#248 Effects of obinutuzumab on urinary renal biomarkers in lupus nephritis: a post hoc exploratory analysis of the phase II nobility study

Résumé fourni par la source

Abstract Background and Aims B cells are central to lupus nephritis (LN) pathogenesis. Formation of T- and B-cell complexes and production/deposition of immune complexes within the kidney lead to inflammation and tissue damage in patients with LN. Positive results from the Phase II NOBILITY (NCT02550652) and Phase III REGENCY (NCT04221477) studies demonstrated the efficacy of B-cell depletion with obinutuzumab (OBI), a humanised type II anti-CD20 monoclonal antibody, in LN. Although a standard measure of kidney involvement, urine protein-to-creatinine ratio (UPCR) provides limited information on underlying kidney pathology. Urine biomarkers such as CD163 (monocyte/macrophage marker), CCL2/MCP1 (monocyte chemoattractant), epidermal growth factor (EGF, marker of renal repair and tubule health/function) and kidney injury molecule-1 (KIM1, proximal tubular injury marker) have been shown to correlate with histological activity and treatment response in LN, offering potential insights into disease activity and treatment responses. This exploratory post hoc analysis investigated the impact of OBI on urine biomarker samples from the NOBILITY study. Method Patients with active LN received standard therapy (mycophenolate mofetil and glucocorticoids) plus OBI 1000 mg or standard therapy plus placebo (PBO) on Weeks 0, 2, 24 and 26. The study's primary endpoint was complete renal response (CRR) at Week 52: a composite measure requiring UPCR <0.5, normal renal function (serum creatinine ≤ upper limit of normal) without worsening of baseline serum creatinine by >15% and inactive urinary sediment (<10 red blood cells [RBCs]/HPF without RBC casts). Urine samples were analysed using ELLA immunoassays. Urine biomarker concentrations were normalised to urine creatinine (reported as “pg/mg uCr”) and were analysed using mixed models for repeated measures. Models included baseline biomarker value for each patient, visit, treatment received, baseline UPCR category (≥ vs <3), study randomisation stratification factors and the interaction between treatment and visit or interaction between CRR status and visit, as covariates. An α = 0.2 significance level was used (80% CIs) for these analyses. Results Following treatment with OBI, significantly greater reductions in urine CCL2, KIM1 and sCD163 and increases in urine EGF were observed compared with the PBO group over the course of the treatment (Fig. 1). Rapid and significantly greater decline in urine CCL2 and KIM1 levels were observed as early as Week 12 and Week 24, respectively, in the OBI group compared with the PBO group (Fig. 1A–B). Significantly greater increases in urine EGF levels were observed in the OBI group by Week 24, while levels in the PBO group did not increase (Fig. 1C). Urine sCD163 levels decreased in both groups through Week 24; however, levels in the OBI group continued to decline and were significantly lower than the PBO group by Week 52 (Fig. 1D). In patients achieving CRR at Week 52, compared with non-responders, significantly greater decreases in urine CCL2, KIM1 and sCD163 and increases in urine EGF were observed at Week 12, persisting through Week 76 (Fig. 2). Conclusion Exploratory analyses from the Phase II NOBILITY study showed that OBI may induce early beneficial effects on kidney inflammation and damage markers in LN, as evidenced by reduced urine CCL2, KIM1 and sCD163 and increased urine EGF. Importantly, these urinary changes occurred within 24 weeks of OBI initiation (later for sCD163), preceding improvements in UPCR observed at Week 52 [1]. These findings suggest (i) a mechanistic hypothesis whereby OBI modulates the kidney inflammatory microenvironment to promote repair and protect the parenchyma and long term function, reinforcing its potential as a promising therapy for patients with LN; and (ii) urine biomarkers may offer early insights into treatment responses and warrant further investigation in larger studies for potential use in therapeutic response monitoring.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.