Inebilizumab MITIGATEs flares in IgG4-RD with pancreatic, hepatobiliary involvement

The post hoc subgroup analysis of the phase III MITIGATE trial shows the benefit of the humanized monoclonal anti-CD19 antibody inebilizumab in adults with IgG4-related disease (IgG4-RD) with pancreas, bile duct, and liver involvement at baseline.

Pancreatic and hepatobiliary disease are common manifestations of IgG4-RD, a rare, immune-mediated, relapsing, fibro-inflammatory disease. [Rheumatol Ther 2023;10:1795-1808; Ann Rheum Dis 2023;82:957-962] “Recurrent, relapsing disease can cause progressive tissue damage and organ function loss,” the researchers noted.

“[In this analysis,] inebilizumab provided treatment benefits in participants with active IgG4-RD in the pancreas, bile duct, and liver, consistent with the overall population,” they said.

MITIGATE comprised adults with an IgG4-RD diagnosis, with ≥2 organs involved, and had an active IgG4-RD flare that warranted glucocorticoid treatment during the screening phase. Participants discontinued all conventional immunosuppressive therapies for IgG4-RD before enrolment, with an appropriate washout phase. They were then randomized 1:1 to IV inebilizumab 300 mg or placebo on days 1 and 15 and week 26. [abstract 5008, AASLD 2025]

The 135 participants (mean age 58.2 years) included in this analysis were stratified by organ involvement. In the inebilizumab arm (n=68; 57.4 percent men, 56 percent Asian), 27, 13, and two had pancreatic, biliary, and hepatic involvement, respectively. The placebo arm (n=67; 73.1 percent men, 37 percent Asian) had similar proportions of participants in the respective subgroups (n=24, 15, and 3).

Overall, ~54 percent had recurrent IgG4-RD manifestations, and the mean disease duration was about 2.5 years. About 40 percent had >4 organs ever affected by IgG4-RD.

In the overall cohort, the incidence of disease flares was lower in the inebilizumab vs placebo arm (10.3 percent vs 59.7 percent; hazard ratio [HR], 0.13; p<0.001).

In the pancreas subgroup, only one inebilizumab recipient experienced a flare vs 17 in the placebo arm. A comparison between arms yielded significant reductions in the risk of flares (3.7 percent vs 70.8 percent; HR, 0.03; p_nominal<0.001) and in annualized flare rate (rate ratio, 0.04; p_nominal=0.0015) in favour of inebilizumab.

There were no flares with inebilizumab in the biliary (0 percent vs 80 percent; HR, 0.00; p_nominal=0.994) and hepatic (0 percent vs 100 percent; HR, 0.00; p_nominal=0.998) subgroups.

Inebilizumab improved flare-free and treatment-free complete remission (odds ratio [OR], 10.84; p<0.001) and reduced mean total glucocorticoid use (prednisone or equivalent; 32.22 vs 1,690.35 mg) in the pancreas subgroup. These treatment effects were similarly seen in the biliary subgroup (OR, 35.75; p<0.001 and 0 vs 1,934.27 mg, respectively).

Safety

In the safety analysis (n=54), the inebilizumab arm had more grade ≥3 treatment-emergent adverse events (TEAEs) than the placebo arm (17.2 percent vs 12 percent). The most common TEAEs with inebilizumab were lymphopenia, COVID-19, and pyrexia (24.1, 20.7, and 13.8 percent, respectively).

Nonetheless, the researchers noted that the safety profile of inebilizumab was favourable across subgroups and aligned with that observed in the overall IgG4-RD cohort, with no new safety signals or cholangitis.

B cells an effective Tx target

“[Furthermore,] inebilizumab induced rapid, significant B-cell reduction within the first 2–4 weeks and a sustained B-cell suppression over the full 52 weeks, suggesting strong long-term efficacy in depleting peripheral B cells and reducing disease biomarkers,” they said.

Of note, the CD20+ B cell count decreased from baseline as early as week 2 and was sustained over time. For the serum IgG4 Levels, the curves began to separate at week 4.

B cells, specifically plasmablasts and plasma cells, play vital roles in the pathophysiology of IgG4-RD and serve as an effective treatment target, the researchers noted. Evidence shows that inebilizumab causes rapid B-cell depletion, including plasmablasts and some plasma cells. [Lancet 2019;394:1352-1363; Mult Scler 2021;28:925-932; Arthritis Res Ther 2016;18:131]

“This analysis of IgG4-RD patients with pancreatic and hepatobiliary involvement in the MITIGATE trial demonstrates the efficacy and safety of CD19-targeted B-cell depletion by inebilizumab,” they concluded.