A phase 3 clinical trial has revealed that inebilizumab, a CD19-directed antibody, significantly reduces the risk of disease flares in patients with immunoglobulin G4-related disease (IgG4-RD). The international, multicenter, double-blind, randomized, placebo-controlled trial, published in the New England Journal of Medicine, offers a potential new treatment option for this rare and often debilitating condition.
The study, known as MITIGATE, involved 135 adults with active IgG4-RD who were randomized in a 1:1 ratio to receive either inebilizumab (300-mg intravenous infusions on days 1 and 15 and week 26) or placebo for a 52-week treatment period. All participants received identical glucocorticoid tapers. The primary endpoint was the time to first treated, adjudicated disease flare during the treatment period.
Significant Reduction in Flare Risk
The results showed a marked reduction in flare risk with inebilizumab. Only 7 participants (10%) in the inebilizumab group experienced at least one flare, compared to 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). This translates to an 87% reduction in the risk of flares.
The annualized flare rate was also significantly lower with inebilizumab (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). Furthermore, more participants in the inebilizumab group achieved flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001).
Addressing an Unmet Need
IgG4-RD is a multiorgan, relapsing, fibroinflammatory, immune-mediated disorder affecting fewer than 200,000 people in the United States. It is characterized by a buildup of immune cells that produce the IgG4 antibody in various organs, leading to symptoms driven by the affected organs. Current treatment typically involves steroids, which are associated with significant side effects, particularly in patients with pancreatic involvement.
"When you have a patient who already has an inflamed pancreas that is functioning poorly on that basis and not making enough insulin, the addition of steroids leads to diabetes mellitus in a high percentage of cases," said lead author John Stone, MD, MPH, a rheumatologist at Massachusetts General Hospital.
Mechanism of Action and Safety Considerations
Inebilizumab, manufactured by Amgen, depletes CD19-expressing B cells, which are believed to play a crucial role in IgG4-RD. While effective, B-cell depletion therapies can increase the risk of infections due to impaired vaccine responses. The authors recommend ensuring patients are vaccinated before starting treatment and using the therapy prudently, guided by markers of inflammation.
Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo. Longer-term data will be needed to fully establish the treatment's safety profile.
Implications for Patient Care
The findings from the MITIGATE trial offer hope for improved management of IgG4-RD. "This is a huge day in the history of this disease," said Dr. Stone. "We are thrilled to have worked so closely with patients to undertake a trial specifically focused on their disease, with the goal of finding a therapy that we hope will be approved shortly for them."
Increased awareness of IgG4-RD, coupled with the availability of effective therapies like inebilizumab, may lead to earlier diagnoses and better patient outcomes.
