1172: A Phase II, Single-site, Open-label Study of Zanubrutinib in Patients with igg4-related Disease

Background/Purpose: IgG4-related disease (IgG4-RD) is a chronic, systemic, immune-mediated disease that is commonly treated with B cell depletion. However, due to potential risks associated with long-term B cell depletion, there is a need for alternative, non-depleting treatment options. Bruton’s tyrosine kinase (BTK) plays a critical role in B cell activation and proliferation, and inhibiting BTK is efficacious in B cell driven diseases, without meaningfully reducing B cell numbers. In this phase 2 proof-of-concept study (NCT04602598), we report the efficacy and safety of zanubrutinib in patients with IgG4-RD affecting the lacrimal and/or salivary glands.

Methods: This open-label study was conducted at a single center in the United States. Eligible adult patients with symptomatic IgG4-RD affecting the submandibular and/or lacrimal glands, with prior inadequate response to glucocorticoids, and meeting the 2019 ACR/EULAR Classification Criteria for IgG4-RD, received oral zanubrutinib 80 mg twice daily for up to 24 weeks. The primary endpoint was the change from baseline in the volume of the submandibular and/or lacrimal glands on ¹⁸F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (FDG-PET/MRI) at Week 24, as determined by two board-certified radiologists blinded to scan order. Secondary endpoints included the change in metabolic activity on FDG-PET/MRI, laboratory parameters such as IgG4 serum concentration, and patient reported outcomes. The Wilcoxon signed rank exact test was used to evaluate changes on imaging.

Results: Ten patients were enrolled; most were male (70.0%), Asian (60.0%), and with a median age of 58 (range, 38-74) years. Prior treatments included prednisone (10 patients), azathioprine (2 patients), and rituximab (5 patients); for rituximab-treated patients, the mean (standard deviation [SD]) time since last dose was 2.5 years (1.5). No patients were receiving glucocorticoids or a steroid-sparing immunosuppressive treatment at the time of enrollment or during the study. The mean (SD) number of organs ever affected by IgG4-RD was 4.4 (1.4), and all patients had both lacrimal and submandibular gland disease. At Week 24, the mean (SD) percent changes from baseline were -45.4% (17.4) for lacrimal gland volume (p < 0.001) and -30.0% (18.6) for submandibular gland volume (p < 0.001) (Figure 1). In addition, reductions were observed in all measures of metabolic activity, including a mean (SD) change from baseline in total lesion glycolysis of -91.6 grams (98.5; p = 0.05) (Figure 2). Representative FDG-PET/MRI images are shown in Figure 3. The mean (SD) change in the serum IgG4 concentration over 24 weeks was -417.0 mg/dL (410). All patients had at least one treatment-emergent adverse event (TEAE), most of which were mild, and there was one serious TEAE from COVID-19.

Conclusion: Treatment with zanubrutinib alone, without the need for glucocorticoid induction or other background immunosuppression, significantly reduced both lacrimal and submandibular gland volume and metabolic activity on FDG-PET/MRI, as well as reduced serum IgG4 concentrations, with an acceptable safety profile. Given these results, zanubrutinib warrants further investigation as a treatment for IgG4-RD.