First-in-class obexelimab offers a new B-cell inhibition strategy for IgG4-related disease

A novel approach to B-cell inhibition could reshape IgG4-related disease management. Learn more from phase 3 data presented at EULAR 2026.

INDIGO (NCT05662241) is a randomized, double-blind, placebo-controlled phase 3 trial investigating obexelimab in adults with active IgG4-related disease (IgG4-RD). Obexelimab is an investigational, humanized monoclonal antibody which inhibits B-cell activity, without depleting them.

In this interview, Dr Emanuel Della Torre (Vita-Salute San Raffaele University, Milan MI, Italy) highlights the unmet needs in the treatment of IgG4-RD, and the mechanism of action of the investigational therapy, obexelimab. Dr Della Torre also explores the aims, methodology and findings from the phase 3 INDIGO study.

Abstract: Obexelimab, a B Cell Inhibitor, in IgG4-Related Disease: Results from the Phase 3 INDIGO Trial. EULAR 2026, June 3– 6, London, UK.

touchIMMUNOLOGY coverage of EULAR 2026

I am Dr Emanuel Della Torre. I am a clinical immunologist by training and a rheumatologist. I’m an Associate Professor of Medicine at Vita Salute San Rafael University in Milan, Italy, where I lead the IgG4-related disease clinic in San Raffaele Hospital, in Milan, Italy.

What are the unmet needs in the treatment of IgG4-RD?

There are many as IgG4-related disease is a protean condition, affecting every organ system in the body and then for each organ system there are specific needs regarding the biology and physiology of each organ.

The first unmet need relates to the nature of IgG4-related disease itself; its chronic, relapsing-remitting course. Even when treatment is successful, the disease returns, sometimes within months and sometimes after years. We are still not able to achieve long-term, complete remission or cure the disease in every patient. Each relapse also carries the risk of additional organ damage beyond that already present at disease onset. Therefore, the primary unmet need is to better control relapses and flares and silence the disease.

The second unmet need concerns the limitations of the available therapies. We currently have only two treatment options, which is itself a major limitation. Neither is able to prevent disease recurrence once treatment is stopped, so patients often relapse.

In addition, both treatments are associated with side effects. Glucocorticoids, the historical first-line therapy, are associated with significant metabolic complications, such as obesity, diabetes, cataracts, osteoporosis, and hypertension.

The other option is B-cell depletion with monoclonal antibodies, particularly rituximab and, more recently, inebilizumab, an anti-CD19 monoclonal antibody recently approved by the FDA and EMA. While these agents are highly effective, they are associated with long-term immunosuppression, including the risk of hypogammaglobulinemia and increased infections. Their prolonged effects also mean they cannot easily be withdrawn if side effects, infections, or other medical interventions arise. Finally, these therapies are administered intravenously, creating additional logistical challenges, such as the need for infusion facilities and potential delays in treatment delivery.

What is the mechanism of action of obexelimab?

Obexelimab is a first-in-class B-cell inhibitor, and it is important to stress the concept of B-cell inhibition rather than B-cell depletion. Unlike B-cell depleting therapies, obexelimab does not kill or completely eliminate B cells. Instead, it inhibits their function through its unique mechanism of action.

Obexelimab is a bifunctional antibody with two binding sites. One binds to CD19, which is expressed on all B lymphocytes, while the other binds to Fc-gamma receptor 2B, the only inhibitory receptor expressed on B cells. By engaging Fc-gamma receptor 2B, obexelimab prevents the full activation of B cells that is normally induced through the B-cell receptor. Through the inhibition of intracellular signalling pathways, it limits the ability of B cells to function as antigen-presenting cells and antibody-producing cells.

To some extent, this may induce apoptotic effects, resulting in a slight and reversible reduction in peripheral B-cell counts, but this is not a depletion. All of this is achieved through weekly injections of the drug, which is an important feature, as treatment can be discontinued if new side effects arise.

What were the aims, design and eligibility criteria of the study?

The INDIGO trial is a phase 3, double-blind, placebo-controlled, multicentre study designed to assess the efficacy of obexelimab in preventing relapse of IgG4-related disease in a large international cohort of patients.

Eligibility required patients to fulfill the ACR-EULAR classification criteria for IgG4-related disease. Both newly diagnosed patients with active disease and patients with an established diagnosis experiencing a new flare were eligible for enrollment.

All enrolled patients had active disease and were initially treated with steroids to control disease activity. By day 1 of the randomized treatment period, patients were required to taper prednisone, or its equivalent, to 20 mg. They were then randomized to receive either obexelimab 250 mg administered subcutaneously once weekly for 52 weeks or placebo administered subcutaneously on the same schedule. By Week 8, all patients were expected to be off steroids.

The primary endpoint was time to first disease flare requiring treatment, assessed through Week 52. Disease flares were defined using organ-specific flare criteria developed by an international expert panel. Importantly, these criteria were designed to detect not only clinically apparent flares but also subclinical and asymptomatic disease activity through serial imaging performed throughout the study, with a key imaging assessment at Week 52.

This is an important feature that differentiates the INDIGO trial from previous studies, as it closely reflects routine clinical practice. In clinical care, patients are re-imaged periodically based on clinical experience, and disease flares are often detected even in asymptomatic individuals. The trial design therefore provided an accurate approach to identifying both symptomatic and asymptomatic flares.

What were the primary and secondary endpoints, and how well were they achieved?

The primary endpoint of the INDIGO study was the time to first IgG4-related disease flare requiring initiation of rescue therapy, as determined by both the investigator and an independent adjudication committee. The role of this independent committee, composed of internationally recognized experts, was to confirm and strengthen the investigators’ assessments, reinforcing the robustness of the primary endpoint.

Secondary endpoints included time to first investigator-determined flare requiring rescue therapy, the number of investigator- and adjudication committee-determined flares requiring rescue therapy, the proportion of patients achieving complete remission at Week 52, and the cumulative dose of glucocorticoids required as rescue treatment through Week 52. Complete remission was defined as no flare, no rescue treatment, an IgG4-related disease Responder Index of 0, and a Visual Activity Scale of 0.

The primary endpoint was achieved, with a significant reduction in both the rate of flares and the time to first flare. The treatment arms began to separate after approximately three months, likely reflecting the withdrawal of steroids and the emerging effect of obexelimab. By Week 52, 73% of patients receiving obexelimab remained flare-free, corresponding to an overall hazard ratio for flare of 0.44. In total, 26 of 97 patients treated with obexelimab experienced a flare within 52 weeks, compared with 53 of 97 patients receiving placebo.

All secondary endpoints were also met. There was a significant reduction in the time to first investigator-determined flare and in the annualized rate of adjudicated flares requiring rescue therapy. In addition, a significantly higher proportion of patients achieved complete remission at Week 52 compared with placebo.

These benefits were accompanied by a significant steroid-sparing effect, as the cumulative dose of rescue glucocorticoids was substantially lower in the obexelimab group than in the placebo group, representing an important clinical achievement. Consequently, glucocorticoid-related toxicity was also significantly higher in the placebo arm.

Mechanistically, these results were associated with a reduction in B-cell activation. Serum IgG4 levels decreased during the initial steroid treatment and remained low throughout the 52 weeks in patients receiving obexelimab, whereas they began to rise again in the placebo arm. Similarly, B-cell counts declined after initial glucocorticoid treatment and remained low, but still above the lower limit of normal, in the obexelimab group, while increasing again in patients receiving placebo.

What was the safety profile of obexelimab?

Overall, the incidence of adverse events in the two arms was very similar. Serious adverse events and grade 3 or higher adverse events were observed less frequently in the obexelimab group compared to placebo. The most commonly reported adverse events were generally also similar between the two groups, including nasopharyngitis, upper respiratory tract infections, arthralgia, insomnia, and lower back pain. Hypersensitivity events were slightly more frequent in the obexelimab group, but these were not grade 3 and did not lead to discontinuation.

What will be the clinical implications of these findings?

These findings shift the paradigm of treating B-cell-mediated diseases from a B-cell-depleting strategy to a B-cell-inhibiting strategy. In addition, these findings provide clinicians with a new treatment approach, broadening the therapeutic armamentarium and fostering a future of more personalized and individualized therapy for our patients.