D’Haens GR, Lee S, Taylor SA, Serone A, Rimola J, Colombel JF; DIVERGENCE 1 Study Group.
Gastroenterology 2023;165:289–92.e3. doi: 10.1053/j.gastro.2023.03.234.
Despite an increasing number of therapeutic options for patients with Crohn's Disease (CD), one-third of individuals develop intolerance or lose response to current pharmacological treatments, and up to half of patients require surgery within ten years of diagnosis. One of the reasons often highlighted for such figures has been the increasing understanding that different sub-types of CD may require different treatment approaches. Indeed, multiple clinical and molecular studies in recent years have demonstrated the differences between ileal and colonic CD in terms of pathophysiological mechanisms , as well as clinical features such as disease progression and treatment efficacy. In fact, although there is a lack of reported data on the comparative efficacy of biologics in achieving segment-specific healing in CD , evidence from observational studies and post-hoc analyses of interventional trials has shown that deep ulcers in the ileum are more challenging to heal than those located in the colon , with rates of endoscopic healing after one year of therapy ranging from 19% to 38% .
In addition to treatment, another distinct challenge is posed by monitoring. The most commonly used non-invasive monitoring tool of faecal calprotectin has been reported to have a lower association in small bowel CD with endoscopic, transmural and histological disease activity . Moreover, small bowel lesions often cannot be viewed by standard ileocolonoscopy, and alternative options such as device-assisted enteroscopy may be difficult to perform. Indeed, even options such as capsule endoscopy may be contraindicated for patients with potential stricturing disesase, and such investigations would also not provide data on the transmural component of the disease.
Given some of the many distinct aspects of small bowel CD highlighted above, there have been growing calls for randomised clinical trials focusing solely on small bowel CD. Accordingly, in the DIVERGENCE 1 trial, D’Haens and colleagues evaluated the efficacy and safety of the Janus kinase 1 preferential inhibitor filgotinib in patients with small bowel CD.
DIVERGENCE 1 was a phase 2, double-blind, placebo-controlled, multicentre trial which enrolled patients with moderate to severe clinical activity and a score of at least 7 points in at least one small bowel segment (terminal ileum, distal ileum and/or jejunum), using the magnetic resonance index of activity (MaRIA) score. Despite recruiting patients from 39 sites across 12 different countries, and an initial plan to recruit 100 participants, ultimately 78 participants were enrolled and randomised. Subsequent to enrolment, patients had serial magnetic resonance enterography (MRE) imaging performed, with the primary outcome measure being assessed at week 24.
In this trial, 24 weeks of treatment with filgotinib failed to achieve significant clinical and transmural remission (25% and 7% for filgotinib versus 17% and 0% for placebo, respectively). The results showed failure to achieve clinical remission, small bowel MaRIA remission or remission using the total MaRIA score in any small bowel segment. These results would suggest that filgotinib does not appear to be effective in small bowel CD at the doses used and over the timeframe assessed. The results are in line with the topline data of a phase 3 trial including patients with “pan-location” CD (DIVERSITY trial, NCT02914561), in which filgotinib failed to induce clinical remission and endoscopic response after ten weeks of therapy.
In this trial, patients who had clinical “non-response” at week 10 then discontinued the trial. However, this resulted in a sizeable proportion of patients failing to complete 24 weeks of treatment, resulting in a heavily underpowered analysis even in the context of a phase 2 trial. Moreover, the application of the MaRIA remission endpoint in the context of small bowel CD, and whether transmural remission is readily achievable using this outcome measure, had not been explored prior to this trial.
One further major aspect that should be acknowledged is that one-third of the cohort in DIVERGENCE 1 had previously received at least three biological agents and that two-thirds of the patients had severe activity on MRE (MaRIA >11). It may be that the severity of disease activity, length of disease duration and multiple prior treatments did not provide an optimal environment for any treatment to show efficacy for small bowel CD. Conducting this trial in an early-disease cohort, with shorter disease duration and treatment exposure, would be likely to provide a more optimal setting for investigating any potential future therapeutic application for small bowel CD.
In addition to being one of the first phenotype-specific trials to focus on small bowel CD, this trial is also one of the first to monitor patients using serial MRE images. Use of such non-invasive imaging offers an attractive alternative to relying on regular endoscopic assessments. As well as highlighting the value of MRE in clinical trials of small bowel CD, the authors underscore the crucial role of blinded central reading for MRE scans. In this trial, the investigators used the validated MaRIA score . However, an important step going forward will be to determine whether central reading can also be performed using other simpler and perhaps more pragmatic MRI scores, including for protocols that do not require gadolinium contrast administration (which has been associated with increased toxicities) . An interesting area for future research will be to compare the utility of MRI with that of intestinal ultrasound in randomised clinical trials (given the successful implementation of intestinal ultrasound in the recent STARDUST trial) . Moreover, with increasing understanding of small bowel imaging outcome measures, it may be that future trials focus more on the relevance of bowel motility using assessment tools such as the GIQuant, which may be of particular interest in the context of fibro-stenosing CD. Ultimately, the methods used in and the findings from the DIVERGENCE 1 trial may help to inform the future design of clinical trials in small bowel CD, which remains an area of unmet clinical need.
Maria Manuela Estevinho - Short Biography
Maria Manuela Estevinho is undertaking her Residency Programme in Gastroenterology at the Hospital Centre of Vila Nova de Gaia Espinho, in Portugal. Alongside her clinical training, Manuela is completing a PhD in Experimental and Clinical Pharmacology and Toxicology in the setting of IBD, under the supervision of Professor Fernando Magro. Since her graduation, Manuela has sought to be involved in clinical and translational research activities and is currently contributing to multiple projects in the field of IBD. Moreover, since 2021 she has been one of the members of Y-GEDII, the young committee of the Portuguese IBD group.