The Phase III MITIGATE trial has demonstrated that Uplizna (inebilizumab) significantly reduces the risk of disease flares and decreases glucocorticoid dependence in patients with immunoglobulin G4-related disease (IgG4-RD), a chronic, systemic, immune-mediated fibroinflammatory condition that can impact multiple organs.
Results from the randomized, double-blind, placebo-controlled trial showed that patients receiving Uplizna experienced a 90% reduction in flare risk compared to placebo, with only 10% of treated patients experiencing at least one flare versus 60% in the placebo group (hazard ratio, 0.13; 95% CI, 0.06 to 0.28; P<0.001).
Uplizna is a humanized, afucosylated IgG1 kappa monoclonal antibody designed to target CD19, inducing rapid, deep, and durable B-cell depletion. It is currently approved for treating neuromyelitis optica spectrum disorder in adults who are anti-aquaporin-4 antibody positive.
Trial Design and Patient Population
The MITIGATE trial (NCT04540497) enrolled 135 adult patients with IgG4-RD who had multi-organ disease history and active disease treated with glucocorticoids at screening. Participants were randomized 1:1 to receive either 300 mg of intravenous Uplizna (n = 68) or placebo (n = 67) on days one and 15, and at week 26 after premedication, followed by a 52-week randomized control period.
Key secondary endpoints included annualized flare rate, flare-free and treatment-free complete remission, and flare-free and corticosteroid-free complete remission. The trial also includes an optional three-year open-label treatment period and a safety follow-up period of up to two years.
Significant Clinical Benefits
The annualized flare rate was substantially lower among patients receiving Uplizna compared to placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). Additionally, more patients in the Uplizna group achieved flare-free and treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001), as well as flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001).
Dr. John Stone and colleagues, who published their findings in The New England Journal of Medicine, noted that "The MITIGATE trial showed the efficacy of CD19-targeted B-cell depletion by inebilizumab for the treatment of IgG4-related disease." They emphasized that participants receiving Uplizna required lower cumulative glucocorticoid exposure to induce remission and maintain disease control during the treatment period compared to those receiving placebo.
Enhanced Efficacy in Gastrointestinal Manifestations
A subgroup analysis presented at Digestive Disease Week revealed that Uplizna was particularly effective for patients with pancreatic and biliary manifestations of IgG4-RD, which affect more than 50% of patients with the disease.
At baseline, 38% of patients exhibited disease activity in the pancreas and 21% in the bile ducts, with 19% showing activity in both organs. The analysis showed that patients with IgG4-RD affecting the pancreas (66.7%) and bile ducts (84.6%) were more likely to achieve glucocorticoid-free, flare-free complete remission with Uplizna compared to the overall IgG4-RD population (58.8%).
"The surprising finding in this sub-analysis was that the effect of the drug was even better in patients with these manifestations compared with the entire group," said lead investigator Matthias Löhr, MD, PhD, professor of gastroenterology and hepatology at Karolinska Institute in Stockholm. "With regard to reduced annualized flare rate vs. placebo during the observation period, the effect was even bigger in the pancreatobiliary group compared with the overall [IgG4-RD] group."
Safety Profile
In terms of safety, rates of adverse events were similar between both treatment groups; however, more adverse events of grade 3 or higher, serious adverse events, adverse events of special interest, and adverse events causing treatment discontinuation occurred in the Uplizna group. Serious adverse events were reported by 18% of patients receiving Uplizna compared to 9% in the placebo group.
For patients with gastrointestinal involvement, the most common adverse events included back pain, COVID-19, hyperuricemia, lymphopenia, fever, and urinary tract infection, particularly among those with both pancreatic and biliary involvement.
Potential to Change Clinical Practice
The MITIGATE trial results suggest that CD19-targeted B-cell depletion with Uplizna could represent a significant advancement in the treatment of IgG4-RD, particularly for patients with pancreatobiliary manifestations.
"For the first time, we have a drug that is not only approved for IgG4-related disease, but works best in the GI manifestations of the disease, including autoimmune pancreatitis and immune-related cholangitis," Dr. Löhr stated. "This will be a game changer in clinical practice, especially for patients who have a flare or rare manifestation of the disease and do not respond to initial therapy with steroids."
The researchers concluded that after initial treatment with first-line glucocorticoids, Uplizna could become the new standard second-line therapy for IgG4-RD, potentially changing clinical practice for this challenging condition.
