학술논문
CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.
Document Type
Academic Journal
Author
St Clair EW; Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC, USA. eugene.st.clair@duke.edu.; Baer AN; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Ng WF; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; NIHR Newcastle Biomedical Research Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; HRB Clinical Research Facility, University College Cork, Cork, Ireland.; Noaiseh G; Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, University of Kansas, Kansas City, KS, USA.; Baldini C; Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa, Italy.; Tarrant TK; Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC, USA.; Durham Veterans' Administration Hospital, Durham, NC, USA.; Papas A; Division of Oral Medicine, Tufts School of Dental Medicine, Boston, MA, USA.; Devauchelle-Pensec V; Department of Rheumatology, Brest University Hospital and INSERM U1227, Brest, France.; Wang L; Amgen Inc., Thousand Oaks, CA, USA.; Xu W; Amgen Inc., Thousand Oaks, CA, USA.; Pham TH; Amgen Inc., Thousand Oaks, CA, USA.; Sikora K; Amgen Inc., Thousand Oaks, CA, USA.; Rees WA; Amgen Inc., Thousand Oaks, CA, USA.; Alevizos I; Amgen Inc., Thousand Oaks, CA, USA.
Source
Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
Subject
Language
English
Abstract
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 .
(© 2024. The Author(s).)
(© 2024. The Author(s).)