Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn's Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study
Joel R Rosh, Dan Turner, Anne Griffiths, Stanley A Cohen, Douglas Jacobstein, Omoniyi J Adedokun, Lakshmi Padgett, Natalie A Terry, Christopher O'Brien, Jeffrey S Hyams, Joel R Rosh, Dan Turner, Anne Griffiths, Stanley A Cohen, Douglas Jacobstein, Omoniyi J Adedokun, Lakshmi Padgett, Natalie A Terry, Christopher O'Brien, Jeffrey S Hyams
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.
© European Crohn’s and Colitis Organisation 2021.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0001.jpg)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0002.jpg)
Figure 3.
Lower and higher dose paediatric…
Figure 3.
Lower and higher dose paediatric vs adult mean serum UST concentrations through Week…
Figure 4.
Summary of mean serum UST…
Figure 4.
Summary of mean serum UST concentrations through Week 16 by body weight. BW,…
Figure 5.
[a] Clinical response at Weeks…
Figure 5.
[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at…
Figure 5.
[a] Clinical response at Weeks…
Figure 5.
[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at…
Figure 5.
[a] Clinical response at Weeks…
Figure 5.
[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at…
Figure 6.
Inflammatory biomarkers through Week 16.…
Figure 6.
Inflammatory biomarkers through Week 16. BW = body weight; IQR, interquartile range; IV,…
Figure 7.
Clinical response, clinical remission, and…
Figure 7.
Clinical response, clinical remission, and median improvement from baseline in the PCDAI score…
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- Does Pyroptosis Play a Role in Inflammasome-Related Disorders?Zhang J, Wirtz S. Zhang J, et al. Int J Mol Sci. 2022 Sep 9;23(18):10453. doi: 10.3390/ijms231810453. Int J Mol Sci. 2022. PMID: 36142364 Free PMC article. Review.
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-
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-
- Janssen Pharmaceutical Companies. STELARA [ustekinumab] [package insert] .High Wycombe, UK: Janssen Pharmaceutical Companies; 2020.].
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- Feagan BG, Sandborn WJ, Gasink C, et al. ; UNITI–IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016;375:1946–60. - PubMed
- Clinical Trial, Phase I
- Multicenter Study
- Administration, Intravenous
- Adolescent
- Antibodies, Monoclonal / pharmacokinetics
- Antibodies, Monoclonal / pharmacology
- Antibodies, Monoclonal / therapeutic use
- Child
- Crohn Disease / drug therapy*
- Double-Blind Method
- Female
- Humans
- Injections, Subcutaneous
- Male
- Patient Safety / standards
- Patient Safety / statistics & numerical data
- Pediatrics / methods
- Pediatrics / trends
- Treatment Outcome
- Ustekinumab / pharmacokinetics*
- Ustekinumab / pharmacology*
- Ustekinumab / therapeutic use
- Antibodies, Monoclonal
- Ustekinumab
- Full Text Sources
- Other Literature Sources
- Medical
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![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0003.jpg)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0004.jpg)
Figure 5.
[a] Clinical response at Weeks…
Figure 5.
[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at…
Figure 5.
[a] Clinical response at Weeks…
Figure 5.
[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at…
Figure 5.
[a] Clinical response at Weeks…
Figure 5.
[a] Clinical response at Weeks 3, 8, and 16. [b] Clinical remission at…
Figure 6.
Inflammatory biomarkers through Week 16.…
Figure 6.
Inflammatory biomarkers through Week 16. BW = body weight; IQR, interquartile range; IV,…
Figure 7.
Clinical response, clinical remission, and…
Figure 7.
Clinical response, clinical remission, and median improvement from baseline in the PCDAI score…
- Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease.MacDonald JK, Nguyen TM, Khanna R, Timmer A. MacDonald JK, et al. Cochrane Database Syst Rev. 2016 Nov 25;11(11):CD007572. doi: 10.1002/14651858.CD007572.pub3. Cochrane Database Syst Rev. 2016. PMID: 27885650 Free PMC article. Review.
- Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease.Khanna R, Preiss JC, MacDonald JK, Timmer A. Khanna R, et al. Cochrane Database Syst Rev. 2015 May 5;(5):CD007572. doi: 10.1002/14651858.CD007572.pub2. Cochrane Database Syst Rev. 2015. PMID: 25942580 Updated. Review.
- IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn's Disease.Hanauer SB, Sandborn WJ, Feagan BG, Gasink C, Jacobstein D, Zou B, Johanns J, Adedokun OJ, Sands BE, Rutgeerts P, de Villiers WJS, Colombel JF, Ghosh S. Hanauer SB, et al. J Crohns Colitis. 2020 Jan 1;14(1):23-32. doi: 10.1093/ecco-jcc/jjz110. J Crohns Colitis. 2020. PMID: 31158271 Clinical Trial.
- Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.Sandborn WJ, Rutgeerts P, Gasink C, Jacobstein D, Zou B, Johanns J, Sands BE, Hanauer SB, Targan S, Ghosh S, de Villiers WJS, Colombel JF, Feagan BG. Sandborn WJ, et al. Aliment Pharmacol Ther. 2018 Jul;48(1):65-77. doi: 10.1111/apt.14794. Epub 2018 May 24. Aliment Pharmacol Ther. 2018. PMID: 29797519 Free PMC article. Clinical Trial.
- Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease.Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, Blank MA, Johanns J, Gao LL, Miao Y, Adedokun OJ, Sands BE, Hanauer SB, Vermeire S, Targan S, Ghosh S, de Villiers WJ, Colombel JF, Tulassay Z, Seidler U, Salzberg BA, Desreumaux P, Lee SD, Loftus EV Jr, Dieleman LA, Katz S, Rutgeerts P; UNITI–IM-UNITI Study Group. Feagan BG, et al. N Engl J Med. 2016 Nov 17;375(20):1946-1960. doi: 10.1056/NEJMoa1602773. N Engl J Med. 2016. PMID: 27959607 Clinical Trial.
- Ustekinumab for steroid-refractory pancolitis in a biologically naive child: A case report and literature review.Alhalabi M. Alhalabi M. Medicine (Baltimore). 2023 Mar 3;102(9):e33061. doi: 10.1097/MD.0000000000033061. Medicine (Baltimore). 2023. PMID: 36862878 Free PMC article. Review.
- Does Pyroptosis Play a Role in Inflammasome-Related Disorders?Zhang J, Wirtz S. Zhang J, et al. Int J Mol Sci. 2022 Sep 9;23(18):10453. doi: 10.3390/ijms231810453. Int J Mol Sci. 2022. PMID: 36142364 Free PMC article. Review.
- Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum.Saito J, Kaneko K, Kawasaki H, Hayakawa T, Yakuwa N, Suzuki T, Sago H, Yamatani A, Murashima A. Saito J, et al. J Pharm Health Care Sci. 2022 Jul 1;8(1):18. doi: 10.1186/s40780-022-00249-8. J Pharm Health Care Sci. 2022. PMID: 35773736 Free PMC article.
- Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix.Atia O, Pujol-Muncunill G, Navas-López VM, Orlanski-Meyer E, Ledder O, Lev-Tzion R, Focht G, Shteyer E, Stein R, Aloi M, Russell RK, Martin-de-Carpi J, Turner D. Atia O, et al. Aliment Pharmacol Ther. 2022 Sep;56(5):794-801. doi: 10.1111/apt.17092. Epub 2022 Jun 23. Aliment Pharmacol Ther. 2022. PMID: 35735987 Free PMC article.
- Therapy Strategies for Children Suffering from Inflammatory Bowel Disease (IBD)-A Narrative Review.Légeret C, Furlano R, Köhler H. Légeret C, et al. Children (Basel). 2022 Apr 26;9(5):617. doi: 10.3390/children9050617. Children (Basel). 2022. PMID: 35626795 Free PMC article. Review.
-
- Fumery M, Pariente B, Sarter H, et al. ; Epimad Group. Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study. Dig Liver Dis 2019;51:496–502. - PubMed
-
- Vernier-Massouille G, Balde M, Salleron J, et al. . Natural history of pediatric Crohn’s disease: a population-based cohort study. Gastroenterology 2008;135:1106–13. - PubMed
-
- Assa A, Hartman C, Weiss B, et al. . Long-term outcome of tumour necrosis factor alpha antagonist treatment in paediatric Crohn’s disease. J Crohns Colitis 2013;7:369–76. - PubMed
-
- Janssen Pharmaceutical Companies. STELARA [ustekinumab] [package insert] .High Wycombe, UK: Janssen Pharmaceutical Companies; 2020.].
-
- Feagan BG, Sandborn WJ, Gasink C, et al. ; UNITI–IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016;375:1946–60. - PubMed
- Clinical Trial, Phase I
- Multicenter Study
- Administration, Intravenous
- Adolescent
- Antibodies, Monoclonal / pharmacokinetics
- Antibodies, Monoclonal / pharmacology
- Antibodies, Monoclonal / therapeutic use
- Child
- Crohn Disease / drug therapy*
- Double-Blind Method
- Female
- Humans
- Injections, Subcutaneous
- Male
- Patient Safety / standards
- Patient Safety / statistics & numerical data
- Pediatrics / methods
- Pediatrics / trends
- Treatment Outcome
- Ustekinumab / pharmacokinetics*
- Ustekinumab / pharmacology*
- Ustekinumab / therapeutic use
- Antibodies, Monoclonal
- Ustekinumab
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0005.jpg)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0008.jpg)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0009.jpg)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0006.jpg)
Figure 7.
Clinical response, clinical remission, and…
Figure 7.
Clinical response, clinical remission, and median improvement from baseline in the PCDAI score…
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8575045/bin/jjab089f0007.jpg)
References
- Fumery M, Pariente B, Sarter H, et al. ; Epimad Group. Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study. Dig Liver Dis 2019;51:496–502.
- Vernier-Massouille G, Balde M, Salleron J, et al. . Natural history of pediatric Crohn’s disease: a population-based cohort study. Gastroenterology 2008;135:1106–13.
- Assa A, Hartman C, Weiss B, et al. . Long-term outcome of tumour necrosis factor alpha antagonist treatment in paediatric Crohn’s disease. J Crohns Colitis 2013;7:369–76.
- Janssen Pharmaceutical Companies. STELARA [ustekinumab] [package insert] .High Wycombe, UK: Janssen Pharmaceutical Companies; 2020.].
- Feagan BG, Sandborn WJ, Gasink C, et al. ; UNITI–IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016;375:1946–60.
- Sandborn WJ, Rutgeerts P, Gasink C, et al. . Long-term efficacy and safety of ustekinumab for Crohn’s disease through the second year of therapy. Aliment Pharmacol Ther 2018;48:65–77.
- Hanauer SB, Sandborn WJ, Feagan BG, et al. . IM-UNITI: three-year efficacy, safety, and immunogenicity of ustekinumab treatment of Crohn’s disease. J Crohns Colitis 2020;14:23–32.
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