In a significant advancement for the treatment of Sjögren’s disease (SjD), a phase 2 clinical trial published in Nature Medicine has demonstrated the efficacy of dazodalibep (DAZ), a CD40 ligand antagonist, in reducing disease activity and symptoms. This randomized, double-blinded, placebo-controlled study involved two distinct populations of SjD patients, revealing promising results that could pave the way for new therapeutic approaches.
The trial, which incorporated a crossover stage, involved participants diagnosed with SjD, with a subset also suffering from associated connective tissue diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus. Population 1 consisted of patients with moderate-to-severe systemic disease activity, while Population 2 included those with a high symptom burden but limited systemic organ involvement. These groups comprised 74 and 109 participants, respectively.
In Population 1, treatment with DAZ led to a significantly greater reduction in ESSDAI scores, with a mean change from −6.3 ± 0.6 for DAZ, compared to −4.1 ± 0.6 for the placebo group (P 0.0167). Similarly, in Population 2, DAZ resulted in a significant improvement in ESSPRI scores, with a mean change of −1.8 ± 0.2 with DAZ, compared to −0.5 ± 0.2 for placebo (P 0.0002). These results highlight the potential of DAZ as an effective treatment option for SjD, particularly in patients with varying degrees of disease severity. DAZ was generally well tolerated among participants, with the most frequently reported adverse events including COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infections, arthralgia, constipation, and urinary tract infections. Despite these side effects, the safety profile of DAZ remained favorable throughout the study.
DAZ is a non-antibody biologic that antagonizes CD40 ligand. In several autoimmune diseases, including SjD, the CD40/CD40L pathway is activated across various cell types, such as T cells, B cells, antigen-presenting cells, and activated epithelial cells. DAZ disrupts this pathway by blocking costimulatory signals between T cells and CD40-expressing B cells, thereby inhibiting the formation of germinal centers, pathogenic B cells, plasma cells, and autoantibodies, which are characteristic of SS. The development of first-generation anti- CD40 ligand monoclonal antibodies (mAbs) was discontinued due to thromboembolic complications caused by the Fc region of their mAb structure. To avoid this issue, DAZ was engineered with antigen-binding sites on a Tn3 scaffold, a non-mAb platform that lacks an Fc region. Unlike first-generation anti-CD40 ligand mAbs, DAZ does not induce platelet aggregation in vitro, and clinical trials involving healthy individuals and participants with RA have not shown any thromboembolic safety concerns.
The findings of this trial suggest that DAZ could be a promising new therapy for SjD, particularly given its role in modulating the CD40/CD40 ligand pathway, which is believed to be central to the disease’s pathogenesis. As SjD patients and healthcare providers eagerly await further research, this study marks a hopeful step toward improving the lives of those affected by this chronic autoimmune condition.
References
- St Clair EW, Baer AN, Ng WF, Noaiseh G, Baldini C, Tarrant TK, et al. 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.
- Smith M, Mittereder N, Gunsior M, Karnell J, Legrand F, Der K, et al. Pos0815 Cd40l Blockade with Dazodalibep (vib4920/Hzn4920) Reduces Blood Biomarkers of T and B Cell Costimulation in Subjects with Systemic Sjögren’s Syndrome. Annals of the Rheumatic Diseases. 2023 Jun 1;82(Suppl 1):702–3.