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
  • 1. Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC, USA. [email protected].
  • 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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