Novel Biologic Performs Well in IgG4-Related Disease

LONDON — An investigational monoclonal antibody drug for immunoglobulin (Ig)G4-related disease called obexelimab substantially outperformed placebo in the phase III INDIGO trial, researchers reported, positioning it to take on the only drug now specifically approved for the condition.

Time to first disease flare after starting therapy was more than halved with obexelimab, and twice as many patients obtained complete remission in the yearlong study, according to John Stone, MD, MPH, of Mass General Brigham in Boston, and colleagues.

Obexelimab also appeared to be reasonably well tolerated, with joint pain and diarrhea the most common adverse effects, the group reported in the New England Journal of Medicine. The study is also slated for presentation at the European Alliance of Associations for Rheumatology (EULAR) annual meeting, which starts this week.

Inebilizumab (Uplizna) was approved to treat IgG4-related disease in April 2025, making it the first and only drug with this specific indication. Corticosteroids have traditionally been the mainstay of therapy and are reasonably effective, but IgG4-related disease is lifelong and steroids’ side effects with chronic use often become intolerable after a few years.

The condition has its roots in overactive B cells, and the potent B-cell-depleting drug rituximab (Rituxan) is frequently prescribed off-label, but the evidence to support it has been less than rigorous. Inebilizumab also eliminates B cells but in a different way: it binds the CD19 antigen rather than rituximab’s CD20 target. This, it’s believed, allows inebilizumab to deplete the autoantibody-producing B cells without completely disrupting normal infection-fighting cells. Besides IgG4-related disease, the product is also approved for two autoimmune neurologic disorders: neuromyelitis optica and myasthenia gravis.

With obexelimab, developer Zenas BioPharma hopes to do that mechanism one better. It’s bifunctional, targeting not only CD19 but also the FcγRIIB protein on B cells; the latter is an inhibitory receptor that helps stave off immune overactivation. This “results in broad inhibition of B-cell receptor-dependent and B-cell receptor-independent activity,” Stone’s group explained. (Stone also led the pivotal trial that gained inebilizumab’s FDA nod for IgG4-related disease.)

In an accompanying editorial to the INDIGO study, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin in Germany, agreed that this strategy appears more likely to succeed than those that just obliterate B cells indiscriminately with the hope that they will be less pathogenic when they eventually reconstitute. The trial shows that “in at least some cases, the critical therapeutic objective may be selective silencing of pathogenic B-cell function rather than elimination of the lineage itself,” he wrote.

“Obexelimab provides proof,” he added, “that mimicking natural inhibition of B-cell activation and function is a therapeutic option. Depletion is no longer the only credible B-cell therapeutic paradigm.”

For the INDIGO trial, Stone and colleagues enrolled 194 patients assigned in equal numbers to obexelimab or placebo, given by weekly injection. Steroids were to be tapered to zero by week 8, but could be reintroduced if needed to control flares.

Mean patient age was 59, and (unlike the case with most autoimmune diseases) two-thirds were men. About half came from Asia and the rest were divided between North America and Europe. Two-thirds had recurrent flares — a very common feature of IgG4-related disease — while the other third were newly diagnosed. Mean disease duration was 2.8 years. More than 90% had multiple organ involvement, with five or more organs hit in 33%. Salivary and lacrimal glands were most commonly affected.

Disease flares during the 1 year of treatment were the trial’s primary outcome. These occurred in 27% of the obexelimab group versus 55% of those assigned to placebo, for a hazard ratio of 0.44 (95% CI 0.28-0.71). Similarly, the number of flares that required “rescue” steroids was halved with the biologic agent.

Complete remissions were observed for 37.1% taking obexelimab as compared with 19.6% in the placebo group (P=0.005). Mean aggregate steroid doses were far lower (330 mg) with obexelimab than with placebo (930 mg), suggesting that flares were not only more numerous with placebo but also more severe.

Biomarkers were also tracked in the study, including B cell counts and serum IgG4 levels. Both were reduced more with obexelimab, although there was a clear placebo effect, with the control group also showing (smaller) reductions at least initially. Importantly, B cell counts were not reduced to zero with the active drug but remained within the normal reference range, albeit near the lower limit of 74 per μL. IgG4 titers fell by roughly 20% in the first 4 weeks with obexelimab and then remained stable for the rest of the study.

Arthralgia and diarrhea were the adverse events that were more common with the active drug versus placebo, and overall events were also more common with obexelimab. But rates of serious adverse events favored the drug (10.3% vs 18.6%), primarily due to the superior flare control.

Zenas filed a marketing application for obexelimab in IgG4-related disease with the FDA last week. The company is also pursuing an indication for lupus, another B-cell-driven disease, with a phase II study now underway.

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