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P311 Pharmacokinetics and exposure–response relationships of intravenously administered ustekinumab during induction treatment in patients with ulcerative colitis: Results from the UNIFI induction study

O. J. Adedokun*1, Z. Xu1, C. Marano1, C. D. O'Brien1, P. Szapary1, H. Zhang1, J. Johanns1, R. W. Leong2,3, T. Hisamatsu4, G. Van Assche5, S. Danese6, M. T. Abreu7, B. E. Sands8, W. J. Sandborn9

1Janssen Research and Development, LLC, Spring House, USA, 2Concord Hospital, Sydney, Australia, 3Macquarie University Hospital, Sydney, Australia, 4Kyorin University, Tokyo, Japan, 5University of Leuven, Leuven, Belgium, 6Humanitas Research Hospital, Milan, Italy, 7University of Miami Miller School of Medicine, Miami, USA, 8Icahn School of Medicine at Mount Sinai, New York, USA, 9University of California San Diego, La Jolla, USA

Background

Pharmacokinetic (PK) and exposure–response (ER) data for ustekinumab (UST) from the UNIFI study in ulcerative colitis (UC)1 were evaluated.

Methods

PK, efficacy, and safety data were obtained from this Phase 3, double-blind, placebo-controlled induction trial which enrolled 961 patients with moderate–severe UC. Pts who previously failed biologics (1 or more TNF-blockers or vedolizumab) or conventional therapy (corticosteroid and/or 6-MP/AZA) were included. Pts were randomised 1:1:1 to receive an IV induction dose of UST 130 mg or a weight-range based dose of ~6 mg/kg, or placebo at Week 0. Serum UST concentrations and antibodies to UST were evaluated with validated assays. Clinical efficacy outcomes based on the Mayo score were assessed at Wk8; C-reactive protein (CRP) and faecal markers were evaluated as efficacy biomarkers. The relationships between serum UST concentrations and efficacy, as well as the incidence of infections, serious infection and serious adverse events (SAE) during induction were evaluated.

Results

Serum UST concentrations over time through Wk8 were dose proportional and similar between biofailure and non-biofailure patients, and patients receiving immunomodulators (IMM) at baseline and those not receiving IMM. Median peak serum UST concentrations for UST 130 mg and ~6 mg/kg dose groups were 43.2 μg/ml and 127.0 μg/ml, respectively; median Wk8 UST concentrations were 2.5 μg/ml and 8.6 μg/ml, respectively. The incidence of antibodies to UST through 8 weeks was 0.6% based on a drug-tolerant assay. Wk8 serum UST concentrations were positively associated with the proportions of patients achieving clinical response, clinical remission, and endoscopic healing (Figure 1), and inversely related to CRP and faecal calprotectin/lactoferrin levels. Greater proportions of patients in the ~6 mg/kg group achieved UST exposures in the upper quartiles of UST exposure associated with higher efficacy. Serum UST concentrations were not associated with the incidence of infections, serious infections or SAEs.

Figure 1. Relationship between serum ustekinumab concentrations at Week 8 and clinical efficacy outcomes at Week 8.

Conclusion

Serum UST concentrations were approximately dose-proportional and a positive E-R relationship for efficacy was observed during UST induction treatment in patients with UC. No associations were observed between systemic UST exposure and selected safety events at the IV doses evaluated. These results are consistent with those reported for patients with Crohn's disease.

Reference

1. Sands BE, Sandborn WJ, Panaccione P, et al. Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: results from the Phase 3 UNIFI Study. Oral Presentation at ACG 2018, Philadelphia, PA.