MITIGATE Trial Shows Uplizna Significantly Lowers Flare Risk, Glucocorticoid Dependence in IgG4-Related Disease

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Findings from the Phase III MITIGATE trial (NCT04540497) show the efficacy of Uplizna (inebilizumab) in lowering the risk of flares and reducing glucocorticoid dependence with higher rates of treatment- and glucocorticoid-free remission in patients with immunoglobulin G4-related disease (IgG4-RD).^1,2 Uplizna is a humanized, afucosylated IgG1 kappa monoclonal antibody that was designed to target CD19 to induce rapid, deep, and durable B-cell depletion. The medication is currently indicated to treat neuromyelitis optica spectrum disorder in adults who are anti-aquaporin-4 antibody positive. IgG4-RD is a chronic, systemic, immune-mediated, fibroinflammatory condition that can potentially impact multiple organs.

“B-cell–targeted treatments offer potential benefits in the treatment of IgG4-related disease, but supporting data are derived exclusively from case reports and open-label studies. In an open-label study involving 30 patients, rituximab, a CD20-targeted, B-cell–depleting agent, appeared to induce remission, but data from randomized, controlled trials of rituximab for the treatment of persons with IgG4-related disease are lacking,” the study authors wrote. “CD19 expression appears earlier than CD20 expression in B-cell development and persists later, notably on plasmablasts and some plasma cells. Therefore, therapies targeting CD19 may be effective in the treatment of IgG4-related disease and may offer advantages over anti-CD20 strategies by means of targeting broader ranges of B cells that drive IgG4-related disease.”¹

Trial Design

The randomized, double-blind, placebo-controlled, parallel-group, multicenter MITIGATE trial compared the efficacy and safety of Uplizna vs. placebo in lowering the risk of flares in adult patients with IgG4-RD. Investigators enrolled 135 patients with IgG4-RD who met the vast eligibility criteria, which included multi-organ disease history and active disease that was treated by glucocorticoids at the time of screening. This allowed for a patient population with a risk of flares to better assess the primary endpoint of time to first treated and adjudicated IgG4-RD flare, according to the investigators.

Patients enrolled in the trial were screened for up to 28 days, at which point they were randomly assigned in a 1:1 ratio to receive either 300 mg of intravenous Uplizna (n = 68) or placebo (n = 67) on days one and 15, and week 26 after premedication, and then followed for the subsequent 52-week randomized control period.

The trial’s key secondary endpoints included annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission. An optional three-year open-label treatment period and a safety follow-up period following discontinuation of Uplizna will run for up to two years as part of the trial. Results show that patients administered Uplizna experienced a reduction in flare risk, with 10% having at least one flare compared to 60% in the placebo cohort (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001).

The annualized flare rate was also lower among patients administered Uplizna compared to the placebo cohort (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). Further, a greater number of patients in the Uplizna cohort had flare-free and treatment-free complete remission compared to placebo (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001), as well as flare-free, glucocorticoid-free complete remission compared to placebo (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001).

In terms of safety, rates of adverse events (AEs) were similar among both cohorts; however, more AEs of grade 3 or higher, serious AEs, AEs of special interest, and AEs causing treatment discontinuation occurred in the Uplizna cohort. Serious AEs were reported by 18% of patients in the Uplizna cohort compared to 9% of patients in the placebo cohort.

“The MITIGATE trial showed the efficacy of CD19-targeted B-cell depletion by inebilizumab for the treatment of IgG4-related disease,” the study authors concluded. “Inebilizumab reduced the risk of disease flares and the annualized flare rate relative to placebo over the 52-week treatment period. More participants who received inebilizumab had treatment-free and glucocorticoid-free complete remission than did participants who received placebo. Participants who received inebilizumab required lower cumulative glucocorticoid exposure to induce remission and maintain disease control during the treatment period than participants who received placebo.”¹

References

1. Stone J., et al. Inebilizumab for Treatment of IgG4-Related Disease. N Engl J Med 2025;392:1168-1177. DOI: 10.1056/NEJMoa2409712. Vol. 392 No. 12.

2. A Study of Inebilizumab Efficacy and Safety in IgG4- Related Disease. ClinicalTrials.gov. Updated November 5, 2024. Accessed March 28, 2025. https://clinicaltrials.gov/study/NCT04540497