POS0334 DAPIROLIZUMAB PEGOL IMPACTS IMPORTANT IMMUNOLOGIC PATHWAYS IN SYSTEMIC LUPUS ERYTHEMATOSUS: PHARMACODYNAMIC ANALYSIS OF B CELL AND TYPE I INTERFERON PATHWAYS FROM A PHASE 2B TRIAL

Background:

The pivotal role of CD40-CD40L interactions in systemic lupus erythematosus (SLE) pathogenesis stems from the orchestration of a range of immune and inflammatory responses involving B cells, T cells, other antigen-presenting cells, and type I interferon (IFN) production.[1,2] Dapirolizumab pegol (DZP), a polyethylene glycol-conjugated antigen-binding fragment lacking a functional Fc domain that inhibits CD40L, was associated with improvements in several measures of disease activity in the phase 2b RISE trial in SLE (NCT02804763).[3] DZP is under investigation in an ongoing phase 3 trial in patients (pts) with SLE (PHOENYCS GO; NCT04294667).

Objectives:

To conduct a post hoc pharmacodynamic analysis to explore the impact of DZP on B cell and type I IFN pathways using data from the phase 2b RISE trial.[3]

Methods:

In RISE, pts received placebo (PBO) or DZP (6/24/45 mg/kg) alongside standard of care (SOC) for 24 weeks (wks); adults with active SLE with moderate-to-severe disease manifestations receiving stable doses of SOC treatments were included in the trial.[3] Analyses focused on a subgroup of pts from RISE similar to the PHOENYCS GO population, namely those with persistent active SLE or acute worsening of SLE in the scope of frequent flaring/relapsing-remitting disease (n=131), previously identified as predictors of a lower response to SOC+PBO.[4] Results are shown for the PBO and DZP 24 mg/kg arms. RNA sequencing was performed on available blood samples at baseline, Wks 2, 4, 12, and 24 (Wks 2 and 24 only presented). Samples were not available for all pts at all timepoints. Gene expression changes were analyzed and competitive gene set analyses performed for pathways relevant to SLE immunopathology, selected from Gene Ontology Biological Processes and augmented with gene signatures that discriminate immune cell types in SLE.[5-7] Differential expression results for DZP treatment were corrected for SOC effects. Pts were also stratified post hoc by baseline type I IFN expression levels using a 4 gene type I IFN signature.[8]

Results:

DZP significantly downregulated genes related to immunoglobulin production compared with PBO, and this effect was observed as early as Wk 2 following a single dose (Figure 1A). A similar trend was observed in clinical levels of autoantibodies (anti-dsDNA), which has been previously reported.[3] Compared with PBO, DZP also significantly downregulated genes that play a critical role in B cell biology, specifically those involved in B cell-mediated immunity and B cell receptor signaling pathways (Figure 1B). At baseline, across all treatment arms, 76/120 (63.3%) pts showed a high type I IFN gene signature. In pts with high expression, DZP caused a marked and sustained inhibition of type I IFN gene signatures compared with PBO; this inhibitory effect was observed as early as Wk 2 (Figure 1C).

Conclusion:

DZP broadly suppresses B cell biology, decreasing the expression of numerous gene sets involved in B cell activation and immunoglobulin production. DZP also decreases expression of type I IFN signatures in pts with high baseline type I IFN expression. The impacts of DZP were seen as early as Wk 2 following a single dose. These findings demonstrate the potent modulatory effects of DZP in SLE immunopathology.

REFERENCES:

[1] Ramanujam M. Autoimmun Rev. 2020;19(11):102668. [2] Rönnblom L. Lupus Sci Med. 2019;6(1):e000270. [3] Furie RA. Rheumatology (Oxford). 2021;60:5397–407. [4] Askanase A. Ann Rheum Dis. 2023;82(Suppl 1):272. [5] Wu D. Nucleic Acids Res. 2012;40(17):e133. [6] Mandric I. Nat Commun. 2020;11(1):5504. [7] Gene Ontology Consortium. Nucleic Acids Res. 2021;49(D1):D325–34. [8] Felten R. Drug Des Devel Ther. 2019;13:1535–1543.

Acknowledgements:

Funded by UCB Pharma and Biogen Inc. Medical writing support provided by Costello Medical and funded by UCB Pharma and Biogen Inc.

Disclosure of Interests:

Ioana Cutcutache Shareholder of UCB Pharma, Employee of UCB Pharma, Alex S. Powlesland Former employee of UCB Pharma, Andrew Skelton Shareholder of UCB Pharma, Employee of UCB Pharma, Yunyun Sun Former employee of UCB Pharma, Matthew Page Shareholder of UCB Pharma, Employee of UCB Pharma, George Stojan Shareholder of UCB Pharma, Employee of UCB Pharma, Peter E. Lipsky Employee of AMPEL BioSolutions, LLC, Ania Skowera Shareholder of UCB Pharma, Employee of UCB Pharma, Christian Stach Shareholder of UCB Pharma, Employee of UCB Pharma.