New treatments for ulcerative colitis: do we have pediatric data?

KEYWORDS:

• Ulcerative colitis
• children
• fecal transplant
• vedolizumab
• diet

1. Introduction

The ECCO/ESPGHAN guidelines extensively reviewed how to employ the existing therapies for active pediatric ulcerative colitis (UC), including helpful algorithms for guiding treatment decisions [1,2]. These guidelines center on initial use of mesalasine, before using steroids, thiopurines and anti-TNF for more severe or refractory cases. As many as 20% of children will require colectomy within childhood/early adult life [3,4]. In this review we aim to discuss new approaches for using existing therapies and discuss data on emerging therapies, both of which are likely to lead to improved disease outcome in pediatric UC.

2. New ways of using current therapies

In case of suboptimal response to management, current therapies should be optimized before the introduction of new treatments. A number of adult studies have shown once daily mesalasine to be at least as effective as twice daily dosing in active and inactive UC [5]. Recently, a pediatric single-blinded clinical trial randomized 86 children with mild-moderate UC (i.e. PUCAI 10–55 points) into once versus twice daily Pentasa according to weight, with a maximal dose of 3 g daily [6]. This provides early data to support once daily dosing in patients who are non-compliant with more frequent daily dosing regimes. Dose optimization of thiopurines based on metabolite testing (i.e. 6TG and 6MMP) may increase thiopurines effectiveness [7]. Use of therapeutic drug monitoring for patients on infliximab has gained wide acceptance following on from the publication of the initial pediatric UC and infliximab study [8,9]. This strategy may be especially important in the setting of acute severe colitis. The role of adalimumab in pediatric UC is currently undergoing investigation in a clinical trial (M11–290) but there are some preliminary data from case series suggesting a treatment benefit [10]. Biosimilar infliximab is now being used for new and established UC patients on Infliximab, including switching of patients from originator infliximab onto biosimilar [11].

3. Difficulties in developing new treatments in children

Performing timely, well designed and ethical clinical trials in pediatric inflammatory bowel disease (IBD) is a priority as too many medications are prescribed as ‘off label’ in children, largely driven by the long delay from adult to pediatric drug approval. However, less children than adults are generally available for recruitment and there are several age-specific considerations that must be considered in the design of pediatric trials. Invasive procedures and the use of placebo pose significant barriers to the conduct of pediatric trials. No child enrolled in a trial should receive a known inferior treatment both within and outside the trial. According to a recent statement from ESPGHAN, ECCO, PIBDnet and Canadian network, placebo should only be used if there is genuine equipoise between the active treatment and placebo [12]. Given the similarity between pediatric and adult IBD in regards to pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if efficacy has already been proven in adults. Therefore, small underpowered comparative trials in children should merely confirm the prior findings in adult trials, providing that pharmacokinetic (PK)/pharmacodynamic (PD) findings are similar to adults and adult efficacy data already exists, thus allowing extrapolation from prior trials.

4. New biologics

Vedolizumab is an anti-α₄β₇ integrin monoclonal antibody which blocks lymphocyte migration into intestinal tissue. The landmark multicenter adult study of vedolizumab in UC focused at response in patients unresponsive to other treatments, including prior anti-TNF in 48% of cases [13]. This high bar of prior therapy will be a prominent feature of future IBD treatment studies and is a challenge to bringing new therapies to market in an ever diminishing therapeutic window in an increasingly treatment-resistant cohort. The GEMINI-1 trial demonstrated statistically significant, but disappointingly low, clinical remission rates at week 6 against placebo of 16.9% versus 5.4%, with mucosal healing and clinical response rates also significant at 40.9% versus 24.8% and 47.1% versus 25.5%, respectively [13]. Extending the time period out to 52 weeks increased the remission figures to 41.8% (8 weekly infusions) versus 15.9% (placebo). The message of vedolizumab, in adults at least, then is an additive role in resistant disease but with a slower time course to effect. Patience will be needed in a generation of gastroenterologists more accustomed to the relative quick fix of anti-TNF therapies for refractory patients.

Pediatric retrospective observation data in largely TNF-exposed patients, suggested a remission rate of 100% at 14 weeks in three patients with UC, an improvement to the comparative 44% reported in nine Crohn’s patients [14]. In the two pediatric studies reported to date only five of the 35 patients treated have had UC [15]. A phase III study of vedolizumab of patients 15 years and older is currently ongoing (ClinicalTrials.gov Identifier: NCT02039505) and a phase III PK/PD pediatric trial is about to start. Nonetheless, this treatment is already being utilized off label by many pediatric gastroenterologists in TNF-failure children with UC, based on the adult experience.

Golimumab is a subcutaneously administered anti-TNF agent but with higher affinity for TNF-α [16]. Nevertheless, adult data supports golimumab in anti-TNF naïve patients with active UC, with a statistically significant improvement in both mucosal healing (42.3% at 200 mg baseline, 100 mg at 2 weeks dosing vs. 28.7% placebo) and clinical remission (17.8% same dose vs. 6.4%) compared with placebo [17]. A recent pediatric randomized controlled trial (PURSUIT-PED-PK) examined golimumab in 35 anti-TNF naïve patients with moderate to severe UC, demonstrating 34% PUCAI remission and 54% near mucosal healing by (i.e. Mayo subscore 0 or 1) at week 6, with equivalent PK to adult experience [18].

Two further new biological therapies are currently under study. Daclizumab (humanized anti-IL2) is in phase II in patients with moderate-to-severe ulcerative colitis (age 12 and older, ClinicalTrials.gov Identifier: NCT00073047) and visilizumab (anti-CD3 antibody) is in a phase I/II study (age 16 and older ClinicalTrials.gov Identifier: NCT00267306).

5. Fecal microbial transplantation (FMT) and dietary treatments

Few people now need to be convinced of the importance of the gut microbiome in IBD, but the development of microbial therapeutics to specifically address this facet of pathophysiology remains in its infancy. In Crohn’s disease exclusive enteral nutrition (EEN) leads to a broad reduction in bacterial abundance, probably driven by a reduction in available colonic substrate [19]. This therapeutic approach has not historically been shown to be effective in UC but there are now a series of studies set to re-explore this. A new pilot EEN study in pediatric UC is proposed (Clinical trials NCT02521064). Additionally, two specific studies are looking at dietary treatments in UC (ClinicalTrials.gov Identifiers: NCT02345733 and NCT02217722) and another is looking at the role of the specific carbohydrate diet (ClinicalTrials.gov Identifier: NCT02213835). A trial of using horse milk as a treatment had to be terminated with 17 patients recruited because of slow enrolment (ClinicalTrials.gov Identifier: NCT00940576).

There has been a rush of enthusiasm for fecal microbial transplantation (FMT) in IBD. The broad concept of FMT is the crude supplementation of the patient’s own pathological (dysbiotic) gut microbial community with that of a healthy donor. Clearly, many considerations must be addressed before this intervention can be implemented (Box 1). It is likely that with time key microbial/efficacy signals will lead to more refined microbial therapy as a result of FMT studies, but the possibility of unlocking a new treatment paradigm for the disease, less reliant on immunosuppression, is exciting.

Currently, six active studies of FMT in pediatric ulcerative colitis are listed on clinicaltrials.gov (Table 1). These take very different approaches to address some of the issues raised in Box 1. One small published pediatric study suggested that an enema approach to FMT was safe in 10 UC patients and seemed to lead to short-term improvement in symptoms [20]. A further study supported the safety of nasogastric administration, but minimal efficacy signal in four UC patients [21]. One pediatric FMT study in UC, (abstract only), looked at an intensive regimen of colonoscopic transplant supported by frequent enema ‘top-up’ in three patients, demonstrating the safety of this approach plus weaning of standard immunosuppressant therapy during ongoing FMT treatment [22]. Remission was sustained for 11–16 weeks after discontinuation, suggesting no long-term benefit. Early FMT data delivered by upper gastrointestinal endoscopy and colonoscopy, has recently been reported. [23]. At 6 months 4/7 had short-lived clinical improvement, 2/7 had no response and 1/7 was in remission. Three of seven had a >15-point reduction in PUCAI. Therefore the FMT was safe and well-tolerated, but any effect was relatively short-lived. Significant publication bias may exist in reporting the success of an intervention as intriguing as FMT. By way of example, one of the authors (DT) has unpublished experience in four children treated with FMT for UC, with only one showing modest and transient improvement.

Table 1. Fecal microbial transplantation studies listed on ClinicalTrials.gov.

Identifier	Lead center	Target cohort	Study design	FMT method	Recruitment target	Status
NCT02330653	Massachusetts, USA	Age 5–30, active UC who have failed 5-ASA	Phase I/II, randomized, placebo controlled	Frozen encapsulated orally with enemas	60	Not yet recruiting
NCT01947101	Texas, USA	Age 12–20, mild active UC on standard therapy (allows anti-TNF) at recruitment	Phase I, open label	Colonoscopic with enema top-up	10	Ongoing, not recruiting
NCT02033408	Israel	Age 2–75, acute severe colitis requiring intravenous steroids	Complex study looking at steroid ± antibiotics or in acute severe UC with FMT in non-responders	Not stated	28	Recruiting
NCT02487238	Ontario, Canada	Age 6–17, active UC or IBDU on stable background therapy	Single-blind, randomized, placebo controlled	Enemas	50	Recruiting
NCT02108821	Pennsylvania, USA	Age 2–22, known IBD patients with flare on standard therapy	Open label	Not stated	50 (25 UC)	Recruiting
NCT02636517	Pennsylvania, USA	Age 3–21, known IBD patients with recurrent Clostridium difficile (and non-IBD with recurrent C. difficile)	Open label	Colonoscopic	50	Recruiting

Two adult randomized control trials were published last year, the first of which reported on a placebo-controlled, enema-based trial which at first glance demonstrated a disappointing, though significant, remission rate of 24% versus 5% at 7 weeks [24]. On further exploration however, seven of the nine patients who entered remission received donations from the same donor, a subject with enrichment in the bacterial family Lachnospiraceae and the genus Ruminococcus when compared to other donors. This study in essence shows that whilst FMT is not a ‘skeleton key’ for inducing remission in all UC patients, there may be specific microbiome signature of both the donor and recipient that is associated with treatment success. The second published adult study utilized the naso-duodenal route, for administration, and compared healthy donor feces against the patient’s own feces in the control arm and demonstrated no difference between the two study arms [25]. We therefore cannot currently recommend FMT for UC outside clinical research study, but await with interest the ongoing and planned studies on this subject.

Box 1. Aspects of fecal microbial transplantation requiring further study in inflammatory bowel disease.

Donor selection

Donor/recipient matching

Pre-treatment (to open an ecological ‘niche’ for colonization)

Method and intensity of administration

Markers of successful engraftment

Durability of microbial graft

Maintenance of microbial graft

6. Summary

In summary there are recent pediatric data for vedolizumab and FMT but an expansion of this data, together with new data from dietary studies, will hopefully lead to new ways to treat what continues to be a challenging disease with a considerable continued reliance on colectomy in cases of treatment failure.

Declaration of Interests

RK Russell has received speaker’s fees, travel support, or participated in medical board meetings with MSD Immunology, Nestle, AbbVie,Dr Falk, Janssen, Takeda and Napp. R Hansen has received speaker’s fees, travel support, or consultancy fees with MSD Immunology, Nutricia, Dr Falk, and 4D Pharma. In the last 3 years D Turner received consultation fee, research grant, royalties, or honorarium from Janssen, Pfizer, SickKids, Ferring, MegaPharm, AstraZeneca, Abbvie, Takeda, BMS, Rafa, Boehringer Ingelheim, Biogen, Atlantic Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.