OP0058 DAZODALIBEP (ANTI-CD40L) EFFECTIVELY REDUCES MULTIPLE PROTEINS ASSOCIATED WITH B-, T-, AND DENDRITIC CELL BIOMARKERS IN SJӦGREN’S DISEASE: CORROBORATION OF IMMUNOPHENOTYPING FINDINGS FROM THE ALISS PHASE 2 STUDY

Background:

Dazodalibep (DAZ) is a non-antibody fusion protein that acts as a CD40L antagonist and blocks costimulatory signals between immune cells, including T cells, B cells, and antigen-presenting cells. CD40L inhibition disrupts costimulatory signals that lead to activation of germinal centers (GC) and the formation of pathogenic B cells, plasma cells, and autoantibodies, mechanistic hallmarks of Sjögren's Disease.

Objectives:

To evaluate the effects of DAZ on the serum proteome in the ALISS phase 2 clinical trial of subjects with Sjogren's disease (NCT04129164).

Methods:

This study enrolled two distinct populations with Sjögren's disease. Population 1 (Pop1) included 74 subjects with moderate-to-severe systemic disease activity as defined by the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥ 5. Population 2 (Pop2) consisted of 109 subjects with unacceptable symptom burden and limited extraglandular systemic involvement as defined by the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5 and ESSDAI < 5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo. The Olink Explore 3072 panel was used to comprehensively profile the serum proteome at baseline, Day 15, and Day 169. Protein profiles were analyzed using AUC-ROC analysis to identify proteins which differentiated subjects with Sjogren's disease at baseline from age-matched healthy individuals (n=50) with AUC-ROC > 0.7. A mixed linear model was applied to identify proteins impacted by DAZ treatment with Benjamini Hochberg FDR < 10%. Matrix decomposition techniques and pathways analysis were applied to identify protein networks within the dataset. Factor Analysis followed by a Varimax rotation was further used to identify proteins that shared correlation with high loadings (> 0.45) across a common vector.

Results:

A combination of unsupervised machine learning and statistical analysis identified a core set of 29 correlated proteins elevated in subjects with Sjogren's disease at baseline compared to healthy individuals that were impacted by DAZ treatment. We found no significant differences at baseline in these biomarkers between Pop 1 and Pop 2 despite the difference in clinical disease manifestation. Pathway assessments revealed these 29 biomarkers were enriched for activation of B-, T-, and dendritic cells (e.g., LAMP3) and were significantly reduced (FDR < 10%) in Pop1 and Pop2 subjects with Sjӧgren's disease by DAZ treatment.

Conclusion:

Compared to a healthy cohort, serum proteomics profiling revealed a core set of 29 biomarkers elevated in subjects with Sjogren's disease at baseline and were associated with inflammatory and adaptive immune responses, particularly activation of B-, T-, and dendritic cells. Importantly, these biomarkers were shown to be significantly reduced by DAZ. These proteomics findings corroborate previous immunophenotyping flow cytometry data from the ALISS phase 2 study that demonstrated significant reductions of B and T cell activation and proliferation by DAZ in subjects with Sjogren's disease across populations with either moderate-to-severe disease activity or high symptomatic burden.

REFERENCES:

NIL.

Acknowledgements:

Medical writing support provided by B Lujan, PhD, CMPP, an employee of Amgen Inc. (formerly Horizon Therapeutics plc).

Disclosure of Interests:

Tuyet-Hang Pham is an employee of Amgen, and owns stock, Michael A. Smith is an employee of Amgen, and owns stock, Ilias Alevizos is an employee of Amgen, and owns stock, E. William St. Clair has consulted for Amgen, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics, and receive royalties from UpToDate, Claire Emson is an employee of Amgen, and owns stock.