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LONDON — For patients with active immunoglobulin (Ig)G4-related disease (IgG4-RD), weekly subcutaneous injections of the novel B-cell inhibitor obexelimab successfully lowered the risk for disease flare-ups and significantly cut down the need for toxic steroid treatments, according to results from the phase 3 INDIGO trial.

The findings, presented at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting and published in The New England Journal of Medicine, signal a potential shift in how clinicians manage this chronic, relapsing condition.

“The most relevant unmet need in our clinical management stands in the chronic and relapsing nature of IgG4-related disease,” explained first author Emanuel Della Torre, MD, PhD, of the IRCCS San Raffaele Scientific Institute in Milan, Italy, during his presentation. “IgG4-RD keeps on coming back, flares, and it flares despite the temporary efficacy of the only two available drugs that we have currently, which are glucocorticoids and B-cell depletion.”

Glucocorticoids carry severe side effects, while traditional intravenous B cell-depleting agents, such as rituximab or the recently approved inebilizumab, can trigger prolonged immunosuppression, hypogammaglobulinemia, and impaired vaccine responses, alongside the logistical burden of clinic-based infusions.

Obexelimab is designed to quiet B cells without wiping them out, and because it can be self-administered at home, it offers a safer, more convenient long-term option for managing this chronic condition, Della Torre said.

A Quieting Rather Than Depleting Approach

Obexelimab offers a fundamentally different mechanistic approach. It is a humanized, bifunctional monoclonal antibody that binds CD19 on one arm and the inhibitory receptor FcγRIIB on the other.

This co-engagement mimics natural inhibitory signaling, effectively quieting overactive B cells, halting their proliferation, and curbing antibody production without causing cellular destruction or widespread cytotoxicity.

“The INDIGO trial demonstrates the efficacy, for the first time, of subcutaneous [inhibitory] engagement in IgG4-related disease,” Della Torre said. “And [it] provides evidence for a potential paradigm shift, not only to treat IgG4-related disease, but possibly other B cell-mediated diseases from B-cell depletion to B-cell inhibition.”

Because the drug acts as an inhibitor rather than a depleter, circulating B-cell counts decrease but remain safely above the lower limit of normal during active treatment, allowing for a rapid immunologic recovery once the therapy is stopped.

“We can expect fewer infections and a higher response to vaccination,” Tomás Abrantes da Fonseca, MD, an assistant professor of internal medicine at the University of Porto and a clinician at the Santo António Hospital in Porto, Portugal, who was not involved in the study, told Medscape Medical News.

Robust Flare Reduction and Steroid Sparing

The INDIGO trial is the largest randomized controlled trial ever conducted in IgG4-RD, spanning 114 sites across 15 countries. Investigators randomized 194 adults with active disease in a 1:1 ratio to receive either weekly subcutaneous injections of obexelimab 250 mg or a matching placebo for 52 weeks.

To isolate the therapeutic impact of the study drug, all patients underwent a standardized glucocorticoid taper, completely discontinuing their baseline steroids by week 8. Thereafter, steroids were used only as emergency rescue therapy for flares.

The main goal of the study was to determine how long patients could go before experiencing their first disease flare-up requiring emergency steroid treatment.

Obexelimab was significantly more effective than placebo. Only 26.8% of patients on obexelimab had a disease flare compared to 54.6% of patients on the placebo. More than twice as many patients on obexelimab achieved complete remission by week 52 compared to the placebo group (37.1% vs 19.6%).

Because they had fewer flares, patients taking obexelimab needed far less rescue steroid medication over the year, with an average of 329.5 mg compared to 929.8 mg in the placebo group. This also meant they suffered from fewer steroid-related side effects.

The safety data revealed no unexpected or systemic safety signals. The most common side effects of obexelimab included joint pain, common colds, allergic reactions, and diarrhea. Severe adverse events were less frequent in the obexelimab group than in the placebo group (10.3% vs 18.6%), likely reflecting the protective effect of avoiding high-dose rescue steroids.

“With this new drug, we could spare patients from a lot of side effects of steroids,” Abrantes da Fonseca said.

In Clinical Practice

Session moderator and a coinvestigator on the INDIGO trial, Tobias Alexander, MD, head of the outpatient clinic and a specialist in internal medicine and rheumatology at the University of Berlin, Berlin, Germany, questioned how clinicians should choose among obexelimab, existing standard therapies such as rituximab, and the newly approved inebilizumab.

Della Torre recommended viewing the options as cooperative rather than competitive. “At this time, we can only celebrate the possibility of having a new drug in our weaponry for patients with IgG4-related disease,” he said. “I see the two of them as an integrative, complementary approach to individualized and personalized treatment of our patients.” However, he said that gathering long-term, real-world registry data will be important to definitively map out clinical sequencing and treatment algorithms.

When asked if obexelimab could successfully manage the profound atopic and allergic manifestations that frequently complicate IgG4-RD, Della Torre confirmed that co-administration with other targeted therapies is feasible. In his clinical experience, patients with severe, unmitigated atopic features that fail traditional B-cell depletion can be successfully managed by combining therapies.

Another audience member raised questions regarding structural complications, such as esophageal varices resulting from peripancreatic inflammation or retroperitoneal fibrosis. Della Torre said that the therapeutic outcome depends entirely on how early the drug is initiated. If severe, irreversible scarring and advanced mechanical tissue damage have already set in, even highly effective targeted therapies will show limited structural reversibility. “But in general, they meliorate if you treat them early,” he said.

The trial was funded by Zenas BioPharma. Della Torre reported serving as a consultant to Amgen, which manufacturers inebilizumab, and Alexander reported serving as a consultant to Zenas and Amgen. Both also reported having financial relationships with other pharmaceutical companies. Some of the other study coauthors also reported financial relationships with Zenas, Amgen, and/or other pharmaceutical companies. Several coauthors are employees of Zenas. Abrantes da Fonseca had no conflicts of interest.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.