PO:14:193 | Dapirolizumab Pegol Demonstrated Significant Improvement in Systemic Lupus Erythematosus Disease Activity: Efficacy and Safety Results of a Phase 3 Trial

Megan EB Clowse¹, Marta Mosca², David A Isenberg³, Joan T Merrill⁴, Thomas Dörner⁵, Michelle Petri⁶, Edward M Vital^7|8, Eric F Morand⁹, Teri Jimenez¹⁰, Stephen Brookes¹¹, Janine Gaiha-Rohrbach¹², Christophe Martin¹³, Annette Nelde¹⁴, Christian Stach¹⁵ | ¹Duke University - Division of Rheumatology and Immunology Durham, USA; ²University of Pisa - Rheumatology Unit, Department of Clinical and Experimental Medicine Pisa, Italy; ³University College London - Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine London, United Kingdom; ⁴Oklahoma Medical Research Foundation Oklahoma City, USA; ⁵Charité Universitätsmedizin Berlin - Department of Medicine/Rheumatology and Clinical Immunology Berlin Germany; ⁶Johns Hopkins University School of Medicine Baltimore, USA; ⁷University of Leeds - Leeds Institute of Rheumatic and Musculoskeletal Medicine Leeds, United Kingdom; ⁸Leeds Teaching Hospitals NHS Trust - NIHR Leeds Biomedical Research Centre Leeds, United Kingdom; ⁹Monash University - Centre for Inflammatory Diseases Melbourne, Australia; ¹⁰UCB Raleigh, USA; ¹¹Biogen Maidenhead, United Kingdom; ¹²Biogen Cambridge, USA; ¹³UCB Slough, United Kingdom; ¹⁴Biogen Baar, Switzerland; ¹⁵UCB Monheim am Rhein, Germany

Purpose of the Work. Dapirolizumab pegol (DZP) is a novel CD40L inhibitor with broad modulatory effects on systemic lupus erythematosus (SLE) immunopathology; it consists of a polyethylene glycol (PEG)-conjugated antigen-binding fragment (Fab’), which lacks an Fc domain. We report results of the phase 3 PHOENYCS GO trial (NCT04294667) of DZP in SLE.

Materials and Methods. PHOENYCS GO was a 48-week (wk), randomised, double-blind, placebo (PBO)-controlled trial. After the treatment period, patients (pts) could enter an open-label extension or complete a 6-wk safety follow-up. Pts >=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. Pts were randomised 2:1 to intravenous DZP 24 mg/kg plus SOC (DZP+SOC) or PBO+SOC every 4 wks. Primary endpoint was BICLA response at Wk 48. Secondary endpoints included SRI-4 response at Wk 48, change from baseline in SLEDAI-2K at Wk 48 and prevention of severe BILAG flares through Wk 48. Other endpoints included glucocorticoid tapering from >7.5 mg/day prednisone equivalent at baseline to <=7.5 mg/day at Wk 48.

Results. The study was completed to Wk 48 on treatment by 85.4% (182/213) of pts randomised to DZP+SOC and 79.6% (86/108) randomised to PBO+SOC. Baseline characteristics were generally similar between groups (Table). The primary endpoint was met; 49.5% (103/208) of pts receiving DZP+SOC vs 34.6% (37/107) receiving PBO+SOC had BICLA response at Wk 48 (p=0.0110; Figure). SRI-4 response at Wk 48 was achieved by 60.1% (125/208) vs 41.1% (44/107) of pts receiving DZP+SOC vs PBO+SOC (nominal p=0.0014; Figure). At Wk 48, pts receiving DZP+SOC had a greater least squares mean change from baseline in SLEDAI-2K vs PBO+SOC (-6.1 vs -4.2; nominal p=0.0001). Through Wk 48, 11.6% vs 23.4% of pts receiving DZP+SOC vs PBO+SOC had severe BILAG flares (nominal p=0.0257; Figure). Per protocol, pts with a glucocorticoid dose >7.5 mg/day prednisone equivalent at baseline were required to start tapering no later than Wk 8 to reach <=7.5 mg/day. In pts with glucocorticoid dose >7.5 mg/day at baseline, 72.4% (76/105) vs 52.9% (27/51) of pts receiving DZP+SOC vs PBO+SOC reduced to <=7.5 mg/day at Wk 48 (nominal p=0.0404). Treatment-emergent adverse events (TEAEs) occurred in 82.6% vs 75.0% of pts receiving DZP+SOC vs PBO+SOC; 9.9% of pts receiving DZP+SOC had serious TEAEs vs 14.8% of pts receiving PBO+SOC. Opportunistic infections were reported in 2.8% and 0.9% of pts receiving DZP+SOC and PBO+SOC, respectively. There was 1 thromboembolic TEAE (myocardial infarction) and 1 death (due to gangrene-related sepsis) in pts with predisposing medical history receiving DZP+SOC.

Conclusions. Treatment with DZP, a novel CD40L inhibitor, was associated with improvement in disease activity and glucocorticoid tapering in pts with SLE. DZP was generally well tolerated.