Dataset Information

Ustekinumab in Pediatric 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 randomized (1:1) to one of 2 weight range-based intravenous induction doses: 130mg vs 390mg in patients ≥40kg and 3mg/kg vs 9mg/kg in patients <40kg. At week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90mg in patients ≥40kg or 2mg/kg in patients <40kg.

Results

Forty-four patients were randomized 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 <40kg compared with patients ≥40kg and the reference Phase 3 adult population. Through week 16, 73% of patients reported ≥1 adverse event (82.6% lower vs 62% higher dose); 2 discontinued due to adverse events (1 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 (Pediatric 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 <40kg than that employed in this study; additional pharmacokinetic analyses may be needed in this population.

SUBMITTER: Rosh JR

PROVIDER: S-EPMC8575045 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionRisankizumab (RZB) and ustekinumab (UST), interleukin (IL)-23 and IL-12/23 inhibitors, respectively, are approved treatments for moderately to severely active Crohn's disease (CD); direct comparison between the two is ongoing. We indirectly compared efficacy of RZB versus UST using data from phase 3 trials (RZB: NCT03104413; NCT03105128; NCT03105102; UST: NCT01369329; NCT01369342; NCT01369355).MethodsMatching-adjusted indirect comparison was conducted using individual patient-level data from RZB trials and published aggregated data from UST trials. During induction, patients received RZB 600 mg intravenous (IV) at weeks 0, 4, and 8 or a single dose of UST 6 mg/kg IV at week 0. During maintenance, patients received RZB 180 or 360 mg subcutaneous (SC) or UST 90 mg SC every 8 or 12 weeks to 52 weeks. Outcomes included proportion of patients achieving Crohn's Disease Activity Index (CDAI) response (decrease of ≥ 100 points or total score < 150) or remission (CDAI ≤ 150) and endoscopic improvement (measured by the Simple Endoscopic Score in CD [SES-CD]; response, ≥ 50% reduction from baseline; remission, SES-CD ≤ 2) following induction/baseline.ResultsHigher proportions of patients achieved clinical and endoscopic outcomes with RZB vs. UST induction treatment, resulting in significantly (p ≤ 0.05) greater percent differences (95% confidence intervals) between groups for CDAI remission (15% [5%, 25%]) and endoscopic response (26% [13%, 40%]) and remission (9% [0%, 19%]). Following maintenance, rates of CDAI remission were similar (range - 0.3% to - 5.0%) for RZB vs. UST. Differences for endoscopic response and remission ranged from 9.3% to 27.7% and 11.6% to 12.5%, respectively; differences were significant (p < 0.05) for endoscopic response for both doses of RZB compared to UST 12-week dosing.ConclusionsThis indirect comparison demonstrated higher rates of clinical and endoscopic outcomes during induction for RZB compared to UST; CDAI remission following maintenance was comparable. Direct comparisons of RZB and UST are warranted to validate these findings.