INDIGO: Obexelimab's B-Cell Inhibition Reduces IgG4 Flare Risk

Weekly subcutaneous obexelimab significantly reduced the risk of disease flare requiring rescue therapy and decreased cumulative glucocorticoid exposure compared with placebo in patients with active IgG4-related disease (IgG4-RD), according to results from the phase 3 INDIGO trial published June 2, 2026 in the New England Journal of Medicine and presented at the European Alliance of Associations for Rheumatology (EULAR), held June 3-6 in London, United Kingdom.¹

Emanuel Della-Torre, MD, PhD, Assistant Professor of Rheumatology at Università Vita-Salute San Raffaele and Senior Consultant in the Unit of Immunology, Rheumatology, Allergy, and Rare Diseases at IRCCS San Raffaele Scientific Institute, Milan, Italy, presented the data at the meeting and sat down with RheumatologyLive to discuss it in further detail.

INDIGO enrolled 194 adults with active IgG4-RD meeting ACR–EULAR classification criteria, randomized 1:1 to obexelimab 250 mg subcutaneously once weekly or placebo for 52 weeks (n = 97 each). All patients received standardized glucocorticoid induction therapy during screening, tapering to discontinuation by week 8; concomitant immunosuppressants were not permitted. Most patients had recurrent disease (66.5%) and multiorgan involvement (93.3% with ≥2 organs affected). Mean age was 59.1 (standard deviation [SD], 12.7) years, and 66.5% were male, consistent with the known epidemiology of IgG4-RD. The most commonly affected organs were the salivary glands (64.9%), lacrimal glands (53.1%), pancreas (46.9%), and lymph nodes (44.8%).¹

For the primary endpoint, time to first adjudicated IgG4-RD flare requiring rescue therapy was significantly longer with obexelimab than placebo (hazard ratio [HR], 0.44; 95% CI, 0.28–0.71; P <.001). Flares occurred in 26 patients (26.8%) in the obexelimab group versus 53 (54.6%) in the placebo group, with Kaplan–Meier curve separation appearing at approximately month 3, following completion of the glucocorticoid taper.¹

Obexelimab met all 4 key secondary endpoints in prespecified hierarchical order. Time to first investigator-determined flare was also significantly longer with obexelimab (HR, 0.41; 95% CI, 0.26–0.66; P <.001). The adjusted annualized rate of adjudicated flares requiring rescue therapy was 0.34 per year with obexelimab versus 0.70 per year with placebo (adjusted rate ratio, 0.48; 95% CI, 0.32–0.74; P <.001). Complete remission at week 52 — defined as absence of adjudicated flare, no treatment for flare, and either a Responder Index score of 0 or absence of active disease by investigator assessment — was achieved by 37.1% of obexelimab patients versus 19.6% of placebo patients (risk difference, 17.7 percentage points; 95% CI, 5.4–30.0; P = .005). Cumulative glucocorticoid rescue therapy dose through week 52 was substantially lower with obexelimab than placebo (least-squares mean: 329.5 mg vs 929.8 mg; least-squares mean difference, −600.3; 95% CI, −1011.1 to −189.5; P = .004). Glucocorticoid toxicity, measured by the Cumulative Worsening Score of the Glucocorticoid Toxicity Index, was also lower with obexelimab at week 52 (least-squares mean score: 28.2 vs 39.6; difference, 11.4 points; 95% CI, 1.7–21.1).¹

Overall adverse event incidence was similar between arms. Events occurring at least 4 percentage points more frequently with obexelimab included arthralgias (19.6% vs 11.3%), nasopharyngitis (18.6% vs 14.4%), hypersensitivity (16.5% vs 11.3%), diarrhea (11.3% vs 6.2%), pyrexia (7.2% vs 3.1%), and urticaria (6.2% vs 1.0%). Serious adverse events were lower with obexelimab than placebo (10.3% vs 18.6%), and grade 3 or higher adverse events were also less frequent (11.3% vs 23.7%). Cancers were reported in 3 obexelimab patients (3.1%) and none in the placebo group. One death occurred in the placebo group due to a cardiovascular event unrelated to treatment; no deaths occurred in the obexelimab group. The incidence of serious infections was similar between arms.1 Pharmacodynamically, mean CD20+ B-cell counts declined but remained above the lower limit of normal during obexelimab treatment, consistent with B-cell inhibition rather than depletion; serum IgG4 levels, which declined in both arms during glucocorticoid induction, were sustained with obexelimab but rose again in the placebo arm through week 52.¹

"The INDIGO trial shifts the paradigm of treating B-cell–mediated diseases — not with [just] B-cell depletion anymore, but also with B-cell inhibitory strategies," Della-Torre said. "…This is good for physicians because we can broaden our therapeutic choices, and for patients who might have the possibility to choose the better treatment approach for them."

Della-Torre highlighted the significance of the glucocorticoid-sparing findings and the trial's incorporation of serial whole-body imaging at week 52 to detect subclinical flares, which he noted more closely mirrors real-world clinical practice than prior trials. An open-label extension providing up to 3 years of additional follow-up is ongoing and will assess long-term efficacy, safety, immunoglobulin levels, and B-cell recovery after treatment cessation.¹

Della-Torre’s disclosures include Amgen, Zenas BioPharma, and Sanofi.

References

1. Della-Torre E, Baker MC, Zhang W, et al. Obexelimab for the treatment of IgG4-related disease. N Engl J Med. 2026. doi:10.1056/NEJMoa2601337

2. Stone JH, Khosroshahi A, Zhang W, et al. Inebilizumab for treatment of IgG4-related disease. N Engl J Med. 2025;392:1168–1177.