Efficacy and safety of nipocalimab in patients with moderate-to-severe Sjögren's disease (DAHLIAS): a randomised, phase 2, placebo-controlled, double-blind trial

Abstract

Background: Sjögren's disease is characterised by mucosal dryness, fatigue, chronic pain, systemic organ involvement, and elevated autoreactive IgG antibodies. There are no approved disease-modifying treatments. Therefore, we aimed to evaluate nipocalimab, a neonatal Fc receptor blocker that reduces circulating IgG, including autoantibodies, in patients with Sjögren's disease.

Methods: This phase 2, double-blind, multicentre trial enrolled individuals with moderate-to-severe, active Sjögren's disease (ie, Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index [ClinESSDAI] of at least 6) who were seropositive for anti-Ro IgG autoantibodies. Participants were recruited from 69 centres across France, Germany, Italy, Japan, the Netherlands, Poland, Portugal, Spain, Taiwan, and the USA. These centres included rheumatology centres, hospitals, and clinical research centres with experience conducting pharmaceutical company-sponsored phase 2 and phase 3 studies, which reported an ability to enrol eligible patients. Central randomisation assigned participants to one of three treatment groups using an Interactive Web Response System. Randomised (1:1:1) participants received intravenous nipocalimab 5 mg/kg, intravenous nipocalimab 15 mg/kg, or placebo every 2 weeks for 22 weeks. Schedules for administering the study intervention were the same across treatment groups, and labels on the study interventions were prepared by an unmasked pharmacist and were identical to maintain masking for the participants, investigators, site staff, and sponsor. The primary endpoint was change from baseline in ClinESSDAI score at week 24. The primary endpoint and other efficacy and safety analyses included participants who were randomly assigned and who received at least one dose of study intervention. For the primary endpoint, data from the time of discontinuation and onward were considered missing. The primary analysis approach used a mixed model for repeated measures to estimate the average outcome, taking into account the non-missing data and variability. DAHLIAS was registered with EudraCT (2021-000665-32) and ClinicalTrials.gov (NCT04968912) and has been completed.

Findings: 163 participants were recruited between Sept 21, 2021, and April 3, 2023, (53 participants to nipocalimab 5 mg/kg, 54 to nipocalimab 15 mg/kg, and 56 to the placebo). The mean age of participants was 48·1 years (SD 12·12); 151 (93%) participants were female and 12 (7%) were male. The nipocalimab 15 mg/kg group had a significant reduction in ClinESSDAI score at week 24 versus the placebo group (least squares mean difference -2·65, 90% CI -4·03 to -1·28; p=0·0018), and the nipocalimab 5 mg/kg group had a non-significant reduction versus placebo (-0·34, -1·71 to 1·03; p=0·68). The safety profile of nipocalimab was comparable, for both doses, with that of placebo, with generally similar rates of adverse events and serious adverse events across groups.

Interpretation: Fc receptor blockade by nipocalimab 15 mg/kg significantly improved clinical disease activity versus placebo and was safe and well tolerated in participants with moderate-to-severe, active Sjögren's disease. Reductions in IgG autoantibodies during nipocalimab treatment support their contribution to Sjögren's disease pathogenesis.

Funding: Johnson & Johnson.