Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial

By W. Hueber, Bruce E. Sands, S. Lewitzky, M. Vandemeulebroecke, W. Reinisch, P. Higgins, J. Wehkamp, B. Feagan, M. Yao, M. Karczewski and 10 more. Gut, 2012

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Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. Design 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. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). 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 (∆CDAI (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). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Subfields: Epidemiology, Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/4c4ee3e06dfab85bbb3a467595f2d29ee2a2263a

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Citations in the corpus

IL-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability (2015, neutral): “In fact, in the clinical trial with sekukinumab for Crohn’s disease (Hueber et al., 2012), it was specifically the patients with elevated CRP concentrations that experienced a treatment-associated worsening of disease, suggesting an important protective role for IL-17 during an acute and active…”
IL-17 Signaling: The Yin and the Yang (2017, background): “Disappointingly and rather surprisingly, trials of secukinumab and brodalumab (anti-IL-17RA) in Crohn’s disease were terminated early due to worsening of disease in the treatment group [13, 14].”
A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease (2019, background): “This has been shown to be important clinically: monoclonal antibody against IL-17A, secukinumab, is ineffective in treating Crohn’s disease but causes a higher rate of adverse events and increases disease severity [48, 172].”
The IL-17 family of cytokines in health and disease (2019, background): “Of even greater concern were the disease exacerbations observed in some patients treated with secukinumab (anti-IL-17) (Hueber et al., 2012), and increased serum C-reactive protein, an indicator of inflammation, in patients receiving brodalumab (anti-IL-17RA) (Targan et al.”