title: 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.
abstract: 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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  This trial was registered at ClinicalTrial.gov with the number NCT01009281.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland. wolfgang.hueber@novartis.com
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hueber
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Sands
authors.forename: Steve
authors.initials: S
authors.lastname: Lewitzky
authors.forename: Marc
authors.initials: M
authors.lastname: Vandemeulebroecke
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Peter D R
authors.initials: PD
authors.lastname: Higgins
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Yao
authors.forename: Marek
authors.initials: M
authors.lastname: Karczewski
authors.forename: Jacek
authors.initials: J
authors.lastname: Karczewski
authors.forename: Nicole
authors.initials: N
authors.lastname: Pezous
authors.forename: Stephan
authors.initials: S
authors.lastname: Bek
authors.forename: Gerard
authors.initials: G
authors.lastname: Bruin
authors.forename: Bjoern
authors.initials: B
authors.lastname: Mellgard
authors.forename: Claudia
authors.initials: C
authors.lastname: Berger
authors.forename: Marco
authors.initials: M
authors.lastname: Londei
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Bertolino
authors.forename: Gervais
authors.initials: G
authors.lastname: Tougas
authors.forename: Simon P L
authors.initials: SP
authors.lastname: Travis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001499:Bayes Theorem; D015415:Biomarkers / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007262:Infusions, Intravenous; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D005819:Genetic Markers; C508717:IL17A protein, human; D020381:Interleukin-17; D039841:Leukocyte L1 Antigen Complex; C555450:secukinumab