PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS OF INTRAVENOUSLY ADMINISTERED USTEKINUMAB DURING INDUCTION TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS: RESULTS FROM THE UNIFI INDUCTION STUDY

Background: Pharmacokinetic (PK) & exposure-response (ER) data for ustekinumab (UST) from the UNIFI study in ulcerative colitis (UC)1 were evaluated. Methods: PK, efficacy, & safety data were obtained from this Phase 3, double-blind, placebo-controlled induction trial which enrolled 961 pts 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 randomized 1:1:1 to receive an IV induction dose of UST 130mg or a weight-range based dose of ~ 6mg/kg, or placebo at Week 0. Serum UST concentrations & 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 fecal markers were evaluated as efficacy biomarkers. The relationships between serum UST concentrations & efficacy, as well as the incidence of infections, serious infection & serious adverse events (SAE) during induction were evaluated. Results: Serum UST concentrations over time through Wk8 were dose proportional&similar between biofailure&non-biofailure pts, & pts receiving immunomodulators (IMM) at baseline & those not receiving IMM. Median peak serum UST concentrations for UST 130mg & ~6mg/kg dose groups were 43.2čg/mL & 127.0čg/mL, respectively; median Wk8 UST concentrations were 2.5čg/mL & 8.6čg/mL, respectively. The incidence of antibodies to UST through 8wks was 0.6% based on a drug-tolerant assay. Wk8 serum UST concentrations were positively associated with the proportions of pts achieving clinical response, clinical remission, and endoscopic healing (Figure 1), and inversely related to CRP and fecal calprotectin/lactoferrin levels. Greater proportions of pts in the ~6mg/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. Conclusions: Serum UST concentrations were approximately dose-proportional & a positive E-R relationship for efficacy was observed during UST induction treatment in pts with UC. No associations were observed between systemic UST exposure & selected safety events at the IV doses evaluated. These results are consistent with those reported for pts with Crohn's Disease. Reference: 1BE Sands, et al. Safety and Efficacy of Ustekinumab Induction Therapy in Patients with Moderate to Severe Ulcerative Colitis: Results: from the Phase 3 UNIFI Study. Presented at ACG 2018, October 9, 2018, Philadelphia, PA. [Figure presented]