumin levels must be below 30 g/l, and the estimated glomerular filtration rate (eGFR) should be at least 30 ml/min/1.73m². The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on the necessity for immunosuppressive treatment as determined by their treating physician. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **obinutuzumab** in patients with primary membranous nephropathy. This is a Phase 4, low-intervention study, focusing on the exploratory and confirmatory therapeutic use of obinutuzumab for this condition. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from September 2025 to March 2028, with participant involvement expected to last up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), confirmed diagnosis of primary membranous nephropathy, and specific laboratory values. Following the screening, participants will receive obinutuzumab via intravenous infusion. The primary objective is to calculate the disappearance rate (half-life) of anti-PLA2R antibodies, with serum levels measured at baseline and at multiple intervals: 1, 2, 4, 8, 12, 24, 37, and 52 weeks post-infusion.

Follow-up visits are scheduled to monitor the primary and secondary endpoints, which include immunological remission, clinical disease activity, adverse events, and quality of life. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the treating physician deems it necessary for their safety.

The clinical trial involves the administration of **Gazyvaro**, a pharmaceutical product containing the active substance **obinutuzumab**. Gazyvaro is provided as a **concentrate for solution for infusion** and is intended for intravenous infusion. The dosage regimen for this trial specifies a maximum daily dose of 1,000 mg, with a total maximum dose of 4,000 mg over the course of the treatment. The treatment period is set to a maximum of 12 weeks. The product is manufactured and authorized by Roche Registration GmbH, with repackaging and re-labeling performed by DHL. The administration of Gazyvaro is designed to evaluate its effect on the disappearance rate of anti-PLA2R antibodies in patients.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of the experimental medication, Gazyvaro. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The trial aims to measure serum PLA2R antibodies at various intervals, including baseline, and at 1, 2, 4, 8, 12, 24, 37, and 52 weeks following the obinutuzumab infusions. This approach is intended to provide insights into the pharmacokinetics and pharmacodynamics of obinutuzumab in the context of the study's objectives.

The efficacy of the clinical trial will be assessed by evaluating the **disappearance rate (half-life) of anti-PLA2R antibodies** as the primary endpoint. This will involve measuring serum PLA2R antibodies at specified timepoints: baseline, 1, 2, 4, 8, 12, 24, 37, and 52 weeks following obinutuzumab infusions. The secondary endpoints include assessing immunological remission, defined as IFT negative, and evaluating the efficacy on clinical disease activity, characterized as either complete remission (CR) or partial remission (PR) at 12 months. Additionally, adverse events and quality of life during obinutuzumab treatment will be monitored.