Small molecules for small children
Firas Rinawi, P-ECCO Committee Member
|
Firas Rinawi |
The treatment of children with Inflammatory Bowel Disease (IBD) presents unique challenges, largely due to the complex nature of the disease, the limitations of existing therapies in children and the common off-label use of "newer" agents. Paediatric IBD requires careful management to control inflammation, promote growth and maintain a good quality of life. The treatment armamentarium for IBD in adults has expanded rapidly in the past several years, with the approval of new biologic and small-molecule agents for moderate-to-severe Ulcerative Colitis (UC) and Crohn’s Disease (CD) [1–3]. Currently, however, only infliximab and adalimumab are approved for use in children [4, 5]. The fact that all other biologics (vedolizumab, ustekinumab and risankizumab) and new small targeted molecules (tofacitinib, upadacitinib and ozanimod) commonly used in adults have not yet been approved for use in children has led to their widespread off-label use. The use of off-label biologics is often required because approximately 15%–20% of patients with IBD experience primary non-response to anti-TNF agents and another 30%–40% lose response over time [4, 5].
This off-label use poses significant challenges, including uncertainty about appropriate dosing, efficacy and long-term safety as well as a requirement for careful monitoring and individualised dosing strategies, which can be difficult to manage [6–8]. Moreover, the parenteral administration of biologic treatments can be particularly challenging in young children, who may find injections distressing and uncomfortable, leading to poor adherence and suboptimal outcomes and overall treatment burden. In this context, the development of small targeted molecules, given orally, offers a promising alternative for paediatric IBD patients.
In recent years, the development of small targeted molecules, such as Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators, has provided new hope for the treatment of IBD in children [9, 10]. These oral therapies offer a more targeted approach to controlling inflammation by specifically inhibiting key pathways involved in the immune response that drives IBD and have the additional benefit of avoiding the need for injections, which can be particularly advantageous in young children. The application of these small-targeted molecules in children with IBD is still emerging [9, 10], with ongoing clinical trials assessing their safety, efficacy and long-term outcomes in this younger population. Preliminary data suggest that these drugs may offer significant benefits, particularly for children who have not responded adequately to conventional therapies without safety concerns [9, 10]. However, long-term studies are needed to fully understand the risks, benefits and optimal use of these agents in children with IBD.
In conclusion, small-targeted molecules such as tofacitinib, upadacitinib and ozanimod represent a significant advancement in the treatment of paediatric IBD. These therapies offer a more precise approach to managing the disease and have the potential to improve outcomes and reduce the challenges associated with current treatments. As research continues, they may become an integral part of the therapeutic arsenal for children with IBD, hopefully providing safer, more effective and more convenient treatment options.
References
- Gordon H, Minozzi S, Kopylov U, et al. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis 2024 Jun 15. doi: 10.1093/ecco-jcc/jjae091 [Online ahead of print]
- Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis 2022;16:2–17.
- Chang S, Murphy M, Malter L, et al. A review of available medical therapies to treat moderate-to-severe inflammatory bowel disease. Am J Gastroenterol 2024;119:55–80.
- van Rheenen PF, Aloi M, Assa A et al. The medical management of paediatric Crohn’s disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis 2021;15;171–94.
- Turner D, Ruemmele FM, Orlanski-Meyer E et al. Management of paediatric ulcerative colitis – an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;67:257–91.
- Yerushalmy-Feler A, Pujol-Muncunill G, Martin-de-Carpi J, et al. Safety and potential efficacy of escalating dose of ustekinumab in pediatric Crohn disease (the Speed-up Study): a multicenter study from the Pediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2022;75:717–23.
- Rosh JR, Turner D, Griffiths A, et al. Ustekinumab in paediatric patients with moderately to severely active crohn's disease: pharmacokinetics, safety, and efficacy results from UniStar, a phase 1 study. J Crohns Colitis 2021;15:1931–42.
- Atia O, Shavit-Brunschwig Z, Mould DR, et al. Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study. Lancet Gastroenterol Hepatol 2023;8:31–42.
- Moore H, Dubes L, Fusillo S, et al. Tofacitinib therapy in children and young adults with pediatric-onset medically refractory inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2021;73:e57–e62.
- Spencer EA, Bergstein S, Dolinger M, et al. Single-center experience with upadacitinib for adolescents with refractory inflammatory bowel disease. Inflamm Bowel Dis 2023 Dec 22. doi: 10.1093/ibd/izad300 [Online ahead of print].