Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohns disease: unexpected results of a randomised, double-blind placebo-controlled trial
Gut, 06/08/2012Hueber W et al.
Blockade of interleukin (IL)–17A was ineffective and higher rates of adverse events were noted compared with placebo.
In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo.
The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6.
Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response.
59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited.
Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo.
Primary end point analysis estimated <0.1% probability (ΔCDAI (SD)=33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo.
Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo.
Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo).
Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected).
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