B-cell depleting agent reduces risk of flares and increases chance of remission in IgG4-RD

Data from the MITIGATE trial (NCT04540497), presented at the American College of Rheumatology Convergence annual meeting and published in the New England Journal of Medicine, has revealed that inebilizumab (Uplizna, Amgen, Thousand Oaks, CA, USA), a CD19-targeting monoclonal antibody, reduced the risk of disease flares by 87% and increased the likelihood of flare-free remission over a 52-week period in adult patients with active immunoglobulin G4-related disease (IgG4-RD).^1,2

Understanding IgG4-RD

IgG4-RD is a rare, chronic, relapsing condition characterized by fibroinflammatory lesions rich in CD19+ B cells, which can damage multiple organ systems and lead to organ failure.¹ With no approved therapies, glucocorticoids are the primary treatment, but their long-term use is associated with adverse effects and inadequate disease control.¹

Targeting the pathology with inebilizumab

Inebilizumab is a humanized, afucosylated IgG1 kappa monoclonal antibody designed to specifically target and deplete CD19+ B cells, which are believed to play a central role in the pathogenesis of the condition.³

About the MITIGATE trial

The MITIGATE trial, the first randomized, double-blind, placebo-controlled study ever conducted in IgG4-RD, enrolled 135 participants randomized 1:1 to receive either inebilizumab (300 mg intravenously on days 1, 15, and week 26; n=68) or placebo (n=67) over a 52-week period. All participants received glucocorticoid premedication and glucocorticoids were permitted for flare management during the trial. However, concurrent use of immunosuppressants was not allowed. Of those enrolled, 127 participants (94.1%) successfully completed the 52-week treatment period.¹

Reduction in flares

The trial demonstrated that inebilizumab significantly reduced the risk of disease flares. Only 7 participants (10%) in the inebilizumab group experienced at least one flare, compared with 40 participants (60%) in the placebo group (HR: 0.13; 95% CI: 0.06–0.28; p<0.001). Over the year, the annualized flare rate was also markedly lower in the inebilizumab group (rate ratio: 0.14; 95% CI: 0.06–0.31; p<0.001).¹

Higher rates of complete remission

In addition to reducing flares, inebilizumab also achieved higher rates of remission. Among those treated with inebilizumab, 39 participants (57%) achieved flare-free, treatment-free complete remission, compared with 15 participants (22%) in the placebo group (OR: 4.68; 95% CI: 2.21–9.91; p<0.001). Flare-free, glucocorticoid-free complete remission was also significantly higher in the inebilizumab group, with 40 participants (59%) achieving this outcome compared with 15 participants (22%) in the placebo group (OR: 4.96; 95% CI: 2.34–10.52; p<0.001).¹

Safety profile and adverse events

The overall incidence of at least one adverse event was comparable between the inebilizumab and placebo groups, with 66 participants affected in each group. However, severe events were more frequent in the inebilizumab group, including grade 3 or higher adverse events (12 participants [18%] versus 8 participants [12%]) and serious adverse events (12 participants [18%] versus 6 participants [9%]). Adverse events resulted in trial withdrawal for 6 participants (9%) in the inebilizumab group, compared with 3 participants (4%) in the placebo group.¹

Speaking on the results, Dr John Stone, Principal Investigator and Professor of Medicine at Harvard Medical School and Edward A. Fox Chair in Medicine at Massachusetts General Hospital said “These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD, but also key insights into the nature of this condition.”⁴

 

References

1. Stone J, Khosroshahi A, Zhang W, et al. Inebilizumab for treatment of igg4-related disease. N Engl J Med. 2024. doi: 10.1056/NEJMoa2409712. Online ahead of print.
2. Stone J, Culver E, Khosroshahi A, et al. A Phase 3, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study of Inebilizumab in IgG4-Related Disease (MITIGATE): Primary Efficacy and Safety Findings. Presented at: ACR Convergence 2024; Washington, Saturday 16 November 2024. Abstract 0775.
3. Pinheiro F, Pereira IA, de Souza AW, et al. IgG4-related disease-rare but you should not forget it. Adv Rheumatol. 2024;64:35. doi: 10.1186/s42358-024-00374-
4. Amgen. Amgen presents new data across rare inflammatory diseases at ACR 2024. [Press Release] 2024. Available at: https://www.amgen.com/newsroom/press-releases/2024/11/amgen-presents-new-data-across-rare-inflammatory-diseases-at-acr-2024 (accessed 17 November 2024).

Disclosure: This article was created by the touchIMMUNOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article