Obinutuzumab Demonstrates Steroid-Sparing Effects and Consistent Benefit in Patients with Lupus Nephritis When Using Multiple Primary Endpoint Definitions: A Secondary Analysis of Phase III Trial Results

Objectives The Phase III REGENCY study ( NCT04221477 ) demonstrated superiority of obinutuzumab (OBI) over placebo (PBO) in achieving complete renal response (CRR) at Week 76 when added to standard therapy (ST) in patients with active lupus nephritis (LN). There is no standardized CRR definition. These post hoc analyses evaluated OBI+ST vs PBO+ST across different renal response definitions from recent studies, the efficacy of OBI+ST vs PBO+ST on each component of the REGENCY CRR definition and the oral prednisone intake over time. Methods REGENCY, BLISS-LN and AURORA-1 renal response endpoint definitions were used for analysis of the REGENCY dataset at Week 76. The Cochran-Mantel-Haenszel test, stratified by region and race, was used for treatment comparisons. All patients received oral prednisone as part of ST, tapered to 5 mg/day by Week 24. Results At Week 76, 46.4% of patients in the OBI+ST (n=135) and 33.1% in the PBO+ST arm (n=136) achieved CRR (adjusted difference: 13.4%, 95% CI, 2.0 to 24.8%; P=0.0232). The proportions of OBI+ST vs PBO+ST achieving modified BLISS-LN primary efficacy renal response were 51.8% and 39.7% (adjusted difference: 12.1%, 95% CI, 0.5 to 23.8%; P=0.0432); modified BLISS-LN CRR were 48.7% and 33.1% (adjusted difference: 15.7%, 95% CI, 4.3 to 27.2%; P=0.0084); modified AURORA-1 CRR were 48.7% and 33.8% (adjusted difference: 15.0%, 95% CI, 3.6 to 26.5%; P=0.0117). A higher number of patients achieved the individual components of CRR at Week 76 in the OBI vs PBO arm for all 3 components (UPCR <0.5 g/g: 47.4% vs 36.0%; eGFR ≥85% of baseline: 83.7% vs 75.7%; no occurrence of intercurrent events: 88.9% vs 75.0% for OBI+ST and PBO+ST, respectively). In both arms, the main reasons for not attaining CRR were UPCR ≥0.5 or eGFR <85% of baseline (54.8% OBI+ST vs 65.4% PBO+ST). The mean daily prednisone intake was consistently lower in patients in the OBI vs PBO arm from Week 24-76 (Figure 1). The proportions of patients achieving a daily prednisone (or equivalent) dose of ≤5 mg/day were consistently higher in the OBI vs PBO arm from Week 36, reaching a 10 percentage point absolute difference from Week 64-76 (78.5% vs 68.4% for OBI+ST vs PBO+ST; adjusted difference (95% CI): 10.1% (−0.5 to 20.4), P=0.0589). Figure 1. Mean Daily Dose of Prednisone for Patients Treated with Obinutuzumab or Placebo Plus Standard Therapy Conclusion In a post hoc analysis of the REGENCY trial outcomes, OBI showed consistent benefit across patient subgroups, utilizing multiple alternative definitions of CRR and exhibited steroid-sparing properties.