To Örebro University

Background: Fatigue is a common manifestation of systemic lupus erythematosus (SLE). It is associated with severe impairments to patients' quality of life, diminishes their function, and can be particularly difficult to treat. 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 SLE immunopathology. 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 [6].

Objectives: To report the impact of DZP on patient-reported fatigue in patients with SLE participating 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. Fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and FATIGUE-PRO, a measure recently developed to capture the patient experience of fatigue in SLE. FACIT-Fatigue assesses levels of fatigue during usual daily activities over the past seven days, based on responses to 13 questions using a five-point Likert scale [8, 9]. The FACIT-Fatigue score ranges from 0 to 52, with lower scores indicating more fatigue and an increase in score over time reflecting improvement. FATIGUE-PRO captures the patient experience of fatigue and consists of 31 items across three scales: Physical Fatigue, Mental Fatigue and Susceptibility to Fatigue. A score ranging from 0 to 100 is calculated for each scale based on patients' responses about how frequently they experienced fatigue in the past seven days, with higher scores indicating more fatigue and a decrease in score over time reflecting improvement. The least squares (LS) mean change from baseline is reported for FACIT-Fatigue at Weeks 12, 24, 36 and 48, and for the three FATIGUE-PRO scales at Weeks 4, 8, 12, 24, 36 and 48. The LS mean, difference between DZP+SOC and PBO+SOC, 95% CIs and p-values were computed using a mixed model for repeated measurements (MMRM). For FACIT-Fatigue, the proportion of patients with an improvement of ≥4 (minimal clinically important difference [MCID]) [10] at Week 48 is also reported. The difference in proportion of responders between DZP+SOC and PBO+SOC, 95% CIs and p-values were estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate controlling for 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 fatigue scores were comparable between patients receiving DZP+SOC (n=208) and PBO+SOC (n=107; Table 1). Mean baseline FACIT-Fatigue scores were <30 for both groups (median: DZP+SOC: 28.0; PBO+SOC: 27.0), indicating substantial fatigue. Patients receiving DZP+SOC demonstrated consistently larger LS mean change from baseline in FACIT-Fatigue score, reflecting greater improvement, compared with PBO+SOC at all assessed visits (nominal p<0.05 for all; Figure 1). At Week 48, the LS mean change from baseline in FACIT-Fatigue was 8.9 versus 5.2 for patients receiving DZP+SOC versus PBO+SOC (difference: 3.7; nominal p=0.0024; Figure 1). A greater proportion of patients receiving DZP+SOC (50.5%) achieved an improvement of ≥4 (MCID) in FACIT-Fatigue at Week 48 compared with PBO+SOC (35.5%; difference: 14.5% [95% CI: 3.0, 25.9]; nominal p=0.0131). Similarly, the LS mean change from baseline in scores for all three FATIGUE-PRO scales was greater for patients receiving DZP+SOC compared with PBO+SOC at Week 48 (nominal p<0.05; Figure 1). Greater differences (nominal p<0.05) in patients receiving DZP+SOC compared with PBO+SOC were observed in the Physical Fatigue scale as early as Week 4 and at all visits from Week 12 onwards, in the Mental Fatigue scale at Weeks 36 and 48, and in the Susceptibility to Fatigue scale at all visits from Week 8 onwards.

Conclusion: Improvements in FACIT-Fatigue and all FATIGUE-PRO scales were greater in patients treated with DZP+SOC versus PBO+SOC. Alongside the previously reported significant improvements in overall SLE disease activity, these data support the potential of DZP as a valuable treatment option for improving fatigue in SLE.