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
- Wolfgang Hueber1,
- Bruce E Sands2,
- Steve Lewitzky3,
- Marc Vandemeulebroecke4,
- Walter Reinisch5,
- Peter D R Higgins6,
- Jan Wehkamp7,
- Brian G Feagan8,
- Michael D Yao9,
- Marek Karczewski10,
- Jacek Karczewski10,
- Nicole Pezous4,
- Stephan Bek1,
- Gerard Bruin1,
- Bjoern Mellgard1,
- Claudia Berger1,
- Marco Londei11,
- Arthur P Bertolino1,
- Gervais Tougas4,
- Simon P L Travis12,
- for the Secukinumab in Crohn's Disease Study Group
- 1Novartis Institutes for BioMedical Research, Basel, Switzerland
- 2Mount Sinai Medical Centre, New York, USA
- 3Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
- 4Novartis Pharma, Basel, Switzerland
- 5Medical University Vienna, Vienna, Austria
- 6University of Michigan, Ann Arbor, Michigan, USA
- 7IKB Robert-Bosch-Krankenhaus, Stuttgart, Germany
- 8Robarts Research Institute University of Western Ontario, London, Ontario, Canada
- 9National Institutes of Health, Bethesda, Maryland, USA
- 10Solumed Research Unit, Poznan, Poland
- 11Novartis Genomics Institute of the Novartis Research Foundation, San Diego, USA
- 12Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
- Correspondence to Dr Wolfgang Hueber, Novartis Institutes for BioMedical Research, Basel, Switzerland;
Contributors Charles Barish, Wake Research Associates, Raleigh NC, United States; Richard Bernstein, University of Manitoba, Winnipeg, Manitoba, Canada; Robert Burakoff, Brigham and Women's Hospital, Division of Gastroenterology, Boston MA United States; Brian Feagan, Robarts Research Institute University of Western Ontario, London, Ontario, Canada; Richard Fedorak, Division of Gastroenterology, University of Alberta , Edmonton, Canada; Thomas Haas, Landeskrankenhaus Salzburg, Salzburg, Austria; Peter D R Higgins, University of Michigan, Ann Arbor MI United States; Kim Isaacs, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Marek Karczewski and Jacek Karczewski, Solumed RU, Poznan, Poland; Arthur Kaser, Universitaetsklinik fuer Innere Medizin, Innsbruck, Austria; Seymour Katz, Nassau Gastroenterology Associates, Great Neck, NY, United States; Bruce Sands and Lloyd Mayer, Mount Sinai Medical Centre, New York, NY, United States; Bogdan Modzelewski, Klinika Chorób Przewodu Pokarmowego Ul, Lodz, Poland; Remo Panaccione, Department of Medicine, University of Calgary, Calgary, Canada; Walter Reinisch, Universitaetsklinik f. Innere Medizin IV, Vienna, Austria; Joseph Saracino, Jack Cole, CTMG, Inc., Greenville, NC, United States; Miroslaw Szura, Specjalistyczne Centum Diagnostyczno-Zabiegowe, Kraków, Poland; Niels Teich, Internistische Gemeinschaftspraxis, Leipzig, Germany; Erol Wiegert, Charité Research Organisation GmbH, Berlin, Germany; Jan Wehkamp, Robert-Bosch-Krankenhaus Gastroenterologie, Stuttgart, Germany; Michael Yao, National Institute of Health, Bethesda, MD, United States; Salam F Zakko, Connecticut Gastroenterology Institute, Bristol, CT, United States.
- Revised 14 March 2012
- Accepted 15 March 2012
- Published Online First 17 May 2012
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.
- 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.