Novel pharmacological developments in the management of paediatric inflammatory bowel disease

Abstract

The article authored by Lee and Gasparetto¹ provides an overview of advanced therapies for the management of inflammatory bowel disease (IBD) in children, with regards to the current and future options. This commentary aims to add an Australasian perspective.

Rates of IBD in Australasian children and adolescents have increased in recent years, similar to changes observed other regions.^{2, 3} IBD can present with typical gastrointestinal symptoms, such as diarrhoea or abdominal pain, but some children may have less obvious or extra-intestinal symptoms, such as poor growth or recurrent oral ulceration.⁴ The consequences of untreated or inadequately managed IBD in children can include delayed puberty, impaired linear growth, disrupted schooling and adverse psychological impacts. Hence, early diagnosis and optimal management are critical to ensure that children with IBD thrive.

Generally, the management of IBD can be considered in terms of therapies that induce remission and agents that maintain remission (prevent relapse).⁵ Goals of interventions include resolution of symptoms, optimising growth and development and normalising inflammatory markers. The achievement of mucosal healing (MH) is increasing seen as a key goal: MH is associated with reduction in rates of hospitalisation, lower risk of relapse and less risk of disease complications.⁶ These therapeutic goals are encapsulated within the treat-to-target concepts, which can be subdivided into short-, medium- and long-term targets.⁷ With these thoughts in mind, the use of specific interventions can be streamlined and optimised to ensure that targets are reached.

Therapeutic interventions can be considered as nutritional, medical or surgical. The range of medical therapies has traditionally included anti-inflammatory agents (such as mesalazine and corticosteroids), antibiotics (such as metronidazole) and immunomodulators (e.g., azathioprine). The biologic generation began with the introduction of the tumour necrosis factor (TNF) inhibitor infliximab in the late 1990s. This agent was followed by adalimumab, another TNF-inhibitor. More recently, an array of other advanced therapies (biologic and small molecule therapies) has been introduced for the management of IBD.

In their review, Lee and Gasparetto¹ present a concise review of randomised controlled trials (RCTs) and observational studies reporting the safety and efficacy of advanced therapies for the management of IBD, and emphasise the relevance to children. These agents fall into a number of groupings, according to their underlying mechanisms of action. The authors also highlight some of the distinctive needs of children with IBD: these include high disease burden, limited approved therapies, along with delays in trials involving children and regulatory approvals. These issues typically lead to significant delays in access to new drugs for children contrasting to much earlier access for adults with IBD.

One key aspect to access and use of these agents in children is encapsulated with the saying: ‘children are not just little adults’. Historically, this has been illustrated with the inadequacy of standard dosing regimens for TNF-inhibitors in children, especially in younger or smaller children.⁸ More recently, it has been highlighted in a large multicentre evaluation of vedolizumab in children (the VEDO-KIDS study).⁹ Whilst the authors reported similar clinical efficacy and safety of vedolizumab in the children with ulcerative colitis (UC) to outcomes seen in adults with UC, they also highlighted the importance of pharmacokinetic studies in children. Note was made of the particular importance of optimised dosing regimens in children weighing 30 kg or less.

Whilst this portfolio of advanced therapies is promising for the management of IBD overall, it is important to note that none of these agents are curative and few are available in Australasia for children with IBD. Up to March 2023, only infliximab and adalimumab were available in NZ for any individual (child or adult) with IBD.^{10, 11} Subsequently, ustekinumab has become available for individuals with IBD who have not achieved treatment targets with a TNF-inhibitor.¹² Furthermore, at the same time, vedolizumab also became available for individuals with IBD requiring escalation of therapy beyond standard treatments (prior biologic exposure is not required).¹³ In contrast, whilst several advanced therapies are available for adults with IBD in Australia, only the TNF inhibitors are currently available for use in children through standard access pathways. Vedolizumab and ustekinumab are available for children only through specific off-label conditions (compassionate or limited hospital supply). Different funding and structural environments contribute to these differences between Australia and New Zealand. It is also relevant to note that changes in access in NZ followed concerted advocacy, including petitions and media updates.^{14, 15}

In conclusion, there is huge promise in the current and emerging suite of advanced therapies for the management of moderate–severe IBD. This enthusiasm is somewhat tempered by the more limited access for children and adolescents with IBD, with the trans-Tasman differences noted. It is hopeful that current RCTs evaluating advanced therapies in children will lead to labelling and eventual access. In the interim, initiatives to develop and maintain Australasian real-world data on the use of advanced therapies in children will also be critical to provide local data and experience.