Efficacy and Safety of Obexelimab to Treat IgG4-Related Disease: Protocol for a Global, Randomized, Placebo-Controlled Trial.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a chronic, multiorgan fibroinflammatory condition characterized by recurring flares that can lead to progressive organ damage and failure, impaired quality of life, and death. Glucocorticoids (GCs) remain the primary therapy despite their significant toxicity. Obexelimab is a humanized, bifunctional, monoclonal antibody designed to inhibit B cells by co-engaging CD19 and FcγRIIb (CD32b), mimicking natural inhibitory signaling triggered by antigen-antibody complexes. Following promising phase 2 results that demonstrated clinical improvement in 93% of patients with IgG4-RD, the phase 3 INDIGO trial was initiated. METHODS: INDIGO is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of obexelimab in patients with IgG4-RD. The trial has enrolled adult patients ≥ 18 years old with active IgG4-RD meeting the 2019 ACR/EULAR classification criteria (score ≥ 20). Following standardized GC induction, patients are randomized 1:1 to weekly subcutaneous obexelimab 250 mg or placebo for 52 weeks. An independent adjudication committee (AC) ensures consistent application of IgG4-RD classification and organ-specific flare criteria developed for the trial. PLANNED OUTCOMES: The primary endpoint is time to first IgG4-RD flare requiring initiation of rescue therapy as determined by both the investigator and AC. Key secondary endpoints are time to first investigator-determined flare requiring rescue therapy, number of investigator- and AC-determined flares requiring rescue therapy, proportion of patients achieving complete remission, and cumulative dose of GC rescue therapy for active IgG4-RD through Week 52. CONCLUSION: The INDIGO trial achieved its global enrollment goal with 194 patients, making it the largest phase 3 trial in IgG4-RD to date and providing 90% power to detect a clinically meaningful reduction in flare risk. This trial will provide critical evidence on B-cell inhibition as a treatment strategy for IgG4-RD and assess obexelimab as a potential steroid-sparing option to address significant unmet needs of this patient population. TRIAL REGISTRATION: NCT05662241.