CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial

Sj & ouml;gren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sj & ouml;gren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sj & ouml;gren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sj & ouml;gren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean +/- standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 +/- 0.6; PBO, -4.1 +/- 0.6; P = 0.0167) and population 2 (DAZ, -1.8 +/- 0.2; PBO, -0.5 +/- 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164. In a phase 2 trial of dazodalibep, a CD40 ligand, with a crossover stage in two distinct populations of patients with Sj & ouml;gren's disease, the compound was well tolerated and led to significantly improved disease activity.