Background/Purpose: IgG4-related disease (IgG4-RD) is a rare, systemic, fibroinflammatory disease characterized by unpredictable and recurring flares, leading to organ damage and decreased quality of life. The role of B cells in the pathophysiology of IgG4-RD and existing clinical experience suggest that B cell depletion may be an effective therapeutic avenue. Inebilizumab (INEB) is a humanized, glycoengineered, CD19-directed, monoclonal antibody that depletes B cells effectively in a targeted manner. The aim is to evaluate the efficacy and safety of inebilizumab monotherapy for reducing the risk of flare in adult participants with IgG4-RD.

Methods: The MITIGATE trial (NCT04540497), conducted at 80 sites in 22 countries, enrolled adult patients who met the ACR/EULAR Classification Criteria for IgG4-RD with a score ≥20.  Key eligibility criteria included a history of multiorgan disease and active disease at screening. Participants were stratified based on newly diagnosed vs. recurrent disease. Randomization was 1:1 with INEB 300 mg IV or Placebo (PBO) treatment on Day 1, 15, and Week 26 of the 52 week Randomized Controlled Period (RCP). Corticosteroids were normalized to 20 mg/day prednisone at the time of randomization and were tapered to discontinuation at the end of study Week 8. An IgG4-RD flare was defined as new or worsening signs and symptoms of IgG4-RD activity that met one or more organ-specific flare criteria developed for this study. The primary endpoint was time to first adjudication committee (AC)-determined and investigator-treated IgG4-RD flare during the RCP. Key secondary endpoints included annualized flare rate during the RCP and the proportion of participants achieving flare-free, treatment-free complete remission or corticosteroid-free complete remission at Week 52. Safety was evaluated.

Results: 135 subjects were randomized and received at least one dose of INEB (n=68) or PBO (n=67). Baseline demographics and disease characteristics were generally balanced between those receiving INEB and PBO (Table 1). 

The primary endpoint was met, with INEB treatment significantly reducing the risk of IgG4-RD flares compared to PBO during RCP (hazard ratio 0.13; 95% CI: 0.06, 0.28; p< 0.0001) (Figure 1). The statistically significant treatment effect of INEB compared to PBO was seen for all key secondary endpoints (Table 2). 

During the RCP, 66 (97.1%) INEB and 66 (98.5%) PBO participants had ≥1 treatment emergent adverse event (TEAE), the most frequent ( >10%) were COVID-19 (16 [23.5%] INEB, 13 [19.4%] PBO), lymphopenia (11 [16.2%] INEB, 6 [9.0%] PBO), and UTI (8 [11.8%] INEB, 4 [6.0%] PBO). No subjects died; no SAE occurred in >1 subject. AEs of special interest included infusion related reactions in 3 (4.4%) INEB and 5 (7.5%) PBO and serious and/or opportunistic infections in 6 (8.8%) INEB and 2 (3.0%) PBO. In INEB participants, serious infections included COVID-19, appendicitis, and diverticulitis, and opportunistic infections were herpes zoster.

Conclusion: The MITIGATE trial, the first randomized, double-blind, placebo-controlled study ever conducted in IgG4-RD, establishes the safety and efficacy of CD19-targeted B cell depletion with inebilizumab in IgG4-RD.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-3-randomized-double-blind-multicenter-placebo-controlled-study-of-inebilizumab-in-igg4-related-disease-mitigate-primary-efficacy-and-safety-findings/