Background and aims Binding of CD40 ligand (CD40L) to CD40 activates B cells, antigen-presenting cells and platelets. Evidence suggests CD40L blockade might provide an effective treatment for systemic autoimmune disorders, including systemic lupus erythematosus (SLE). We report data from a Phase I double-blind, multiple dose study (NCT01764594) of dapirolizumab pegol (DZP), a PEGylated anti-CD40L Fab’ fragment, in SLE patients.
Methods Twenty-four SLE patients were randomised (2:1, stratified by the presence of anti-phospholipid antibodies) to receive DZP (loading dose 30 mg/kg, then 15 mg/kg every 2 weeks for 10 weeks) or placebo. Patients were followed for 18 weeks. Objectives: safety and tolerability of DZP (primary); disease activity measures (BICLA and SRI-4; exploratory). Genes expressed by plasma cells, B cells, other immune cells and transcripts associated with SLE disease activity were analysed by qPCR.
Results No serious adverse events (AEs), thromboembolic events or deaths occurred. Most treatment-emergent AEs (TEAEs) were mild or moderate, transient, and resolved without intervention. Nasopharyngitis was the most common TEAE (6 patients in the DZP group; none with placebo). One patient withdrew due to upper respiratory tract infection (DZP group). Of DZP-treated patients evaluable for BICLA and SRI-4, 46% and 42% respectively, responded by Week 12 (vs 14% placebo; Table 1). Rapid and maintained mechanism-related gene expression changes were observed, particularly in plasma cell genes (IgA, IgG, IgJ) from the DZP group.
Conclusions DZP was well tolerated and demonstrated improvement in clinical measures of disease activity. A Phase II study is evaluating efficacy and safety of DZP in SLE patients (NCT02804763).
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