Obinutuzumab in Adult Rituximab-Dependent Nephrotic Syndrome

Summary

This is a multicenter, open-label, single-arm Phase II clinical trial designed to evaluate the safety, efficacy, and immunological effects of obinutuzumab in adult patients with multi-relapsing, rituximab-dependent steroid-sensitive NS.

Obinutuzumab is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that was initially developed to overcome rituximab resistance in B-cell malignancies. Obinutuzumab induced a longer and deeper B cell depletion than rituximab being able to deplete B cells in lymphoid tissue other than peripheral blood, as shown in both animal models and patients with chronic lymphocytic leukemia or kidney transplantation. Notably, obinutuzumab was found to be more efficient than rituximab in inducing B-cell cytotoxicity in-vitro, especially on naïve (IgD+CD27-) and switched (IgD-CD27+) memory B cells. This is a clinically relevant finding, because memory B cells are known to be associated with the risk of relapse after rituximab treatment in children with nephrotic syndrome. A recent retrospective study in 41 children \[median (IQR) age: 10.6 (8.5-14.29) years\] with steroid-dependent or frequently relapsing nephrotic syndrome, showed that treatment with obinutuzumab achieved B-cell depletion and sustained remission in 38 (93%) and 28 (68%) children at 12 and 24 months after treatment, respectively. Treatment was safe and well tolerated. Moreover, preliminary data indicate that obinutuzumab treatment can achieve complete or partial remission of the nephrotic syndrome in the large majority of adult participants with membranous nephropathy refractory to different immunosuppressive medications including rituximab, and even the human type 1 anti-CD20 antibody ofatumumab or the anti-CD38 antibody felzartamab (NCT05050214). Notably, obinutuzumab treatment achieved B-cell depletion and proteinuria reduction in all treated participants and persistent circulating anti-PLA2R antibody depletion in all participants with PLA2R-related disease even during the recovery of circulating B cells (NCT05050214). Conceivably, obinutuzumab could achieve remission of idiopathic nephrotic syndrome by inducing profound and sustained B-cell depletion, thereby inhibiting the production of anti-podocyte autoantibodies or the production of still unknown B-cell derived nephritogenic mediators and autoantibodies.

Thus, whether obinutuzumab treatment may achieve persistent remission also in adult participants with multi-relapsing, rituximab-dependent nephrotic syndrome, as previously reported in children, and as already observed in adult participants with refractory membranous nephropathy (NCT05050214), and whether this effect is associated with delayed recovery of switched memory B cells and emergence of B cells with a naïve phenotype as well as sustained reduction or depletion of circulating anti-podocyte antibodies is worth investigating.

In parallel to the evaluation of the phenotype of repopulating B cells, we will evaluate serum levels of the B-cell activating factor (BAFF). BAFF is a cytokine that orchestrates peripheral tolerance of B cells and promotes the survival of autoreactive B cells escaping central tolerance mechanisms. In participants with autoimmune diseases, such as systemic lupus erythematosus or rheumatoid arthritis, the relapse of disease activity after rituximab treatment has been associated with compensatory elevation of the B cell-activating factor BAFF levels. Elevated BAFF levels at baseline or during the follow-up may explain the resistance or dependency to anti-CD20 depleting antibodies in participants with idiopathic nephrotic syndrome.

Conditions

• Nephrotic Syndrome，Idiopathic

Interventions

DRUG

Obinutuzumab

After induction of remission is achieved, premedication with 1000 mg of paracetamol per os and intravenous infusion of 10 mg of Chlorphenamine and 80 mg of methylprednisolone will be performed on a case to case basis The, 1000 mg of obinutuzumab diluted in 250 mL of normal saline solution will be infused at an initial rate of 50 mg/hour. After every 30 minutes, provided no adverse reaction will occur, the infusion rate will be increased by 50 mg/hour up to a maximum rate of 400 mg/hour. Vital signs will be monitored prior to the infusion, every 15 minutes during the infusion, after infusion completion and then hourly up to infusion end. Participants will be monitored for four hours after completion of drug administration and will be discharged. Then, 1000 mg of obinutuzumab diluted in 250 mL of normal saline solution will be again infused at two and four weeks after the first infusion.

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research

  lead OTHER

Principal Investigators

• Giuseppe L Remuzzi, M.D. · Istituto Di Ricerche Farmacologiche Mario Negri

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-02-28

Primary Completion

2029-03-31

Completion

2029-03-31

Countries

• Italy

Study Locations