Uplizna Approved for IgG4-RD

This disease is a chronic and debilitating immune-mediated inflammatory condition that can affect multiple organs. The FDA granted Breakthrough Therapy Designation to Uplizna   for the treatment of IgG4-RD, recognizing the high unmet medical need in this serious condition and the medicine's potential to benefit patients.

The approval of Uplizna  for IgG4-RD is supported by data from the MITIGATE trial, the first randomized, double-blind, placebo-controlled trial conducted in IgG4-RD. This trial demonstrated the potential of Uplizna  to decrease disease activity by reducing flares in patients, while maintaining its efficacy and established safety profile.

This is the second approved indication for Uplizna, which was previously approved by the FDA for the treatment of adult patients with AQP4-IgG+ Neuromyelitis Optica Spectrum Disorder (NMOSD) in June 2020. The FDA also granted Uplizna Orphan Drug Designation for the treatment of generalized myasthenia gravis (gMG). Regulatory filing activities are underway for gMG with submission anticipated to be complete in H1 2025.

MITIGATE is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial designed to evaluate the efficacy and safety of Uplizna  compared to placebo in reducing the risk of flares in adults with IgG4-RD. The primary endpoint was time to first treated and adjudicated IgG4-RD flare. The three key secondary endpoints were annualized flare rate; flare-free, treatment-free complete remission; and flare-free, corticosteroid-free complete remission. The MITIGATE trial also includes an optional three-year open-label treatment period and a safety follow-up period after Uplizna  discontinuation of up to two years. 

Key findings from the MITIGATE trial include; 

• i. An 87% reduction in the risk of IgG4-RD flare compared to placebo (Hazard Ratio 0.13, p<0.001) during the 52-week placebo-controlled period; 10.3% (7 of 68) of participants receiving Uplizna  experienced a flare compared to 59.7% (40 of 67) of participants receiving placebo.
• ii. A reduction in annualized flare rate for treated and adjudication committee-determined flares during the placebo-controlled period; 0.10 for participants receiving Uplizna   compared to 0.71 for participants receiving placebo (p<0.001).
• iii. 57.4% (39 of 68) of participants receiving Uplizna   achieved flare-free, treatment-free, and complete remission at Week 52 compared to 22.4% (15 of 67) of participants receiving placebo (p<0.001).
• iv. 58.8% (40 of 68) of participants receiving Uplizna  achieved flare-free, corticosteroid-free, and complete remission at Week 52 compared to 22.4% (15 of 67) of participants receiving placebo (p<0.001).
• v. 89.7% (61 of 68) of Uplizna-treated patients required no glucocorticoid treatment for disease control during the placebo-controlled period, outside of the planned glucocorticoid tapering, compared to 37.3% (25 of 67) of patients on placebo.
• vi. Uplizna -treated patients experienced a ten-fold reduction in mean total glucocorticoid use for disease control per patient relative to placebo (118 mg vs. 1385 mg, respectively) during the placebo-controlled period. The most common adverse reactions in patients with IgG4-RD (at least 10% of patients treated with Uplizna and greater than placebo) were urinary tract infection (12%) and lymphopenia (19%).

• "Targeting CD19+ B cells with UPLIZNA has proven to be a highly effective approach to help address the pathophysiology of IgG4-RD," said Prof. John Stone, principal investigator, Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital. "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."

  "The FDA approval of Uplizna 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," said  Dr.Jay Bradner, executive vice president of Research and Development at Amgen. "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, including neuromyelitis optica spectrum disorder and generalized myasthenia gravis. This approval underscores Amgen's ongoing commitment and leadership in developing innovative treatments targeting CD19+ B-cells across multiple therapeutic areas."

  See citation- Stone JH, Khosroshahi A, Zhang W et al. Inebilizumab for Treatment of IgG4-Related Disease. . N Engl J Med. 2025, 392:1168 doi: 10.1056/NEJMoa2409712.