Abstract

Background: Sjögren's disease (SjD) is a chronic, systemic autoimmune disease characterized by the presence of specific autoantibodies (AAb) and lymphocytic infiltration of exocrine glandular tissues. The pathophysiology of SjD results from dysregulated humoral immunity involving aberrant B-lymphocyte activity, leading to abnormally elevated immunoglobulin G (IgG) and IgG AAb levels, particularly anti-Ro and anti-La, which are associated with disease severity. Nipocalimab is an anti-neonatal Fc receptor (FcRn) monoclonal antibody that reduces circulating IgG, including AAb, by selectively blocking the interaction of IgG with FcRn. In phase 2 studies in AAb/alloantibody-mediated diseases, nipocalimab treatment resulted in rapid, deep, dose-dependent, reversible reductions in serum total IgG and AAb, suggesting therapeutic potential in other AAb-associated diseases, including SjD. Objectives: To evaluate the efficacy and safety of nipocalimab in patients with primary SjD. Methods: A phase 2 study (DAHLIAS; NCT04968912) was conducted in adults (18-75 years) with moderately-to-severely active primary SjD (total Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index [clinESSDAI] ≥6) who were seropositive for anti-Ro60 and/or -Ro52 IgG antibodies. Randomized patients (1:1:1) received IV nipocalimab at 5 or 15 mg/kg, or placebo every 2 weeks (wks) through Wk 22 and protocol-permitted background standard of care. The primary endpoint of change from baseline in clinESSDAI score at Wk 24 was chosen to avoid mechanistic bias with IgG levels. Safety assessments were conducted through Wk 30. Results: In total, 163 patients were enrolled (nipocalimab: 5 mg/kg, n=53; 15 mg/kg, n=54; placebo, n=56). Baseline characteristics were comparable between groups. The nipocalimab 15 mg/kg group met the primary endpoint versus placebo (least squares mean difference for 15 mg/kg, –2.65; 90% CI, –4.03, –1.28; p=0.002; for 5 mg/kg: –0.34; 90% CI, –1.71, 1.03; p=0.681; Table 1). Similar improvements in the 15 mg/kg nipocalimab group versus placebo were observed in most secondary/exploratory endpoints (Table 1), including change from baseline in Physician Global Assessment of Disease Severity at Wk 24 (PhGA), change from baseline in ESSDAI score at Wk 24, treatment response according to Sjögren's Tool for Assessing Response (STAR), Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS), and disease activity level (DAL) response (a decrease in ≥1 clinESSDAI domain), among others. Patient-reported outcome measures were numerically improved in the 15 mg/kg nipocalimab group versus placebo. Efficacy outcomes in the 5 mg/kg nipocalimab group were generally similar to placebo. Serious adverse events were reported in 7.5%, 7.4%, and 5.4% of participants with nipocalimab 5 mg/kg, 15 mg/kg, and placebo, respectively (Table 2). Significant nipocalimab dose-dependent reductions in IgG and AAb were observed. Severe infections or infections requiring IV anti-infectives occurred in 3.8%, 1.9%, and 1.8% of participants, respectively, without a clear correlation with IgG nadir; none were deemed related to study treatment. At Wk 24, changes from baseline in albumin, low-density lipoprotein cholesterol, and total cholesterol were reported at –6.9%, 6.6% and 8.3%, respectively. No opportunistic infections or severe hypoalbuminemia were observed; no deaths were reported. Conclusion: DAHLIAS is the first study of a FcRn blocker in SjD and shows that nipocalimab treatment led to significant improvement over placebo in clinESSDAI and similar trends in other key efficacy endpoints at Wk 24 and is well-tolerated. These results demonstrate the mechanistic relevance of FcRn inhibition in SjD, indicating the potential pathogenicity of IgG AAb. Together, these findings establish proof of concept for nipocalimab in SjD and support further evaluation in patients with moderate-to-severe AAb-positive SjD. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Jacques-Eric Gottenberg AbbVie, Janssen, BMS, UCB, MSD, Novartis, Pfizer, Gilead, Galapagos, Lilly, and Sanofi, Kathy Sivils owns shares/stock options of Johnson & Johnson, Employee of Janssen, Kim Campbell owns shares/stock options of Johnson & Johnson, Employee of Janssen, Jada Idokogi owns shares/stock options of Johnson & Johnson, Employee of Janssen, Kim Hung Lo Employee of Janssen, Sophia Liva Owns shares/stock options of Johnson & Johnson, Employee of Janssen, Harman Dhatt owns shares/stock options of Johnson & Johnson, Employee of Janssen, Jonathan Hubbard owns shares/stock options of Johnson & Johnson, Employee of Janssen, Ghaith Noaiseh: None declared