2019: Incidence of Coronavirus Disease 2019 in Participants with IgG4-Related Disease Treated with Inebilizumab in the MITIGATE Study

Background/Purpose: The potential of B-cell-depleting therapies to diminish humoral responses is recognized, but whether this leads to an increased risk of Coronavirus Disease 2019 (COVID-19) remains unknown. Inebilizumab (INEB) is a humanized, glycoengineered, CD19-directed, monoclonal antibody that depletes B cells, including plasmablasts and some plasma cells, effectively in a targeted manner. MITIGATE (NCT04540497) is an international, randomized, blinded, placebo (PBO)-controlled Phase 3 trial that evaluates the safety and efficacy of INEB as treatment for IgG4 related disease (IgG4-RD). This ad hoc analysis examined whether INEB treatment is associated with an increased risk of COVID-19 infection in adult participants with IgG4-RD.

Methods: Primary results of the MITIGATE trial have been previously reported (Stone et al, 2024). Eligible participants were randomized 1:1 to inebilizumab or placebo and were treated on day 1, day 15, and week 26 of the 1-year randomized controlled period (RCP). Ad hoc analyses were performed to assess the risk of COVID-19 infections with INEB treatment, as COVID-related endpoints were not prespecified. First participant was enrolled October 26, 2020, after COVID-19 was initially reported (December 2019) and before the first vaccine received approval (December 2020). To determine the relationship between COVID-19 infections and immune response, the lowest recorded values of IgG, IgM, and IgA were measured and compared among participants with COVID-19 infections. Vaccination status, incidence of COVID-19, and safety were evaluated.

Results: In the trial population, 28.4% (n=19/67) of PBO-treated and 29.4% (n=20/68) of INEB-treated participants had received a COVID-19 vaccination. COVID-19 infection was reported in 13 (19.4%) PBO-treated and in 17 (25.0%) INEB-treated participants. Most infections were in participants < 65 years of age (84.6% PBO, 58.9% INEB). The majority of infections were mild [Grade 1; PBO: 7/13 (53.8%); INEB: 11/17 (64.7%)] or moderate [Grade 2; PBO: 6/13 (46.2%); INEB: 5/17 (29.4%)]. Serious COVID-19 occurred in 0 PBO-treated and 2 INEB-treated participants, both requiring hospitalizations, but were not life-threatening (Table 1). Both of these subjects had been vaccinated for COVID-19 prior to COVID-19 infection. There was no significant association between immunoglobulin reductions and occurrence of serious COVID.

Conclusion: Treatment with INEB was not associated with a higher incidence or severity of COVID-19 compared with placebo. Despite B-cell depletion, infections were mostly mild, and serious infections were infrequent. These findings support the safety of INEB in the context of the COVID-19 pandemic.