MITIGATE: Inebilizumab Reduces Risk of IgG4-Related Disease Flare

Topline data from the randomized, placebo-controlled Phase 3 MITIGATE study demonstrated inebilizumab-cdon (UPLIZNA®) met all primary and key secondary endpoints in treating immunoglobulin G4-related disease (IgG4-RD).¹

Announced by Amgen on June 5, 2024, these positive results marked the first randomized, placebo-controlled trial to demonstrate the benefit of inebilizumab in the treatment of IgG4-RD. The drug achieved an approximately 90% reduction in the risk of IgG4-RD flare compared with placebo treatment and improved annualized flare rates.

"IgG4-RD is a devastating, chronic, immune-mediated disease that has just begun to be fully understood over the last few decades," said John Stone, MD, MPH, principal investigator, and a professor of medicine at Harvard Medical School and the Edward A. Fox Chair in Medicine at Massachusetts General Hospital.¹ "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."

IgG4-RD is a chronic, systemic, immune-mediated, fibroinflammatory disease that can impact nearly any organ in the body, with often multi-organ involvement that leads to irreversible damage.² A progressive disease, IgG4-RD can impact new organs over time and is characterized by remission periods and unpredictable disease flares.³

The MITIGATE trial marked the first placebo-controlled trial providing class 1 evidence for treating IgG4-RD.¹ The novel, steroid-sparing trial design may allow for a reduced toxicity treatment approach in IgG4-RD.

MITIGATE was performed at 80 sites across 22 countries and enrolled 135 adults with IgG4-RD who met the central eligibility review. Criteria for eligibility included multi-organ disease history and active disease treated with glucocorticoids at screening, to ensure a population at risk of flares.

After a screening period of up to 28 days, patients were randomized to receive 300 mg intravenous inebilizumab or placebo on Days 1, 15, and Week 26 after premedication and followed for a 52-week randomized control period. The primary end point of MITIGATE was the time to first treated and adjudicated IgG4-RD flare.

Three key secondary endpoints comprised the annualized flare rate, flare-free, treatment-free complete remission, and flare-free, corticosteroid complete remission. MITIGATE also involved an optional 3-year, open-label treatment period and a safety follow-up period up to 2 years after discontinuation of inebilizumab.

Upon analysis, the trial met its primary end point, demonstrating a statistically significant 87% reduction in the risk of IgG4-RD flare compared with placebo (hazard ratio [HR], 0.13; P <.0001), during the 52-week placebo-controlled period. All key secondary endpoints were met in the trial.

Safety data revealed no new signals during the study period. The overall safety profile of inebilizumab during the placebo-controlled trial period remained consistent with the understood safety profile of the drug.

Based on the primary results from MITIGATE, Amgen has announced plans to file for approval in the United States, followed by other key markets. The full results from the trial are expected to be presented at a future medical meeting.

“MITIGATE is a landmark study with results that demonstrate an important advance in the treatment of patients with IgG4-RD, a devastating and rare disease that currently has no approved therapy,” said Jay Bradner, MD, executive vice president, research and development, and chief scientific officer, at Amgen.

References

1. _{Amgen announces positive results for phase 3 registrational trial evaluating UPLIZNA® (inebilizumab-CDON) for treatment of immunoglobulin G4-related disease (igg4-RD). Amgen. June 5, 2024. Accessed June 5, 2024. https://wwwext.amgen.com/newsroom/press-releases/2024/06/amgen-announces-positive-results-for-phase-3-registrational-trial-evaluating-uplizna-inebilizumabcdon-for-treatment-of-immunoglobulin-g4related-disease-igg4rd.}
2. _{Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol. 2020;16(12):702-714. doi:10.1038/s41584-020-0500-7}
3. _{Floreani A, Okazaki K, Uchida K, Gershwin ME. IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. J Transl Autoimmun. 2020;4:100074. Published 2020 Dec 19. doi:10.1016/j.jtauto.2020.100074}