Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn's Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study

Abstract

Background and aims: The objective was to evaluate the pharmacokinetics, safety/tolerability, and efficacy of ustekinumab in children with moderately to severely active Crohn's disease.

Methods: In this Phase 1, multicentre, 16-week, double-blind, induction dose-ranging study [NCT02968108], patients aged 2-<18 years [body weight ≥10 kg] were randomised [1:1] to one of two weight range-based intravenous induction doses: 130 mg vs 390 mg in patients ≥40kg and 3 mg/kg vs 9 mg/kg in patients <40kg. At Week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90 mg in patients ≥40kg or 2 mg/kg in patients <40kg.

Results: A total of 44 patients were randomised and treated with ustekinumab [n = 23 lower dose; n = 21 higher dose]; median [interquartile range] age was 13.0 [12-16] years. Pharmacokinetics were similar to those in adults with Crohn's disease. However, serum ustekinumab concentrations were lower among those with body weight <40 kg compared with patients ≥40 kg and the reference Phase 3 adult population. Through Week 16, 73% of patients reported ≥1 adverse event [82.6% lower vs 62% higher dose]; two discontinued due to adverse events [one in each group]. Serious adverse events occurred in 16% [26% lower, 5% higher dose], with Crohn's disease exacerbation being the most frequent. At Week 16, 22%/29% [lower/higher dose] achieved clinical remission [Paediatric Crohn's Disease Activity Index ≤10].

Conclusions: The pharmacokinetics/safety profiles were generally consistent with those observed in adults with Crohn's disease. These results suggest a different dosing regimen may be required for patients <40 kg from that employed in this study; additional pharmacokinetic analyses may be needed in this population.

Keywords: Crohn’s disease; paediatric; ustekinumab.

Figure 1.

UniStar study design. IC, ileocolonoscopy; IV, intravenous; Q8W, every 8 weeks; R, randomized; SC, subcutaneous; UST, ustekinumab.

Figure 2.

Line plot of mean serum UST concentrations [μg/mL] through Week 16. BW, body weight; IV, intravenous; UST, ustekinumab; lower dose, 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; higher dose, 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥40 kg BW.

Figure 3.

Lower and higher dose paediatric vs adult mean serum UST concentrations through Week 8. IV, intravenous; Ped, paediatric; UST, ustekinumab.

Figure 4.

Summary of mean serum UST concentrations through Week 16 by body weight. BW, body weight; IV, intravenous; SC, subcutaneous; UST, ustekinumab; lower dose, 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; higher dose, 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥40 kg BW.

Figure 5.

[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at Weeks 3, 8, and 16. [c] Endoscopic response and remission at Week 16. [d] Clinical response by age at Weeks 3, 8, and 16. [e] Clinical remission by age at Weeks 3, 8, and 16. [f] Clinical response by weight at Weeks 3, 8, and 16. [g] Clinical remission by weight at Weeks 3, 8, and 16. BW, body weight; IV, intravenous; PCDAI, Paediatric Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease; low dose, 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; high dose, 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥40 kg BW. ^aPatients who had a prohibited Crohn’s disease-related surgery, or who discontinued study agent due to an adverse event of worsening Crohn’s disease or due to lack of efficacy or had prohibited concomitant medication changes, were considered not to be in endoscopic response or remission. In addition, patients with missing segments at the designated analysis time point had their baseline score for the missing segment[s] carried forward. Lower dose = 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; higher dose = 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥ 40kg BW.

Figure 5.

[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at Weeks 3, 8, and 16. [c] Endoscopic response and remission at Week 16. [d] Clinical response by age at Weeks 3, 8, and 16. [e] Clinical remission by age at Weeks 3, 8, and 16. [f] Clinical response by weight at Weeks 3, 8, and 16. [g] Clinical remission by weight at Weeks 3, 8, and 16. BW, body weight; IV, intravenous; PCDAI, Paediatric Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease; low dose, 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; high dose, 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥40 kg BW. ^aPatients who had a prohibited Crohn’s disease-related surgery, or who discontinued study agent due to an adverse event of worsening Crohn’s disease or due to lack of efficacy or had prohibited concomitant medication changes, were considered not to be in endoscopic response or remission. In addition, patients with missing segments at the designated analysis time point had their baseline score for the missing segment[s] carried forward. Lower dose = 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; higher dose = 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥ 40kg BW.

Figure 5.

[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at Weeks 3, 8, and 16. [c] Endoscopic response and remission at Week 16. [d] Clinical response by age at Weeks 3, 8, and 16. [e] Clinical remission by age at Weeks 3, 8, and 16. [f] Clinical response by weight at Weeks 3, 8, and 16. [g] Clinical remission by weight at Weeks 3, 8, and 16. BW, body weight; IV, intravenous; PCDAI, Paediatric Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease; low dose, 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; high dose, 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥40 kg BW. ^aPatients who had a prohibited Crohn’s disease-related surgery, or who discontinued study agent due to an adverse event of worsening Crohn’s disease or due to lack of efficacy or had prohibited concomitant medication changes, were considered not to be in endoscopic response or remission. In addition, patients with missing segments at the designated analysis time point had their baseline score for the missing segment[s] carried forward. Lower dose = 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40 kg BW; higher dose = 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥ 40kg BW.

Figure 6.

Inflammatory biomarkers through Week 16. BW = body weight; IQR, interquartile range; IV, intravenous; lower dose, 3 mg/kg IV for patients <40 kg BW or 130 mg IV for patients ≥40kg BW; higher dose, 9 mg/kg IV for patients <40 kg BW or 390 mg IV for patients ≥40kg BW.

Figure 7.

Clinical response, clinical remission, and median improvement from baseline in the PCDAI score at Week 8 by median serum ustekinumab concentrations [µg/mL] at Week 8 [PK Analysis Set]. CRP, C-reactive protein; PCDAI, Paediatric Crohn’s Disease Activity Index; PK, pharmacokinetics.