Journal Article

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

Tarrant, Teresa K., Wang, Liangwei, Baldini, Chiara, Xu, Wenjing, Sikora, Keith, St. Clair, E. William, Noaiseh, Ghaith, Pham, Tuyet-Hang, Alevizos, Ilias, Baer, Alan N., Ng, Wan-Fai, Papas, Athena, Devauchelle-Pensec, Valerie, Rees, William A.

2024

Overview

Sjögren’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 Sjögren’s syndrome. The primary endpoint for population 1 ( n  = 74) was the change from baseline in the European League Against Rheumatism Sjögren’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 Sjögren’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 Sjögren’s disease, the compound was well tolerated and led to significantly improved disease activity.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/249/1313 / 631/250/38 / Adult / Aged / Antigen-presenting cells / Arthralgia / Autoimmune diseases / Autoimmunity / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD40 antigen / CD40 Ligand / CD40 Ligand - antagonists & inhibitors / CD40 Ligand - immunology / Chronic conditions / Connective tissue diseases / Connective tissues / Constipation / COVID-19 / Diarrhea / Double-Blind Method / Female / Fusion protein / Humans / Immunology / Infectious Diseases / Life Sciences / Ligands / Lymphocytes B / Male / Metabolic Diseases / Middle Aged / Molecular Medicine / Neurosciences / Pathogenesis / Placebos / Population (statistical) / Respiratory tract / Respiratory tract infection / Rheumatism / Rheumatoid arthritis / Rhinopharyngitis / Sjogren's Syndrome / Sjogren's Syndrome - drug therapy / Sjogren's Syndrome - immunology / Standard error / Systemic lupus erythematosus / Treatment Outcome / Urinary tract