POS0734 DAPIROLIZUMAB PEGOL DEMONSTRATED SIGNIFICANT IMPROVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE ACTIVITY: EFFICACY AND SAFETY RESULTS OF A PHASE 3 TRIAL

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Background: Dapirolizumab pegol (DZP) is a novel, polyethylene glycol (PEG)-conjugated antigen-binding fragment (Fab'), lacking an Fc domain. DZP binds CD40L, blocking CD40-CD40L interactions and CD40 activation, and has broad modulatory effects on systemic lupus erythematosus (SLE) immunopathology, including reducing B and T cell activation and downregulating interferon pathways [1, 2]. Objectives: To report results of the phase 3 PHOENYCS GO trial (NCT04294667) which evaluated the efficacy and safety of DZP in patients with moderate-to-severe SLE. Methods: PHOENYCS GO was a 48-week, global, randomised, double-blind, placebo (PBO)-controlled trial. After the treatment period, patients could enter an open-label extension or complete a 6-week safety follow-up. Patients aged ≥16 years with moderate-to-severe, active SLE characterised by persistently active or frequently flaring/relapsing-remitting disease activity despite stable standard of care (SOC) medication (antimalarials, glucocorticoids and/or immunosuppressants) were included. Patients were randomised 2:1 to intravenous DZP 24 mg/kg plus SOC medication (DZP+SOC) or PBO+SOC every 4 weeks. The primary endpoint was British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response at Week 48. Secondary endpoints included SLE Responder Index (SRI)-4 response at Week 48, change from baseline in Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) at Week 48 and prevention of severe BILAG flares through Week 48. Other endpoints included the proportion of patients who achieved glucocorticoid tapering from >7.5 mg/day prednisone equivalent at baseline to ≤7.5 mg/day at Week 48, per EULAR 2019 treatment guidelines [3]. Results: Overall, 85.4% of randomised patients receiving DZP+SOC and 79.6% receiving PBO+SOC completed the study to Week 48 on treatment. Baseline characteristics were generally similar between treatment groups (Table 1). The primary endpoint was met; 49.5% (103/208) of patients receiving DZP+SOC versus 34.6% (37/107) of patients receiving PBO+SOC had BICLA response at Week 48 (p=0.0110; difference 14.6%; Figure 1). SRI-4 response at Week 48 was achieved by 60.1% (125/208) versus 41.1% (44/107) of patients receiving DZP+SOC versus PBO+SOC (nominal p=0.0014; difference 18.8%; Figure 1). At Week 48, a greater least squares (LS) mean change from baseline in SLEDAI-2K was seen in patients receiving DZP+SOC compared with PBO+SOC (−6.1 versus −4.2; nominal p=0.0001; difference −1.8). Through Week 48, 11.6% versus 23.4% of patients receiving DZP+SOC versus PBO+SOC had severe BILAG flares (nominal p=0.0257; difference 11.5%; Figure 1). Per protocol, patients with a glucocorticoid dose >7.5 mg/day prednisone equivalent at baseline were required to start tapering no later than Week 8 to reach ≤7.5 mg/day. In patients with glucocorticoid dose >7.5 mg/day at baseline, 72.4% (76/105) versus 52.9% (27/51) of patients receiving DZP+SOC versus PBO+SOC reduced their dose to ≤7.5 mg/day at Week 48 (nominal p=0.0404; difference 17.1%). Treatment-emergent adverse events (TEAEs) occurred in 82.6% of patients receiving DZP+SOC compared with 75.0% of patients receiving PBO+SOC; 9.9% of patients receiving DZP+SOC had serious TEAEs compared with 14.8% of patients receiving PBO+SOC. Opportunistic infections were reported in 2.8% and 0.9% of patients receiving DZP+SOC and PBO+SOC, respectively. There was 1 thromboembolic TEAE (myocardial infarction) and 1 death (due to gangrene-related sepsis) in patients with predisposing medical history receiving DZP+SOC. Conclusion: Treatment with DZP, a novel CD40L inhibitor, was associated with improvement in disease activity and glucocorticoid tapering in patients with SLE. DZP was generally well tolerated. REFERENCES: [1] Cutcutache I. Arthritis Rheumatol 2023;75 (suppl 9). [2] Powlesland A. Annals Rheum Dis 2024;83 (suppl 1):261. [3] Fanouriakis A. Ann Rheum Dis 2019;78:736–45. Acknowledgements: This study was funded by UCB and Biogen. Medical writing support provided by Costello Medical and funded by UCB and Biogen. Disclosure of Interests: Edward M. Vital Paid instructor for Novartis, speaker's bureau for AstraZeneca, Novartis and Otsuka, consultant for AbbVie, Alpine, AstraZeneca, Aurinia, BMS, Eli Lilly, Merck, Novartis, Otsuka, Pfizer, Roche and UCB, received grant/research support from AstraZeneca and Sandoz, Megan E.B. Clowse Consultant for GSK and UCB, received grant/research support from GSK and UCB, David Isenberg Consultant for AstraZeneca, Eli Lilly, GSK, Merck Serono, Novartis, Servier and UCB, Joan Merrill Consultant for AbbVie, Alexion, Almiral, Alumis, Amgen, AstraZeneca, Aurinia, Biogen, BMS, Eli Lilly, EMD Serono, Equillium, Genentech, Gilead, GSK, Kezar, Merck, Novartis, Ono, Remegen, Sanofi, Takeda, Tenet, UCB, Veloxis and Zenas, received grant/research support from AstraZeneca, BMS and GSK, Thomas Dörner Speaker's bureau for Novartis, consultant for AbbVie, Eli Lilly, Janssen, Roche/GNE and UCB, Michelle Petri Speaker's bureau Arthros-FocusMedEd, AstraZeneca and Aurinia, consultant for Amgen, AnaptysBio, Annexon Bio, AstraZeneca, Atara Biosciences, Aurinia, Autolus, Bain Capital, Baobab Therapeutics, Biocryst, Biogen, Boxer Capital, Cabaletta Bio, Caribou Biosciences, CTI Clinical Trial and Consulting Services, CVS Health, DualityBio, Escient Pharmaceuticals, Eli Lilly, EMD Serono, Emergent Biosolutions, Exo Therapeutics, Gentibio, GSK, iCell Gene Therapeutics, IQVIA, Innovaderm Research, Kezar Life Sciences, Kira Pharmaceuticals, Nexstone Immunology, Nimbus Lakshmi, Novartis, Ono Pharma, PPD Development, Proviant, Regeneron, Seismic Therapeutic, Senti Biosciences, Sinomab Biosciences, Steritas, Takeda, Tenet Medicines, TG Therapeutics, UCB, Variant Bio, Worldwide Clinical Trials and Zydus, received grant/research support from AstraZeneca, Aurinia, Eli Lilly, Exagen, GSK and Janssen, Eric Morand Paid instructor for AstraZeneca, speaker's bureau AstraZeneca, BMS and Roche, consultant for AbbVie, AstraZeneca, Biogen, BMS, Dragonfly, Eli Lilly, EMD Serono, GSK, Novartis, Remegen, Takeda and UCB, received grant/research support from AbbVie, Amgen, AstraZeneca, Biogen, BMS, Genentech, GSK, Eli Lilly, EMD Serono, Janssen, Novartis, Takeda and UCB, Teri Jimenez Shareholder of UCB, employee of UCB, Stephen Brookes Shareholder of Biogen, employee of Biogen, Janine Gaiha-Rohrbach Shareholder of Biogen, employee of Biogen, Christophe Martin Shareholder of UCB, employee of UCB, Annette Nelde Shareholder of Biogen, employee of Biogen, Christian Stach Shareholder of UCB, employee of UCB. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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