Today, the FDA approved inebilizumab (Uplizna; Amgen) for the treatment of adults with immunoglobulin G4-related disease (IgG4-RD). With this action, inebilizumab has become the first and only FDA-approved treatment for this patient population. The approval is supported by data from the MITIGATE clinical trial (NCT04540497).1,2
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Inebilizumab is a humanized monoclonal antibody (mAb) that causes targeted and sustained depletion of key cells that contribute to the underlying disease process (autoantibody-producing CD19+ B cells, including plasmablasts and some plasma cells). The precise mechanism that exerts therapeutic effects in IgG4-RD is currently unknown, according to the manufacturer. After 2 initial infusions, patients only need 1 dose of inebilizumab every 6 months.1
This is the second approved indication for inebilizumab, which was previously approved by the FDA for the treatment of adult patients with astrocyte water channel protein aquaporin 4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) in June 2020. Additionally, the FDA also granted inebilizumab an orphan drug designation for the treatment of generalized myasthenia gravis (gMG).1
IgG4-RD is a chronic, systemic, immune-mediated, fibroinflammatory disease that can affect multiple organs of the body. It is a progressive disease that can affect a variety of organ systems, often affecting multiple organs over time, and can potentially progress to fibrosis and permanent organ damage in some patients. It is characterized by periods of remission and unpredictable disease flares. Additionally, IgG4-RD can cause permanent organ damage with or without the presence of symptoms. Awareness of how organ damage manifests is critically important to inform the timely diagnosis of IgG4-RD.1
"The FDA approval of [inebilizumab] marks a significant turning point for IgG4-RD patients and physicians who now have a proven treatment that targets a key driver of the disease, reducing the risk of flares and reliance on harmful long-term steroid use," Jay Bradner, MD, executive vice president of research and development at Amgen, said in a news release. "We are proud to deliver a therapy that has the potential to significantly improve care for patients with IgG4-RD and remain encouraged by UPLIZNA's broader potential in other immune-mediated diseases, NMSOD and gMG."1
The approval follows positive results from MITIGATE, a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3 clinical trial that assessed the efficacy and safety of inebilizumab compared with placebo in the reduction of the risk of flares in adult patients with IgG4-RD. The study’s primary end point was time to first treated and adjudicated IgG4-RD flare, with 3 key secondary end points being annualized flare rate; flare-free, treatment-free complete remission; and flare-free, corticosteroid-free complete remission. The trial also includes an optional 3-year open-label treatment period and safety follow-up period after inebilizumab discontinuation of up to 2 years.1,2
At the end of the 52-week placebo-controlled period, patients treated with inebilizumab experienced an 87% reduction in the risk of IgG4-RD flares compared with those treated with placebo, according to findings published in The New England Journal of Medicine.3In addition, only 7 of 68 patients receiving inebilizumab (10.3%) experienced a flare compared with 40 patients receiving placebo (59.7%). Patients receiving inebilizumab were more likely to achieve flare-free, treatment-free complete remission (57.4%, n = 39), flare-free corticosteroid-free complete remission (58.8%, n = 40), and require no glucocorticoid treatment (89.7%, n = 61) at the 52-week period compared with patients receiving placebo (22.4%, n = 15; 22.4%, n = 15; and 37.3%, n = 25, respectively).1,3
The most common adverse events (AEs) reported were urinary tract infection (12%) and lymphopenia (19%). Serious AEs occurred during the treatment period in 12 patients (18%) who received inebilizumab and 6 (9%) who received placebo, according to the investigators.1
About the Trial
Trial Name: A Study of Inebilizumab Efficacy and Safety in IgG4- Related Disease
ClinicalTrials.gov ID: NCT04540497
Sponsor: Amgen
Completion Date (Estimated): October 31, 2028
"Targeting CD19+ B cells with [inebilizumab] has proven to be a highly effective approach to help address the pathophysiology of IgG4-RD," principal investigator John Stone, MD, MPH, professor of medicine at Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital, said in the news release. "The clinical community now has an FDA-approved therapeutic innovation for patients that targets underlying disease mechanisms and helps to control disease activity by reducing flares in IgG4-RD. Now, our work begins in raising awareness of this disease so that patients can access the right treatment as early as possible, avoiding a long and often harmful diagnostic journey."1
REFERENCES
1. Amgen. UPLIZNA® (inebilizumab-cdon) is now the first and only FDA-approved treatment for IgG4-related disease. News release. April 3, 2025. Accessed April 3, 2025. https://www.amgen.com/newsroom/press-releases/2025/04/uplizna-inebilizumabcdon-is-now-the-first-and-only-fdaapproved-treatment-for-igg4related-disease
2. A Study of Inebilizumab Efficacy and Safety in IgG4- Related Disease. ClinicalTrials.gov identifier: NCT04540497. Updated April 2, 2025. Accessed April 3, 2025. https://clinicaltrials.gov/study/NCT04540497
3. Stone JH, Khosroshahi, Zhang W, et al. Inebilizumab for Treatment of IgG4-Related Disease. N Engl J Med. 2025;392(12):1168-1177. doi:10.1056/NEJMoa2409712