Treatment for IgG4-related disease 'will look very different' in 3-5 years
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IgG4-related disease treatment is expected evolve greatly over the next 3 to 5 years, with a trio of promising drugs — inebilizumab, rilzabrutinib and elotuzumab — on the horizon, according to a speaker at the 2020 Congress of Clinical Rheumatology-West.
“The treatment of IgG4-related disease will look very different in the next 3-5 years, based on what we have come to understand with regard to the pathophysiology,” John H. Stone, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, told attendees at the virtual conference.
Currently, the standard of care for IgG4-related disease around the world remains prednisone, Stone said. Across Asia, treatment starts with 40 mg of prednisone each day for 1 month. That dose is then tapered to, and maintained at, 5 mg to 10 mg per day. Patients in North America and Europe are also treated with 40 mg of daily prednisone for 1 month, but are then tapered down, and eventually taken off the drug completely, over a period of 2 to 3 months.
The problem, according to Stone, is that both regimens not only involve high levels of prednisone, but also a high percentage of flares.
“I think you will agree that 5 to 10 mg of prednisone per day, particularly in a patient of Asian stature, particularly in a patient who may have serious pancreatic disfunction, particularly in a patient who may have other comorbidities, is a lot of prednisone,” Stone said. “Despite that high prednisone use, and the tendency to keep people on prednisone ad infinitum (in Asia), there is a high percentage of patients who flare. Also, the adverse events are high — steroid-induced diabetes, exacerbations of existing diabetes, infections and on and on.”
“Not surprisingly, we see a high percentage of patients who flare as well (in North America and Europe),” he added.
However, according to Stone, three drugs currently in various clinical trials could change how these patients are treated around the world in the coming years — the anti-CD19 inebilizumab (Uplizna, Viela Bio), the BTK inhibitor rilzabrutinib (formerly known as PRN1008, Principia Biopharma) and the SLAMF7-targeted elotuzumab (Empliciti; Bristol-Myers Squibb, AbbVie).
As Stone explained, it is believed that the critical cellular interaction in IgG4-realted disease is when cells of the B lineage are presenting antigen to a particular CD4-positive cytotoxic T-cell. This in turn elaborates fibrogenic mediators — including IL-1-beta and TGF-beta —which drive the fibrosis process in impacted tissues.
“Rituximab works very well, but another therapy that is the subject of a worldwide phase 3 trial is inebilizumab, which should hit an even broader spectrum of B cells than rituximab does,” Stone said. “Another theory being tested right now is rilzabrutinib, again targeting B cells but having an important effect potentially on other cells as well, including eosinophils and even macrophages. As such, it is a another very promising therapy.”
The third therapy under development Stone discussed is a monoclonal antibody directed against SLAMF7, a surface marker found on both B cells and the CD4-positive cytotoxic T-cell. According to Stone, it is through homotypic interactions mediated by SLAMF7 that these cells are thought to interact with each other in the context of antigen presentation.
“There is a monoclonal antibody called elotuzumab, which was the first drug given a breakthrough indication by the FDA, in this case for the treatment of multiple myeloma,” Stone said. “This is also now being tested for IgG4-related disease. So, this is a sense of what is coming, and how the treatment is going to be very different going forward.”
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Stone JH. How to treat IgG4-related disease. Presented at: Congress of Clinical Rheumatology-West annual symposium; October 8-11, 2020 (virtual meeting).
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