Although there have been some advances in recent years, systemic lupus erythematosus (SLE) remains a significant unmet medical need
It is a heterogeneous autoimmune disease associated with a diffuse immune cell dysfunction. As the CD40–CD40 ligand interaction activates the B-cells, antigen presenting cells and platelets, it may be possible that blocking this process could be effective in treating autoimmune diseases such as SLE.
Such a drug is under development at UCB. Dapirolizumab pegol is a polyethylene glycol conjugated anti-CD40L Fab’ fragment. In a randomised, double-blind, single-dose, dose-escalation first-in-human study, 28 healthy individuals were given 0.004–5 mg/kg of the drug in the first part; in the second part, 17 patients with SLE were given doses of 5–60 mg/kg or a placebo.1
Although 76% of the healthy subjects and all those with SLE experienced adverse events, most were mild or moderate. Exposure to the drug increased in a dose-proportional manner.
In another, 32-week, randomised, double-blind study, 24 patients with SLE were given 30 mg/kg of the drug followed by 15 mg/kg every 2 weeks for 10 weeks or a placebo.2
They were followed for 18 weeks after the final dose. There were no serious treatment-emergent adverse events and any adverse events that did occur were mild to moderate, transient and resolved on their own.
Of those patients who had high disease activity at baseline, five out of 11 responded by week 7, compared to one out of seven receiving the placebo. Mechanism-related changes in gene expression were seen in blood RNA samples.
A Phase IIb study has also been done.3 A 24-week double-blind, placebo-controlled period during which the drug was compared with standard of care was followed by a 24-week standard of care only observational period.
In all, 182 subjects were randomised to receive 6, 24 or 45 mg/kg of the drug or a placebo every 4 weeks in the first part of the study.
All those given the drug showed numerically greater improvements in immunological and clinical outcomes than the placebo group and, after active treatment stopped, these declined. However, the primary objective was not met as none of the prespecified dose-response models matched the real-life experience.