Obinutuzumab for Systemic Lupus Erythematosus Pure Membranous Nephropathy: a Phase II Trial

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus and conveys important risk of morbidity and mortality in affected patients. Pure class V LN, also referred to as lupus membranous nephropathy, remains difficult to manage despite available therapy. Current immunosuppressive options proposed in the 2024 international recommendations include mycophenolate mofetil, cyclophosphamide, calcineurin inhibitors, rituximab or azathioprine in situations of uncontrolled or nephrotic proteinuria. However, none of these drugs has been validated through prospective multicenter protocol-based trials specifically dedicated to assess their efficacy and safety in pure class V LN. Therefore no therapy holds specific approval for this condition.

Observational data from multiple French centers highlight the heterogeneous therapeutic choices and variable response rates obtained with treatments. Although efficacy appears broadly similar across these strategies, concerns persist regarding infertility, teratogenicity, myelotoxicity and corticosteroid exposure, reinforcing the need for alternatives with improved tolerance. Rituximab is increasingly used to treat pure lupus membranous nephropathy but is less efficient than obinutuzumab in inducing complete renal response in class III or IV lupus nephritis.

Obinutuzumab is a second-generation therapy targeting B cells, developed to enhance activity compared with rituximab. Clinical studies conducted in follicular lymphoma and chronic lymphocytic leukemia demonstrated superior outcomes and supported its approval. In LN, evaluations combining obinutuzumab with standard-of-care therapy in proliferative classes (NOBILITY and REGENCY trials) reported higher complete renal response than placebo with acceptable safety, although events such as infections, serious adverse events, neutropenia and infusion-related reactions were documented. In contrast, a study using rituximab with standard-of-care therapy (LUNAR) did not show improvement in complete renal response.

Based on these findings, this phase 2 study evaluates obinutuzumab monotherapy in adults with pure class V LN. The main endpoint is complete renal response at week 52 after first infusion, defined by urinary protein creatinine ratio \< 0.5 g/g on 24-hour urine collection, eGFR ≥ 85% of baseline, and absence of intercurrent events including treatment failure, need for rescue therapy, high-dose corticosteroids, long-term dialysis, renal transplantation, death or premature withdrawal.

Secondary objectives include: assessment of safety by recording adverse events, serious adverse events and events of interest (neutropenia, infection, infusion-related events, new cancer) from first infusion to week 52; evaluation of renal outcomes documenting no kidney response, partial renal response, complete renal response and renal relapses free of intercurrent event; monitoring of systemic lupus erythematosus activity based on immunologic remission defined by C3 and C4 normalization and anti-dsDNA negativation, as well as renal and extrarenal flares; estimation of participants without corticosteroids at week 52; and evaluation of quality of life at week 52.

The trial uses a single-arm, open, non-comparative A'Hern phase II design (Category 2, Phase 2). This protocol aims to generate prospective data on the activity and safety of obinutuzumab monotherapy in pure class V LN, with precise definitions of renal response, systematic follow-up of adverse events and detailed assessment of systemic and renal outcomes over a 52-week period.

• To assess the safety of obinutuzumab in patients with pure class V lupus nephritis by quantifying adverse events, serious adverse events, and adverse events of special interest between the first obinutuzumab infusion and W52 [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the overall efficacy of obinutuzumab on pure class V lupus nephritis by quantifying the proportion of patient with no-kidney response, partial response (PRR), complete response (CRR) and renal relapses without any intercurrent event [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the efficacy of obinutuzumab on overall SLE activity by quantifying the proportion of patients reaching immunologic remission (normalization C3 and C4 levels and negativation of anti-dsDNA) and the number of renal and extrarenal flares during f [Срок оценки: First obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the efficacy of obinutuzumab on overall SLE activity by quantifying the proportion of patients reaching immunologic remission (normalization C3 and C4 levels and negativation of anti-dsDNA) and the number of renal and extrarenal flares during f [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the efficacy of obinutuzumab on overall SLE activity by quantifying the proportion of patients reaching immunologic remission (normalization C3 and C4 levels and negativation of anti-dsDNA) and the number of renal and extrarenal flares during f [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the efficacy of obinutuzumab on overall SLE activity by quantifying the proportion of patients reaching immunologic remission (normalization C3 and C4 levels and negativation of anti-dsDNA) and the number of renal and extrarenal flares [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the proportion of patients that are free from corticosteroids at W52 with respect to corticosteroids indication (to treat lupus or another disease). [Срок оценки: week 52 (week 48 to week 56) after the first infusion of obinutuzumab.]
• To assess the quality of life of patients at W52 [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the quality of life of patients at W52 [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]
• To assess the quality of life of patients at W52 [Срок оценки: first obinutuzumab infusion to week 52 (week 48 to week 56)]