An exciting Phase 3 trial has confirmed that obexelimab significantly reduces the risk of disease flare in IgG4-related disease (IgG4-RD) while also delivering measurable reductions in steroid-toxicity.^[1] This condition was only recognized as a single disease entity in 2003, for which patients have relied heavily on steroids. The INDIGO trial results represent a turning point.

The INDIGO trial: what was studied and why it matters

Led by senior authors Dr John H. Stone (Professor of Medicine at Harvard Medical School, and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital) and Dr Emma L. Culver (University of Oxford), alongside first authors Dr Emanuel Della Torre (IRCCS San Raffaele, Milan) and Dr Matthew C. Baker (Stanford University), INDIGO enrolled 194 patients with active IgG4-RD across 114 sites in 19 countries. Investigators from China, Japan, the United States, Europe, and Latin America contributed to a dataset that reflects the global reach of this disease and the breadth of international scientific collaboration behind obexelimab's development.

Patients were randomized 1:1 to weekly subcutaneous obexelimab 250 mg or placebo. All participants underwent a standardized steroid taper to discontinuation by week 8. No concomitant immunosuppressants were permitted, making disease flare a clean primary signal.

The results

Obexelimab reduced the risk of adjudicated disease flare by 56% compared with placebo (hazard ratio 0.44; 95% CI, 0.28 to 0.71; P=0.0005). Flares occurred in just over a quarter of obexelimab-treated patients (26.8%) compared with more than half of those receiving placebo (54.6%). Separation of the Kaplan-Meier curves was evident by month 3 and widened throughout the 52-week treatment period. All four key secondary endpoints were met, including complete remission at week 52 and significantly lower cumulative steroid rescue dosing.

The safety profile was favorable. Serious adverse events occurred in 10.3% of obexelimab-treated patients compared with 18.6% in the placebo group, and no deaths occurred in the obexelimab arm.

Measuring what matters: the GTI in INDIGO

What distinguishes INDIGO from other trials in this space is the inclusion of the Steritas Glucocorticoid Toxicity Index (GTI) as a secondary endpoint. Steroid-toxicity is the central clinical burden for patients with IgG4-RD, and the GTI measures it directly across nine physiological domains.

Obexelimab was associated with an 11.4-point reduction in the GTI Cumulative Worsening Score at Week 52, exceeding the minimum clinically important difference of 10 points,^[3] with improvements across 6 of 8 individual domains. Steroid dose reduction followed, but that is the tail, not the dog: tracking how much steroid a patient receives cannot quantify the toxic burden those steroids impose.

A distinct mechanism with long-term appeal

Obexelimab inhibits B cells rather than depleting them by co-engaging CD19 and FcγRIIb. Where other agents cause sustained B-cell depletion with associated risks of infection, impaired vaccine response, and hypogammaglobulinaemia, obexelimab produces a partial and reversible reduction in circulating B cells. This mechanistic distinction becomes particularly relevant for a relapsing, chronic disease likely to require long-term maintenance therapy.^[3]

The subcutaneous weekly formulation, suitable for self-administration at home, adds further practical appeal for patients managing this condition over years rather than months.

Context: a field that has just gained its first approved therapy

The INDIGO results arrive at a significant moment. In April 2025, the FDA approved inebilizumab^[4] as the first treatment for IgG4-RD, marking the end of a long era in which steroids were the main option. That approval validates the target and the field. INDIGO now establishes that a second, mechanistically distinct therapy is a new option that has prospectively measured steroid-toxicity reduction as part of its evidence package.

For clinical development teams, the contrast is instructive. The MITIGATE trial supporting inebilizumab's approval reported steroid use but did not include a validated steroid-toxicity measure. INDIGO did. As regulatory and payer expectations around steroid-toxicity evidence continue to evolve, that distinction is likely to carry increasing weight in label claim and market access conversations.

What comes next

The regulatory submission for obexelimab is anticipated and an open-label extension of INDIGO is ongoing, with three-year follow-up data expected to further characterize long-term efficacy, safety, and the B-cell recovery profile after treatment cessation.

IgG4-RD has moved from a condition without a name to one with multiple targeted therapies in the space of just over two decades. The INDIGO data suggest the next chapter for patients will be defined not only by fewer flares, but by welcome and meaningful reduction in steroid-toxicity.

References

1. Della-Torre E, Baker MC, Zhang W, Perugino CA, Katz G, Tanaka Y, Khosroshahi A, Kleger A, Schleinitz N, Martinez-Valle F, Schulze-Koops H, Nakayamada S, Rebours V, Okazaki K, Dong L, Carruthers M, Chen LYC, Frulloni L, Meysami A, Takahashi H, Kawano M, Liu Y, Saeki T, Ebbo M, Alexander T, González García A, Karadag O, Maślińska M, Quinn SM, Poma A, Wells A, Greene TJ, Stone JH, Culver EL, for the INDIGO Trial Investigators. Obexelimab for the Treatment of IgG4-Related Disease. N. Engl. J.Med. 2026. https://doi.org/10.1056/NEJMoa2601337 
2. Stone J H, McDowell P J, Jayne D R W, et al. The glucocorticoid toxicity index: Measuring change in glucocorticoid toxicity over time. Semin Arthritis Rheum 2022;55:152010.
3. Della Torre E, Baker MC, Zhang W, et al. Obexelimab for the treatment of IgG4-related disease. N Engl J Med, 2025. NCT05662241.

4. Stone J H, Khosroshahi A, Zhang W, et al. Inebilizumab for Treatment of IgG4-Related Disease. N Engl J Med 2025;392:1168-77.