AB0746 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
Authors: T. H. Pham, M. A. Smith, N. Mittereder, I. Alevizos, E. W. St. Clair, C. Emson
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Dazodalibep (DAZ) is a non-antibody fusion protein which targets CD40L and inhibits costimulatory signals between immune cells, including T cells, B cells, and antigen-presenting cells. CD40L blockade disrupts the formation of germinal centers (GCs), pathogenic B cells, and plasma cells, and the production of autoantibodies in rheumatoid arthritis. CXCL13 is a critical chemokine that enables T- and B-cell migration to the GC and their serum levels may reflect GC formation and activity. <h3>Objectives:</h3> To assess the impact of DAZ on T- and B-cells in using data from the MIDORA phase 2 clinical trial of patients with rheumatoid arthritis (RA, NCT04163991). <h3>Methods:</h3> This biomarker study focused on a total of 47 adult patients with moderate-to-severe active RA that responded inadequately to methotrexate, other conventional disease-modifying anti-rheumatic drugs, or tumor necrosis factor-α inhibitors. Eligible participants in this biomarker study were randomized to receive 1500 mg or 3000 mg intravenously of DAZ or placebo. Disease activity was assessed using the Disease Activity Score-28 with C-Reactive Protein (DAS28-CRP), Patient Global Assessment (PGA), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Physician Global Assessment of Disease Activity (MDGA), Tender Joint Count (TJC), and Swollen Joint Count (SJC). Flow cytometry of whole blood was performed to examine for any changes in B and T cell subsets such as plasmablasts (CD27<sup>br</sup>/CD38<sup>br</sup>/IgD- subsets of CD19+ cells), precursor memory B cells (CD11c<sup>br</sup> subsets of CD19+ cells), T follicular helper cells (CXCR5+/ICOS+ subsets of CD3+/CD4+ cells), proliferation of post-switch memory B cells (Ki67+ subsets of CD27<sup>br</sup>/IgD-/CD19+ cells), and proliferation of total T-cells (Ki67+ subsets of CD3+ cells). Serum levels of CXCL13 and rheumatoid factor (RF) autoantibodies were assessed by immunoassay and nephelometry, respectively. <h3>Results:</h3> DAZ improved DAS28-CRP, PGA, SDAI, CDAI, and MDGA scores, as well as tender and swollen joint total counts in RA participants.<sup>1</sup> Compared to placebo, DAZ treatment also was associated with a reduction in the number of plasmablasts (CD27<sup>br</sup>/CD38<sup>br</sup>/IgD- subsets of CD19+ cells) and T follicular helper cells (CXCR5+/ICOS+ subsets of CD3+/CD4+ cells); the proliferation of post-switch memory B cells (Ki67+ subsets of CD27<sup>br</sup>/IgD-/CD19+ cells) and proliferation of total T-cells (Ki67+ subsets of CD3+ cells); and decreases in serum levels of CXCL13 and RF. No changes were found in the numbers of precursor memory B cells (CD11c<sup>br</sup> subsets of CD19+ cells). <h3>Conclusion:</h3> DAZ-mediated CD40L blockade in patients with moderate-to-severe active RA demonstrated significant improvements in disease activity scores such as DAS28-CRP, Patient Global Assessment, SDAI, CDAI, and Physician Global Assessment including tender and swollen joint counts. Additionally, DAZ reduced biomarkers of T- and B-cell costimulatory blockade, and inhibition of GC formation activity, and autoantibody production. Together, these data demonstrate the biological impact of CD40-CD40L pathway blockade on selected blood biomarkers in RA. <h3>REFERENCES:</h3> [1] Kivitz, A., et al.. <i>RMD Open</i> 2023. 9 (3). <h3>Acknowledgements:</h3> Medical writing support provided by B Lujan, PhD, CMPP, an employee of Amgen Inc. (formerly Horizon Therapeutics plc). <h3>Disclosure of Interests:</h3> Tuyet-Hang Pham owns stock, is an employee of Amgen, Michael A. Smith owns stock, is an employee of Amgen, Nanette Mittereder owns stock, is an employee of Amgen, Ilias Alevizos owns stock, is an employee of Amgen, E. William St. Clair has consulted for Amgen, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics, and receives royalties from UpToDate, Claire Emson owns stock, is an employee of Amgen.