medwireNews: The addition of dapirolizumab pegol to standard therapy may warrant further investigation for the treatment of systemic lupus erythematosus (SLE), phase 2 trial results suggest.
However, the study did not meet its primary endpoint of a dose–response relationship across three doses of the CD40 ligand (CD40L) inhibitor, say Richard Furie (Northwell Health, Great Neck, New York, USA) and co-investigators.
RISE included 182 patients with moderate-to-severe active SLE (SLEDAI-2K ≥6 and ≥1 BILAG A or ≥2 BILAG B domain scores) who were randomly assigned to receive 24 weeks of treatment with intravenous dapirolizumab pegol at one of three doses (6, 24, or 45 mg/kg) or placebo every 4 weeks alongside stable treatment with standard therapy.
Furie and team report that at week 24, BICLA response rates “did not fit any of the pre-specified dose-response models with statistical significance,” and therefore the primary endpoint was not met.
Nevertheless, they say that patients treated with dapirolizumab pegol experienced “consistent numerical improvements” in multiple measures of disease activity compared with those given placebo. For instance, BICLA response rates at week 24 were 48.8%, 56.8%, and 52.2% in the dapirolizumab pegol 6, 24, and 45 mg/kg groups, respectively, compared with 37.2% in the placebo arm. The corresponding decreases in average SLEDAI-2K score from baseline to week 24 were 5.0, 5.1, and 5.3 versus 4.2 points.
The researchers also found that dapirolizumab pegol treatment was associated with improvements in immunologic markers – including a reduction in anti-double-stranded DNA antibodies and an increase in complement C3 and C4 levels – relative to placebo over the 24-week treatment period, “indicating a biologic effect.”
Furie and team say that after week 24, the study drug was withdrawn in all participants, a decision that “was based on research in animal transplant models that reported sustained responses even after withdrawal of CD40L antagonist.”
They report that disease activity scores “stabilized across treatment groups” after week 24, and BICLA response rates “were generally lower at week 48 than at week 24 in all groups,” while immunologic markers “generally worsened and returned to baseline levels, providing further evidence of [dapirolizumab pegol] biologic activity.”
In all, treatment-emergent adverse events occurred in 64.4%, 77.8%, 72.3%, and 62.2% of patients in the 6 mg/kg, 24 mg/kg, 45 mg/kg, and placebo groups, respectively. There was one thromboembolic event among dapirolizumab pegol-treated patients (24 mg/kg group), and three in the placebo arm.
Together, the RISE findings suggest that dapirolizumab pegol “may be efficacious, with an acceptable safety profile,” but the study was “limited by the failure to meet the primary endpoint,” say the researchers in Rheumatology.
They stress the need for future studies “to demonstrate the efficacy and safety of [dapirolizumab pegol] within a larger study population and for a longer duration, using carefully selected endpoints.”
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