IgG4-Related Disease: A UniSR-Led Study on Obexelimab

IgG4-related disease, a rare immune-mediated condition, is now the focus of a phase 3, multicentre trial led by a UniSR research group. The study tested the monoclonal antibody obexelimab for its ability to prevent relapse over one year of treatment. It is the largest randomized, double-blind, placebo-controlled trial conducted to date for a drug targeting this disease. 

The study, published in the New England Journal of Medicine, is first-authored by Emanuel Della Torre, associate professor of Internal Medicine at Vita-Salute San Raffaele University (UniSR) and a physician at the Clinical Unit of Immunology, Rheumatology, Allergy and Rare Diseases of the IRCCS San Raffaele Hospital. The unit is led by professor Lorenzo Dagna, director of UniSR's residency programme in Allergology and Clinical Immunology, who is also among the study's authors. 

The trial enrolled around 200 patients across more than 15 countries and followed them for 52 weeks, comparing the drug against placebo. Obexelimab significantly reduced the one-year risk of relapse compared with placebo, using glucocorticoid doses four times lower. 

This new therapy addresses several unmet needs in the clinical management of IgG4-related disease: it effectively prevents relapse, works without depleting B cells, can be self-administered at home via subcutaneous injection and, by avoiding glucocorticoids, reduces the toxicity associated with corticosteroid use,

says Della Torre.

Studying a rare disease like this in depth requires research collaboration on an international scale. IgG4-related disease is a chronic inflammatory condition that can affect almost any organ in the body, from the pancreas to the salivary glands, from the lungs to the aorta. It produces tumour-like masses packed with immune cells, causing symptoms that vary widely depending on the organ involved. 

The two treatment options available today, glucocorticoids and anti-B-cell biologics, keep the disease under control but do not prevent it from recurring over time. 

The clinical immunology group led by Della Torre and Dagna helped clarify this mechanism of action in detail. Obexelimab also targets B cells, but it dampens their ability to produce antibodies without eliminating them completely, unlike other biologic drugs currently available. It is given as a weekly subcutaneous injection, so it does not require scheduled hospital access. Its half-life, the time needed for its blood concentration to drop by half, is also shorter. This makes it easier to pause treatment in case of fever or ahead of surgery, something not possible with prolonged immunosuppression. 

These features solve the logistical problems tied to the biologic drugs currently used for IgG4-related disease, which must be given intravenously in hospital and persist longer in the body. That longer persistence prolongs the immunosuppressive effects that put patients at higher risk of infection. 

The result builds on the work of the Immunology, Rheumatology, Allergy and Rare Diseases Unit at IRCCS San Raffaele Hospital, which combines patient care for rare immune-mediated diseases with translational research on new therapies. 

The effectiveness of obexelimab in preventing relapse without destroying B cells could mark a shift not only in the treatment of IgG4-related disease, but in many autoimmune conditions where B cells play a central role. 

We are now working to extend the results of this study into an open-label phase, giving everyone with the disease the chance to take the drug for three years. If the results are confirmed, this will open up a new possibility for our patients,

Della Torre concludes.

To know more, read the full study.