Inebilizumab (Uplizna), an anti-CD19 antibody already approved for neuromyelitis optica (NMO), has demonstrated efficacy in treating IgG4-related disease, according to results from a pivotal phase III clinical trial. The study, involving 135 patients, revealed a significant reduction in disease flares among those treated with inebilizumab compared to placebo.
Efficacy Results
The trial, led by John H. Stone, MD, MPH, of Massachusetts General Hospital, showed that only 10% of patients receiving inebilizumab experienced disease flares during a year of follow-up, compared to 60% in the placebo group (P <0.001). Furthermore, 57% of patients on inebilizumab achieved complete flare-free remission without the use of steroids or other medications, whereas only 22% of the placebo group reached the same outcome. These findings were published in the New England Journal of Medicine and presented at the American College of Rheumatology's annual meeting.
Mechanism of Action and B-Cell Depletion
IgG4-related disease is characterized by abnormal B-cell activity. Inebilizumab depletes B cells by binding to the CD19 antigen, a different target than rituximab (Rituxan), which binds to CD20. The study observed profound effects on B-cell counts, with CD20-positive cells disappearing entirely by week 2 and remaining at zero throughout the 52-week study period. Additionally, serum IgG4 levels decreased by approximately 50% from baseline in the inebilizumab group, while remaining relatively stable in the placebo group.
Safety Considerations
While inebilizumab demonstrated significant efficacy, the study also revealed safety concerns. Serious adverse events were more frequent in the inebilizumab group (12 patients) compared to the placebo group (6 patients). These events varied widely, including gout, anal cancer, pulmonary embolism, appendicitis, and hyponatremia. Overall adverse events, such as lymphopenia, COVID-19, urinary tract infection, and serious/opportunistic infections, were also numerically more common with inebilizumab. One patient experienced an anaphylactic reaction. Interestingly, infusion-related reactions were more common with placebo (five vs three).
Study Design and Patient Population
The phase III trial enrolled 135 patients with confirmed IgG4-related disease affecting at least two organ systems. Participants were randomized 1:1 to receive inebilizumab or placebo infusions on days 1 and 15, with another infusion at week 26. Steroids were gradually withdrawn over the first 8 weeks but could be resumed if flares occurred. Patients were followed for 52 weeks. The mean age of participants was 58, and approximately two-thirds were men. Just under half were newly diagnosed, while the rest had recurrent illness lasting a median of 3.6 years. Most participants had not received treatments other than steroids.
Current Treatment Landscape and Unmet Needs
IgG4-related disease is a rare condition, affecting approximately five people per 100,000 in the U.S. Currently, there are no specific approved therapies, and treatment primarily relies on corticosteroids, which can cause serious side effects with long-term use. Immunosuppressants have been explored as alternatives, but their effectiveness has not been established in randomized, placebo-controlled trials.
Limitations and Future Directions
The study's limitations include a follow-up period of only one year and a relatively small number of participants who had received previous treatments other than steroids. To address these limitations, a 3-year open-label extension study is ongoing to further evaluate the long-term safety profile of inebilizumab and to characterize patterns of B-cell and immunoglobulin changes. "Longer-term data are needed to establish the safety profile of inebilizumab in the treatment of IgG4-related disease and to characterize the patterns of B-cell and immunoglobulin changes; for these reasons, a 3-year open-label period is ongoing," Stone and colleagues wrote.
