Obexelimab Lowers Flare Risk in IgG4-Related Disease

Key Takeaways

• Weekly obexelimab was associated with a longer time to first flare requiring rescue therapy and a lower observed flare risk than placebo.
• By week 52, complete remission was more common and cumulative rescue glucocorticoid use was lower with obexelimab.
• Arthralgia, hypersensitivity, and diarrhea were among the most frequent adverse events, and serious adverse events were less common with obexelimab.

In active IgG4-related disease, the New England Journal of Medicine phase 3 trial found that weekly obexelimab prolonged time to first flare requiring rescue therapy versus placebo, with a hazard ratio of 0.44. The randomized comparison assigned patients with active disease to weekly obexelimab or weekly placebo, with glucocorticoids tapered on a standardized schedule to discontinuation by week 8 in both groups. Over 52 weeks after steroid withdrawal, obexelimab was associated with fewer flares requiring rescue therapy and lower rescue glucocorticoid exposure.

The phase 3, double-blind, randomized, placebo-controlled trial enrolled patients with active IgG4-related disease, where relapse after glucocorticoid discontinuation is common. From January 2023 through November 2024, 194 patients were randomized, with 97 assigned to each group for the 52-week comparison. Patients received subcutaneous obexelimab 250 mg once weekly for 52 weeks or placebo once weekly for 52 weeks. Obexelimab was described as a bifunctional monoclonal antibody that coengages CD19 and FcγRIIb without depleting B cells, and glucocorticoids were stopped at week 8 in both groups. The primary endpoint was time to first IgG4-related disease flare requiring rescue therapy, determined by both the investigator and an independent adjudication committee.

Flares requiring rescue therapy occurred in 26 patients (26.8%) with obexelimab and 53 patients (54.6%) with placebo. At week 52, complete remission was 37.1% with obexelimab and 19.6% with placebo, with P=0.005. Cumulative glucocorticoid rescue therapy through week 52 was 329.5 mg with obexelimab and 929.8 mg with placebo, with P=0.004. These week-52 findings were consistent across flare control, remission, and rescue glucocorticoid exposure.

Adverse events included arthralgias in 19.6% with obexelimab and 11.3% with placebo. Hypersensitivity occurred in 16.5% and 11.3%, respectively, and diarrhea in 11.3% and 6.2%. Serious adverse events occurred in 10.3% of the obexelimab group and 18.6% of the placebo group. Over 52 weeks of blinded follow-up, obexelimab was associated with a lower risk of disease flare requiring rescue therapy and less rescue glucocorticoid use.