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

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

  • Nat Med. 2024 Jun;30(6):1583-1592. doi: 10.1038/s41591-024-03009-3.
E William St Clair 1,  Alan N Baer 2,  Wan-Fai Ng 3 4 5,  Ghaith Noaiseh 6,  Chiara Baldini 7,  Teresa K Tarrant 8 9,  Athena Papas 10,  Valerie Devauchelle-Pensec 11,  Liangwei Wang 12,  Wenjing Xu 12,  Tuyet-Hang Pham 12,  Keith Sikora 12,  William A Rees 12,  Ilias Alevizos 12
Affiliations

Affiliations

  • 1 Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC, USA. eugene.st.clair@duke.edu.
  • 2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 4 NIHR Newcastle Biomedical Research Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 5 HRB Clinical Research Facility, University College Cork, Cork, Ireland.
  • 6 Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, University of Kansas, Kansas City, KS, USA.
  • 7 Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa, Italy.
  • 8 Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC, USA.
  • 9 Durham Veterans' Administration Hospital, Durham, NC, USA.
  • 10 Division of Oral Medicine, Tufts School of Dental Medicine, Boston, MA, USA.
  • 11 Department of Rheumatology, Brest University Hospital and INSERM U1227, Brest, France.
  • 12 Amgen Inc., Thousand Oaks, CA, USA.
PMID: 38839899 DOI: 10.1038/s41591-024-03009-3
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 .

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