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Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150-kDa human IgG1 antibody interacting with a soluble target. [ABSTRACT FROM AUTHOR]

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, placebocontrolled 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 2310 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 (ƒ¢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 4e10) showed a significant difference (mean DCDAI.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 DCDAI.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. INSET: Significance of this study. [ABSTRACT FROM AUTHOR]