05 What defines success in lupus/lupus nephritis in 2026?

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Success is defined differently along the drug development path. In the earliest phase of drug development, the goals are to evaluate pharmacokinetics and confirm pharmacodynamics. Above all is safety. It is challenging for a small and short Phase I systemic lupus erythematosus (SLE) study to demonstrate efficacy. As programmes advance to Phases II and III, priorities shift to efficacy with a major focus on safety remaining. Success is met in the pivotal Phase III studies if the primary endpoint is attained along with a tolerable safety profile. However, the endpoints acceptable to regulators for drug approval, such as SLE Responder Index (SRI) or British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA), may not be ones that resonate with clinicians. Given the clinical heterogeneity of SLE, clinicians desire guidance on a drug’s performance in specific domains, such as the mucocutaneous or musculoskeletal domains. 1 While the SLE disease activity index (DAI) and BILAG incorporate such domains, attempts to enhance interpretation of a drug’s impact on arthritis and rash were made by integrating more granular instruments, such as joint scores and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), into SLE clinical trials.The efforts to translate clinical trial results into information that clinicians find useful continued with both post-hoc and prospective analyses of composite indices, such as Definition of Remission in SLE and Lupus Low Disease Activity State.2 These relatively new metrics define states that are associated with short-, intermediate-, and long-term benefits to patients. In lupus nephritis (LN) trials, it is recognized that the traditional endpoint, composed of proteinuria reduction without significant compromise to kidney function, is flawed. Recent LN trials have incorporated eGFR slope, which reflects a long-term trajectory of one’s kidney function and is accepted as an outcome by regulators for other kidney diseases.3–5 Data collected post-approval in real-world settings have been particularly enlightening. In summary, success is defined by outcomes that satisfy three different factions: regulators, physicians, and patients.Learning Objectives Discuss how success is defined at various stages of drug development.Describe attempts to translate trial results to everyday clinical needs.Analyze efforts to incorporate new metrics into clinical trials.References Furie R, Morand EF, Bruce IN, et al. What does it mean to be a British isles lupus assessment group-based composite lupus assessment responder? Post hoc analysis of two phase III trials. Arthritis Rheumatol. 2021;73(11):2059–68. doi: 10.1002/art.41778.Morand EF, van Vollenhoven R, Furie RA, et al. LLDAS and remission attainment with anifrolumab treatment in patients with systemic lupus erythematosus: results from the TULIP and long-term extension randomised controlled trials. Ann Rheum Dis. 2025;84(5):777–88. doi: 10.1016/j.ard.2025.01.016.Furie RA, Rovin BH, Garg JP, et al. Efficacy and safety of obinutuzumab in active lupus nephritis. N Engl J Med. 2025;392(15):1471–83. doi: 10.1056/NEJMoa2410965.Touma Z, Bruce IN, Furie R, et al. Reduced organ damage accumulation in adult patients with SLE on anifrolumab plus standard of care compared to real-world external controls. Ann Rheum Dis. 2025;84(5):767–76. doi: 10.1016/j.ard.2025.01.025.Rovin BH, Furie R, Teng YKO, et al. A secondary analysis of the belimumab international study in lupus nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int. 2022;101(2):403–13. doi: 10.1016/j.kint.2021.08.027.

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