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Abstract
Background Wide-ranging placebo responses challenge SLE trials. This analysis aims to identify predictors of SOC+PBO response in patients with SLE.
Methods Analyses used the SOC+PBO arm of the phase 2b trial of dapirolizumab pegol (NCT02804763), a polyethylene glycol conjugated antigen-binding fragment lacking a functional Fc domain, which inhibits CD40-CD40L interaction.¹ Response was assessed by BILAG-based Composite Lupus Assessment (BICLA) response at Week 24.² Univariate/multivariate analyses were performed, with 22 previously determined potential predictors. Stepwise multivariate analysis included univariate predictors with p<0.25, using p≤0.10 as entry/stay criteria. Disease activity at screening was defined using BILAG 2004 item level scores as acute flare (worsening/new symptoms) or persistent (symptoms the same) based on the past 4 weeks compared with the prior 4 weeks; low C3/C4 was defined as below the lower limit of normal at screening. Results were supported by additional biologic clinical trial datasets.
Results Univariate analysis found the following significant predictors of BICLA non-response at Week 24 (p<0.05): persistent disease (vs acute flare; p=0.003), low C3 and/or C4 (vs normal; p=0.007), low C4 (vs normal; p=0.007), low C3 (vs normal; p=0.042), and SLEDAI-2K score ≥10 (vs <10; p=0.044) (figure 1). In the multivariate stepwise analysis, significant predictors of BICLA non-response (odds ratio [OR]; [95% confidence interval]; p<0.05) were persistent disease (vs acute flare; 0.047 [0.004, 0.491]; p=0.011) and low C4 (vs normal; 0.094 [0.010, 0.857]; p=0.036).
To explore the impact of identified predictors, subgroup analyses showed a higher proportion of patients with acute flare without low C3/C4 (n=10) achieved BICLA response at Week 24 vs patients with acute flare and low C3/C4 or persistent disease activity (n=33) (80.0% vs 24.2%; p=0.005 for OR vs acute flare without low C3/C4).
Conclusions Acute flare with normal complement predicted high placebo response in this analysis. Recent medical history should be considered when defining SLE study populations.
Univariate analysis of predictors of BICLA response at Week 24 in patients who received SOC+PBO. Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; BICLA: BILAG-based Composite Lupus Assessment; BILAG: British Isles Lupus Assessment Group; CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; m: months; PBO: placebo; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; SOC: standard of care.
References
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