Abstract
Background
Ustekinumab (UST) is approved for the treatment of adults with moderate to severe Crohn’s disease (CD) or ulcerative colitis. In the UniStar study, the pharmacokinetics (PK) of UST and its relationship with efficacy was evaluated in children who failed prior therapy. UniStar consisted of a PK portion (week 0–16) and extension (week 16–216); we report data through week 16.
Methods
UniStar is a multicentre, double-blind study (NCT02968108) designed to assess the PK, safety, and efficacy of UST in children (2–<18 years) with moderately to severely active CD, Paediatric CD Activity Index (PCDAI) score >30, and evidence of inflammation as measured by C-reactive protein >3.0 mg/l or faecal calprotectin >250 µg/g or ulcerations on ileocolonoscopy despite adequate treatment with corticosteroids and/or immunomodulators and/or anti-TNF therapies. Patients were randomised (1:1) and stratified by body weight (BW) and prior anti-TNF use for induction to one of 2 weight range-based IV doses: 130mg vs. 390 mg if BW ≥40 kg and 3mg/kg vs. 9 mg/kg if BW <40 kg. At week 8, all patients received a single subcutaneous (SC) UST maintenance dose of 90mg if BW ≥40 kg or 2 mg/kg if BW <40 kg. UST PK outcomes were assessed and compared with adult Phase 3 CD trials.
Results
44 patients (59% ≥40 kg; >90% anti-TNF exposed) were randomised and treated with UST (n = 23 lower dose; n = 21 higher dose). Baseline demographics were generally similar between treatment groups. Most patients (67%) had a severe CD (PCDAI >40). At weeks 0 (1 h after infusion), 3, 6, and 8, mean serum UST concentrations (SUC) in the lower- (51.3, 7.7, 3.0, 1.6 μg/ml) and higher-dose groups (149.0, 23.7, 9.1, 4.8 μg/ml) were generally dose proportional (Figure 1a). Following SC UST at week 8, the impact of the difference in induction doses had diminished by week 16 when mean SUC was 1.5 µg/ml in the lower-dose group vs. 1.8 µg/ml in the higher-dose group. In the overall paediatric population (combined doses), serum UST concentrations were comparable to those in the reference adult CD studies (Figure 1b and c). In the higher dose group, we observed a pattern toward lower mean serum UST concentrations in patients weighing <40 kg vs. those weighing ≥40 kg; thus, UST should be dosed higher in patients <40 kg. Overall at week 8 and week 16, more patients achieved clinical response (PCDAI reduction ≥15) and biomarker improvement with higher UST concentrations, although this pattern was not observed for clinical remission (PCDAI ≤10; Figure 2).
Conclusion
Overall, UST PK was generally comparable between paediatric and adult patients with CD. A trend towards better efficacy outcomes with higher UST concentrations was observed in children similar to adults with CD.
A controlled double blind study of azathioprine in the management of Crohn's disease.
