Results from the Phase 3 MITIGATE trial of a biologic called inebilizumab have raised hopes the tide may be turning in the hunt for an alternative treatment to steroids for IgG4-related disease (IgG4-RD).[1] IgG4-RD is a rare, autoimmune inflammatory condition affecting an estimated 40,000 patients in the US and hundreds of thousands worldwide.[2]
Currently, there are no approved treatments for IgG4-RD, and nearly all patients receive glucocorticoids as the standard first-line treatment. The results from the MITIGATE trial showed that patients treated with inebilizumab, a humanized monoclonal antibody that targets CD19, achieved promising remission rates.[1]
IgG4-RD can affect any organ in the body and is characterized by the development of lesions rich in CD19+ B cells, which are thought to drive fibrosis and inflammation.[1] IgG4-RD responds well to steroid treatment, making it the mainstay approach for the condition. However, while steroids are very effective in treating IgG4-related disease, the long list of toxicities associated with their use makes them dangerous in the long term, and immunosuppressive therapies, such as rituximab, often supplement their use.
Rituximab, a CD20-targeted B cell-depleting agent, was demonstrated to have some efficacy against IgG4-RD in open-label studies,[3] but has yet to be tested in a randomized clinical trial for IgG4-RD. It is thought that CD19-targeting therapies such as inebilizumab and obexelimab (another treatment currently in clinical trials for IgG4-RD) may be more effective treatments for the disease because they target a larger subset of B cells compared to agents that target CD20.[1]
One of the co-authors of the trial was Wen Zhang, MD PhD, who recently told Steritas:
“Steroid treatment really is a double-edged sword. While steroids have a dramatic effect on inflammatory diseases such as IgG4-related disease, there is a long list of toxicities associated with their use… and whenever my patients suffer any of these, I really feel sorry for them and wish we had alternative treatments we could prescribe.”
The MITIGATE Phase 3 double-blind, randomized placebo-controlled trial was conducted at 80 sites across 22 countries. One hundred thirty-five adult patients, with a new or existing diagnosis, were randomized 50:50 to receive either inebilizumab or placebo. All participants had an IgG4-related disease flare, which required initiation or continuation of glucocorticoid treatment for 3 to 8 weeks prior to randomization.
Steroid doses were reduced to 20mg a day before randomization and then tapered to zero over the first 8 weeks of the study. Steroid therapy was allowed to treat flares but not to prevent them.
Overall, 127 (94.1%) participants completed the 52-week treatment period, with the results offering real hope of a new and effective steroid-sparing therapy for IgG4-RD:
From a safety perspective, the number of participants with at least one adverse event was similar in the two arms. Adverse events of grade 3 and above were higher in the inebilizumab arm (18%) than in the placebo arm (12%). Infection rates were also higher in the inebilizumab arm, including COVID-19 (24%) and urinary tract infections (12%).
The MITIGATE study has established the efficacy of CD19-targeted B cell depletion in IgG4-RD, but longer follow-up is required to establish the long-term safety and efficacy of this approach.
While the IgG4-RD world awaits the results of the longer-term study into inebilizumab, there is still much we can learn from the MITIGATE study. The high proportion of inebilizumab patients who achieved steroid-free remission and a total steroid dose of less than 10% of that in the placebo arm suggest real potential as a steroid-sparing option for IgG4-RD.
With the promise of new, monoclonal antibody therapies for IgG4-related disease on the horizon, it’s worth exploring the challenge of ensuring access for those patients who would benefit most from the treatment. Monoclonal antibodies have become a powerful tool in modern medicine, but they’re expensive drugs; the average price for monoclonal antibody treatment in the United States is $15k-200k per year. As a result, access to these drugs can be limited, particularly in low- and middle-income countries.[4]
A recent study published in the Journal of Rheumatology demonstrated the Steritas GTI could be used in a clinical practice setting to prospectively assess glucocorticoid-related toxicity in patients. The study showed the GTI is sensitive enough to identify patient-specific sensitivity to steroid-toxicity and has the potential to be used to identify patients with the highest steroid-toxicity burden and prioritize their access to these new therapies.