Dazodalibep Significantly Improves Disease Activity in Rheumatoid Arthritis

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Dazodalibep significantly improves disease activity and swollen and tender joint counts in patients with moderate-to-severe active rheumatoid arthritis (RA), according to new findings from the Phase 2 MIDORA clinical trial.¹

The drug, a non-antibody fusion protein that targets CD40L, also reduced biomarkers of T- and B-cell costimulatory blockage and inhibited germinal center formation activity and autoantibody production, in a population with RA.

These data were presented at the 2024 European Congress of Rheumatology (EULAR) in Madrid, Spain.

“Dazodalibep-mediated CD40L blockade in patients with moderate-to-severe active RA demonstrated significant improvements in disease activity scores such as Disease Activity Score-28 with C-Reactive Protein (DAS28-CRP), Patient Global Assessment (PGA), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and Physician Global Assessment including tender (TJC) and swollen joint counts (SJC),” wrote investigators, led by Tuyet-Hang Pham, Clinical Biomarkers and Diagnostics, Amgen Inc.¹

Dazodalibep targets CD40L and inhibits costimulatory signals between immune cells, including T cells, B cells, and antigen-presenting cells.² Its blockade can disrupt the formation of germinal centers, pathogenic B cells, and plasma cells, as well as autoantibody production in RA.

CXCL13 is a significant chemokine enabling T- and B-cell migration to the germinal center.³ Thus, serum levels of CXCL13 can represent germinal center formation and activity. In this biomarker analysis, investigators sought to evaluate the effect of dazodalibep on T- and B-cells using data from the MIDORA trial of patients with RA.¹

A total of 47 adult patients with moderate-to-severe active RA who responded inadequately to methotrexate, other conventional disease-modifying anti-rheumatic drugs, or tumor necrosis factor-α inhibitors were enrolled for the study. Those eligible were randomized to receive 1500 mg or 3000 mg intravenous dazodalibep or placebo.

For the analysis, disease activity was measured using the DAS28-CRP, PGA, SDAI, CDAI, PGA of Disease Activity (MDGA), TJC, and SJC. Flow cytometry of whole blood was performed to examine for any changes in B- and T-cell subsets, including plasmablasts (CD27 br /CD38 br /IgD- subsets of CD19+ cells), precursor memory B cells (CD11c br subsets of CD19+ cells), T follicular helper cells (CXCR5+/ICOS+ subsets of CD3+/CD4+ cells), the proliferation of post-switch memory B cells (Ki67+ subsets of CD27 br /IgD-/CD19+ cells), and the proliferation of total T-cells (Ki67+ subsets of CD3+ cells).

Immunoassay and nephelometry were used to assess serum levels of CXCL13 and rheumatoid factor autoantibodies, respectively.

Upon analysis, dazodalibep benefited DAS28-CRP, PGA, SDAI, CDAI, and MDGA scores, including TJC and SJC total counts, in participants with RA. Compared with placebo, dazodalibep also reduced the number of plasmablasts and T follicular helper cells, as well as the proliferation of post-switch memory B cells and total T-cells.

Further, dazodalibep was linked to decreases in serum levels of both CXCL13 and Rheumatoid Factor. Pham and colleagues identified no changes in the amount of precursor memory B cells

“Together, these data demonstrate the biological impact of CD40-CD40L pathway blockade on selected blood biomarkers in RA,” they added.

References

1. _{Pham TH, Smith MA, Mittereder N, Alevizos I, St. Clair EW, Emson C. CD40L Blockade with Dazodalibep Significantly IMproves Disease Activity, Swollen and Tender Joint Counts, While Reducing Multiple T- and B-Cell Biomarkers in the MIDORA Phase 2 Study of Patients with Moderate-To-Severe Active Rheumatoid Arthritis. Presented at EULAR 2024. Vienna, Austria. June 12 – 15, 2024.}
2. _{Smith M, Mittereder N, Gunsior M, et alPOS0815 CD40L Blocks with Dazodalibep (VIB4920/HZN4920) Reduces Blood Biomarkers of T and B Cell Costimulation in Sujects with Systemic Sjogren's Syndrome Annals of the Rheumatic Diseases 2023;82:702-703.}
3. _{Crichton ES, Zeng S, La Muraglia GM 2nd, Badell IR. CXCL13 Is an Indicator of Germinal Center Activity and Alloantibody Formation Following Transplantation. Transplant Direct. 2021;7(12):e785. Published 2021 Nov 5. doi:10.1097/TXD.0000000000001247}