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.[1,2] In the phase 3 PHOENYCS GO trial (NCT04294667) in patients with SLE, DZP resulted in significant improvement in disease activity at Week 48 versus placebo (PBO) and was generally well tolerated.[3] Remission (based on Definition of Remission in SLE [DORIS]) and low disease activity (based on Lupus Low Disease Activity State [LLDAS]) are recommended treatment targets in SLE.[4] Achievement of both DORIS and LLDAS have been associated with reduced organ damage accrual and improved outcomes in patients with SLE.[5,6]

Objectives: To report the achievement of LLDAS and DORIS in patients with SLE treated with DZP in the phase 3 PHOENYCS GO trial.

Methods: PHOENYCS GO was a 48-week, global, randomised, double-blind, PBO-controlled trial. 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. Achievement of LLDAS in ≥50% of visits through Week 48, achievement of LLDAS by visit, cumulative number of visits in LLDAS through Week 48 and achievement of DORIS[7] by visit are reported. Differences in proportions between DZP+SOC and PBO+SOC, 95% CIs and p-values for achievement of LLDAS in ≥50% of visits and achievement of LLDAS and DORIS by visit were estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate controlling for stratification factors. The least squares (LS) means, difference between DZP+SOC and PBO+SOC, 95% CIs and p-values for the cumulative number of visits in LLDAS were estimated using analysis of covariance (ANCOVA) including stratification factors. All p-values are nominal and were not controlled for multiplicity. Analyses were performed on the full analysis set.

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 patients receiving DZP+SOC (n=208) and PBO+SOC (n=107; mean [SD] age: 43.5 [12.3] versus 41.5 [12.4] years; 92.8% versus 93.5% female; mean [SD] SLE Disease Activity Index-2K score: 10.7 [3.5] versus 11.2 [3.4]; mean [SD] Physician’s Global Assessment: 58.9 [14.1] versus 59.7 [14.1]; mean [SD] glucocorticoid dose at baseline: 7.9 [5.9] versus 9.6 [8.1] mg/day). Through 48 weeks, 23.6% of patients receiving DZP+SOC achieved LLDAS in ≥50% of visits, compared with 15.9% of patients receiving PBO+SOC (nominal p=0.1042). At Week 48, 40.9% of patients receiving DZP+SOC achieved LLDAS compared with 19.6% of patients receiving PBO+SOC (nominal p<0.0001; Figure 1). As early as Week 12 greater proportions of patients receiving DZP+SOC achieved LLDAS versus PBO+SOC (nominal p<0.05). The proportion of patients receiving DZP+SOC achieving LLDAS continued to rise through to Week 48, while in patients receiving PBO+SOC achievement of LLDAS plateaued from Week 28. The LS mean (SE) cumulative number of visits in LLDAS through Week 48 was greater in patients receiving DZP+SOC (2.9 [0.2]) than in patients receiving PBO+SOC (1.8 [0.3]; nominal p=0.0016; Figure 1). A higher proportion of patients receiving DZP+SOC versus PBO+SOC also achieved DORIS at Week 48 (19.2% versus 8.4%; nominal p=0.0056); more patients receiving DZP+SOC versus PBO+SOC also achieved DORIS at Weeks 20, 32 and 36 (nominal p<0.05; Figure 2).

Conclusion: Compared with PBO+SOC, treatment with DZP+SOC resulted in higher rates of achievement and time in the prognostically important endpoints of LLDAS and DORIS. These findings provide further insights into the potential benefits of treatment with DZP for patients with SLE.

REFERENCES: [1] Cutcutache I. Arthritis Rheumatol 2023;75 (suppl 9).

[2] Powlesland AS. Annals Rheum Dis 2024;83 (suppl 1):261.

[3] Clowse M. Arthritis Rheumatol 2024;76 (suppl 9).

[4] Parra Sánchez AR. Rheumatol Ther 2023;10:1459–77.

[5] Fanouriakis A. Ann Rheum Dis 2024;83:15–29.

[6] Tani C. Lupus Sci Med 2018;5:e000234.

[7] van Vollenhoven RF. Lupus Sci Med 2021;8:e000538.

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: Eric Morand Speaker’s bureau for AstraZeneca and BMS, consultant for AbbVie, AstraZeneca, Biogen, BMS, Dragonfly, Eli Lilly, EMD Serono, GSK, Janssen, Novartis, RemeGen and UCB, received grant/research support from AbbVie, Amgen, AstraZeneca, Biogen, BMS, Genentech, GSK, Eli Lilly, EMD Serono, Janssen, Novartis, Takeda and UCB, Lucy M. Carter Paid instructor for Alumis Inc., consultant for UCB, Maria Dall’Era Consultant for AstraZeneca, Aurinia, Biogen, Genentech, GSK and Janssen, Michelle Petri 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, Eli Lilly, EMD Serono, Emergent, Escient Pharmaceuticals, 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, 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, Teri Jimenez Shareholder of UCB, employee of UCB, Janine Gaiha-Rohrbach Shareholder of Biogen, employee of Biogen, Bernard Lauwerys Shareholder of UCB, employee of UCB, Annette Nelde Shareholder of Biogen, employee of Biogen, Christian Stach Shareholder of UCB, employee of UCB, Ronald F. van Vollenhoven Consultant and/or speaker for AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, Pfizer, RemeGen and UCB, received grant/research support from Alfasigma, AstraZeneca, BMS, Galapagos, MSD, Novartis, Pfizer, Roche, Sanofi and UCB.

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