Exciting results from an open-label Phase 2 pilot trial published in Lancet Rheumatology[1] suggest that obexelimab, a potential new treatment for IgG4-related disease (IgG4-RD), may become an important alternative to long-term glucocorticoid treatment.
Glucocorticoids are the cornerstone of treatment for IgG4-RD, a chronic condition recognized as a unique disease only 20 years ago. IgG4-RD is an autoimmune inflammatory condition that affects blood vessels of all sizes and targets particular organs such as the pancreas and bile ducts, the major salivary glands, the kidneys, and the aorta, among others.
As John H. Stone, MD MPH, Edward Fox Chair of Medicine and Professor of Medicine at Harvard Medical School discussed at the American College of Rheumatology 2022 Annual Meeting, “While there is a growing body of case work on IgG4-related disease, people still find it a revelation that IgG4-related disease is actually a form of vasculitis, and many cases are misdiagnosed as cancers.”
Currently, there are no approved treatments for IgG4-RD and nearly all patients receive glucocorticoids as the standard first-line treatment. Patients frequently experience significant and often irreversible steroid-toxicities, and after reducing or stopping glucocorticoid treatment experience disease flare-ups that necessitate continued treatment.
IgG4-RD affects the pancreas, the organ responsible for producing insulin, the hormone critical to the maintenance of normal glucose tolerance. The use of glucocorticoids for IgG4-RD poses a significant challenge due to their tendency to raise blood glucose levels. This situation creates a perfect storm, leading to increased risks of weight gain and diabetes.
The exact cause of IgG4-related disease is not fully understood, but there is evidence suggesting that immune B cells play a significant role in driving the condition. Some treatments that permanently deplete B cells have shown promise, but they also have significant downsides, including increased infection risk and decreased response to vaccines.
Unlike other treatments such as rituximab, obexelimab, does not permanently deplete B cells. Rather, obexelimab quickly but reversibly inhibits B cell function by selectively binding to CD19 and Fc gamma receptor IIb (FcγRIIb).
The results from this pilot study of 15 IgG4-RD patients show the bifunctional antibody demonstrated treatment responses in all but one patient and complete clinical remissions - meaning freedom from glucocorticoid use - in eight. The five patients who started the study receiving glucocorticoids were able to taper to discontinuation within the first two months of the trial.
Obexelimab treatment led to reductions in circulating B cells, plasmablasts, and CD4+ cytotoxic T lymphocytes, which are associated with the positive effects observed. The trial also suggests that obexelimab is well-tolerated and safe in patients.
A Phase 3 study (NCT05662241) in patients with IgG4-RD is under way to investigate the safety and efficacy of obexelimab in a definitive manner. The trial employs the Steritas Glucocorticoid Toxicity Index (GTI) to assess this therapeutic antibody’s ability to reduce glucocorticoid toxicity, naming glucocorticoid toxicity reduction as a major secondary endpoint.
References
- Perugino, CA et al., Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial, Lancet Rheumatology, 2023, 5, e442-e450, https://doi.org/10.1016/S2665-9913(23)00157-1