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.
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- Crohn's disease
- clinical trials
- inflammatory bowel disease
- ulcerative colitis
- genetic polymorphisms
- chronic IBD
- antibody targeted therapy
- immune response
- antibacterial mucosal immunity
- mucosal defense
- antibacterial peptide
- IBD basic research
- gut immunology
- gut inflammation
- inflammatory mediators
- 5-aminosalicylic acid
Funding Novartis Pharma AG, Basel, Switzerland funded this study. External advisors (B Feagan, P D R Higgins, M and J Karczewski, W Reinisch, B Sands, S Travis, J Wehkamp, M Yao) together with the NIBR clinical team supervised the study and assisted with data interpretation. Investigators (see also Acknowledgements) gathered data and Novartis staff entered them into the clinical database. Novartis statisticians and programmers together with Covance statisticians did the analyses, and advisory committee members together with Novartis experts prepared this manuscript. The corresponding author had full access to all data and had final responsibility for the decision to submit for publication.
Competing interests Dr Wolfgang Hueber is an employee of Novartis Pharma and owns shares; Dr Bruce E Sands received consulting fees for service on a scientific advisory board for Abbott Immunology, Avaxia Biologics, Bristol-Myers Squibb, Elan Pharmaceuticals, Glaxo SmithKline Welcome, Novartis Pharmaceuticals, Pfizer and Prometheus Laboratories; consulting fees from Emmi Solutions; and holds common stock in Avaxia Biologics (a company that is not publicly traded); Steve Lewitzky is an employee of Novartis Pharma; Dr Marc Vandemeulebroecke is an employee of Novartis Pharma and owns Novartis shares; Dr Walter Reinisch is a medical advisor to Novartis; Dr Peter D R Higgins consults for Amgen, Genentech and JBR Pharma, and receives honoraria from Abbott; Dr Jan Wehkamp has no conflict of interest; Dr Brian G Feagan has been a scientific advisor for Protein Design Labs, Astra Zeneca, Elan/Biogen, Celltech, Synta, Merck, Celgene, Novartis, Given Imaging Inc., UCB Pharma, Salix Pharmaceuticals, Abbott Laboratories, Centocor Inc. Pfizer, Axcan, Tillotts Pharma AG, Prometheus Laboratories, a consultant for Synta, Millennium, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Protein Design Labs, ISIS, Teva Pharmaceuticals, Santarus, Bristol-Myers Squibb, Celgene, UCB Pharma, Abbott, Proctor and Gamble, Genentech, Tillotts, Given Imaging Inc., Salix Pharm., Ore Pharm. (previously GeneLogic), Novo Nordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Alba Therapeutics, Axcan, Pfizer, Shire, Wyeth, Zealand Pharm and has received a research grant from Merck, Milllennium, Tillotts, Abbott, Engelheim, Novartis, Centocor, Synta, Elan/Biogen, UCB Pharma, BMS, Proctor and Gamble, Genentech, CombinatoRx, ActoGeniX; Dr Michael D Yao has nothing to disclose; Dr Marek Karczewski was an external consultant for Novartis Pharma AG; Dr Jacek Karczewski was an external consultant for Novartis Pharma AG; Nicole Pezous is an employee of Novartis Pharma; Dr Stephan Bek is an employee of Novartis Pharma; Dr Gerard Bruin is an employee of Novartis Pharma and owns Novartis shares; Dr Bjoern Mellgard is an employee of Novartis Pharma; Claudia Berger is an employee of Novartis Pharma and owns Novartis shares; Dr Marco Londei is an employee of Novartis Pharma; Dr Arthur P Bertolino is an employee of Novartis Pharma; Dr Gervais Tougas is an employee of Novartis Pharma and owns Novartis shares; Dr Simon P L Travis has received honoraria for advisory boards or consultancy from Abbott; Asahi; Aspreva; BMS; Centocor; Cosmo; Elan; Ferring; Genentech; Genzyme; Giuliani; GSK; Glenmark; MSD; Novartis; Ocera; Procter & Gamble Pharmaceuticals; PDLBiopharma; Santarus; Schering-Plough; Shire; Takeda; Tillotts; UCB Pharma; Vertex; Vifor and Warner Chilcott. He has given expert testimony on behalf of Elan, Cosmo, Ocera, Procter & Gamble, Santarus and Tillotts, and received unrestricted educational grants from Abbott, Ferring, MSD, Procter & Gamble, Schering Plough and Warner Chilcott.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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