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10. Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD)

W. Hueber1, B.E. Sands2, M. Vandemeulebroecke3, W. Reinisch4, P.D.R. Higgins5, J. Wehkamp6, B. Feagan7, M. Yao8, A.P. Bertolino1, S. Travis9

1Novartis Institutes for BioMedical Research, Basel, Switzerland; 2Mount Sinai Medical Center, New York, NY, United States; 3Novartis Pharma, Basel, Switzerland; 4Medical University Vienna, Vienna, Austria; 5University of Michigan, Ann Arbor, MI, United States; 6IKB Robert-Bosch-Krankenhaus, Stuttgart, Germany; 7Robarts Research University of Western Ontario, London, ON, Canada; 8National Institutes of Health, Washington, DC, United States; 9University of Oxford, Oxford, United Kingdom

Background: Animal models of inflammatory bowel disease and accumulation of IL-17A in inflamed human gut suggest a prominent role for IL-17A in the pathogenesis of Crohn's disease (CD). We tested the hypothesis that the anti-IL17A monoclonal antibody secukinumab (AIN457) is safe and effective in CD.

Methods: In a double-blind, placebo-controlled proof-of-concept study, 59 patients with moderate to severe CD (CDAI ≥ 220 ≤ 450) were randomized 2:1 to receive 2×10 mg/kg i.v. secukinumab or placebo spaced three weeks apart. A Bayesian analysis approach was used that included additional historical placebo information from six representative trials. The primary endpoint was the probability that secukinumab reduces the CDAI by at least 50 points more than placebo at week 6.

Results: 59 patients (39 secukinumab, 20 placebo) entered safety and efficacy analyses, with mean baseline CDAI 307 and 301 and disease duration 12 and 10 years, respectively. Mismatch in the two groups occurred for prior bowel surgery (49% vs 15%), antibiotics (18% vs 5%), and previous TNF-inhibitors (18% vs 0%) for secukinumab and placebo, respectively. 18/59 (31%) patients discontinued prematurely (12/39 [31%] secukinumab, 6/20 [30%] placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 on secukinumab, 2/20 placebo). CDAI100 response rates at the week-6 primary endpoint were 7/39 (18%, secukinumab) vs. 6/20 (30%, placebo) and remission rates were 4/39 (10%) vs 3/20 (15%), respectively. 14 SAEs occurred in 10 patients (7 secukinumab, 3 placebo). Most were worsening of disease. 17/39 on secukinumab and 0/20 on placebo had infections, all of mild/moderate severity, except one severe upper respiratory tract infection. Primary endpoint Bayesian analysis estimated <0.1% probability that secukinumab reduced CDAI by at least 50 points more than placebo. Moreover, area under the response curve (AUC) analysis between weeks 4 and 10, showed a significant treatment effect (mean ΔCDAI = 49; 95%CI: [2, 96], p = 0.043) in favour of placebo. Post-hoc AUC analysis showed that response rates in favour of placebo were driven by those patients (n = 33) with elevated baseline markers of inflammation (CRP > 10 mg/L and/or faecal calprotectin >200 ng/mL), suggesting that inhibition of IL-17A exacerbated CD in a subset of patients with objective markers of inflammation (mean ΔCDAI = 62; 95%CI: [−1, 125], p = 0.054). The pharmakokinetic profile was as expected for an IgG1 mAb and comparable to secukinumab given for other indications.

Conclusions: Blockade of IL-17A appears ineffective in patients with CD. This contrasts with secukinumab efficacy in rheumatoid arthritis, psoriasis and non-infectious uveitis, indicating different potential roles for IL-17A between CD, RA and other inflammatory disorders.