OP028 Pharmacokinetics and exposure-response relationships of intravenously administered ustekinumab during induction treatment in patients with Crohn’s disease: results from the UNITI-1 and UNITI-2 studies
O. J. Adedokun*1, Z. Xu1, C. Gasink1, J. Friedman1, P. Szapary1, Y. Lang1, J. Johanns1, L.-L. Gao1, Y. Miao1, H. Davis1, S. Hanauer2, B. Feagan3, W. Sandborn4
1Janssen R & D, LLC, Spring House, Pennsylvania, United States, 2Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States, 3Robarts Clinical Trials Inc., Robarts Research Institute, University of Western Ontario, London, Ontario, Canada, 4UCSD, Medicine, La Jolla, California, United States
Pharmacokinetics (PK) and exposure-response (ER) data of UST from UNITI-1 & UNITI-2 IV induction studies in Crohn’s disease (CD) were evaluated.
PK, efficacy, and safety data were obtained from 2 Ph3, double-blind, PBO-controlled induction trials which enrolled 741 patients with tumour necrosis factor (TNF) antagonist-failure (UNITI-1) and 628 undergoing conventional therapy-refractory (including TNF antagonist-naïve) (UNITI-2) with moderate-severe CD. Participants were randomly assigned in 1:1:1 ratio to receive a single IV induction treatment with UST 130 mg, tiered doses by weight approximating 6 mg/kg UST (~6mg/kg), or PBO at week 0. Blood samples were collected during the studies for measurement of serum UST concentrations and evaluation of immunogenicity. Patients who did not enter the companion maintenance study had a safety follow-up visit 20 weeks after study agent dose. Clinical efficacy outcomes (based on Crohn’s Disease Activity Index score) were assessed through week 8. C-reactive protein (CRP) level was also evaluated as an efficacy measure. Relationships between serum UST concentrations and efficacy, as well as incidence of selected safety events including, infections, serious infection, and serious adverse events (SAE) during induction were evaluated.
Serum UST concentrations over time were proportional to dose and were similar between patients who were TNF antagonist refractory and those who were conventional therapy-refractory (including TNF antagonist-naïve). Based on pooled data from induction studies, median peak serum UST concentrations were 41.9 μg/mL and 126.1 μg/mL for the 130 mg and ~6mg/kg dose groups, respectively. At the end of induction (week 8), median UST concentrations were 2.1 μg/mL and 6.4 μg/mL for these dose groups, respectively. The incidence of antibodies to UST through the final safety visit was 0.2% based on a drug-tolerant assay across both UST dose groups. At week 8, serum UST concentrations were positively associated with the proportions of patients achieving remission (Figure 1), and inversely related to CRP levels. Greater proportions of patients in the ~6 mg/kg group achieved the UST exposures associated with higher efficacy. There was no relationship between serum UST concentrations & the incidence of infections, serious infections or SAEs following induction treatment with UST.
Serum UST concentrations were approximately dose-proportional, and a positive E-R relationship for efficacy was observed during UST induction treatment of adult patients with CD. No associations were observed between systemic UST exposure and selected safety events at the doses evaluated across the 2 IV induction studies.
Figure 1. PK induction UNITI 1 and UNITI 2.