Y-ECCO Literature Review: Nathan Grellier

Methods

EXPLORER was a prospective, single-arm, open-label, multicentre study which evaluated triple combination therapy with vedolizumab, adalimumab and methotrexate in biologic-naïve patients with newly diagnosed CD. All three treatments started at week 0. The study comprised 26 weeks of triple combination therapy followed by 76 weeks of vedolizumab monotherapy. Patients received usual induction doses of each biologic and methotrexate was given orally 15 mg weekly. Crohn’s Disease Activity Index (CDAI) diaries were completed by patients daily and colonoscopies were performed during screening and at weeks 26 and 102. The primary endpoint was the proportion of patients achieving endoscopic remission at week 26, defined as Simple Endoscopic Score for CD (SES-CD) ≤2. The secondary endpoints were the proportion of patients with clinical remission at weeks 10 and 26, defined as CDAI <150, and incidences of adverse events (AEs) and serious adverse events (SAEs). A post hoc Bayesian analysis was then performed to compare the endoscopic remission rates with those reported for placebo and biologics used as monotherapy in previous studies.

Key findings 

Fifty-five patients were enrolled from 23 sites across the United States and Canada. Forty-four patients (80%) completed the triple combination therapy period. The mean disease duration at enrolment was just 0.4 years. At baseline, the mean SES-CD was 12.6 and the mean CDAI score was 265.5. About one-third of the patients used concomitant corticosteroids at baseline. Forty-five patients had endoscopic results at week 26 and 19 of these patients achieved endoscopic remission (42.2%). The mean SES-CD at week 26 was 3.9, with a mean reduction of 8.9 points from baseline. In terms of secondary endpoints, at week 10, 61.8% of patients were in clinical remission, while at week 26, 54.5% of patients were in clinical remission. Clinical response was achieved by 47.3% of patients at week 10 and by 43.6% at week 26. Regarding all AEs with triple combination therapy, the most frequent were arthralgia, relapse of CD and nasopharyngitis. As for SAEs, small-intestine obstruction occurred in two patients and abscess occurred in only one patient. Using a post hoc Bayesian analysis, the authors showed that triple combination therapy had a high probability to achieve a greater endoscopic remission rate than placebo (99.9%), vedolizumab monotherapy (86.3%) or adalimumab monotherapy (71.4%).

Implications 

EXPLORER was a proof-of-concept study that evaluated the efficacy of two biologics with concomitant use of an immunosuppressant. It was also the first prospective study to assess the efficacy of vedolizumab with an anti-TNF molecule to treat CD. Triple combination therapy using vedolizumab, adalimumab and methotrexate achieved endoscopic remission and clinical remission in 34.5% and 54.5% of patients, respectively. The findings suggest that the combination of biologic therapies with conventional immunosuppressants might improve efficacy outcomes in patients with early-stage CD. Recruitment to this study was challenging and the authors highlight the many difficulties of conducting interventional studies in early disease and treatment-naïve cohorts. In addition, the study lacked a control group, which represents its main limitation. The authors tried to overcome this issue by using a post hoc Bayesian analysis with a chosen benchmark for endoscopic remission rate determined from clinical trials of each treatment in monotherapy [3, 4]. Although this was quite a novel approach to analysis, the conclusions should be treated with some caution due to the heterogeneity of previous studies.

Understandably, one of the main concerns with the described triple immunosuppressive therapy was potential side effects. Patients treated with multiple immunosuppressive treatments have a higher risk of opportunistic infections, particularly pulmonary infections [5]. In this study, the rates of AEs were similar to previous data and the risk of SAEs appeared to be mainly linked to CD severity itself [6]. However, six months on triple immunosuppressive therapy is a short time to develop side effects, especially in a small study population. As a result, studies with longer-term follow-up, as well as more detail on steroid-free remission data, are needed to adequately assess the safety effects of such immunosuppressive regimens.

As regards the rationale for blocking different inflammatory pathways, combining biologics could have a synergistic effect in terms of clinical efficacy. However, the opposite is also possible. Blocking one inflammatory pathway with a first biologic might reduce the efficacy of the other. In this regard, more recent data from the VEGA trial corroborate the idea that biologic therapies targeting distinct pathways may help to overcome the efficacy ceiling of each molecule [7]. In the phase 2 VEGA trial, the combination of guselkumab (anti-interleukin 23) and golimumab (anti-tumour necrosis factor) showed promising results, with higher clinical response rates in the combination therapy arm than in the monotherapy arm. Regarding combination therapy using α4-β7 antibodies, one previous prospective study has evaluated natalizumab in combination with infliximab to treat CD [8] while only a few retrospective studies have assessed the efficacy of the association of vedolizumab and anti-TNF in Inflammatory Bowel Diseases (IBD) [9]. Combination therapy with biologics therefore remains an innovative concept but one which is likely to be among the main areas of IBD research over the coming years.

Conclusions

Combination of advanced therapies in CD has typically been used and reported in the context of treatment-refractory cohorts with long disease duration. In the EXPLORER trial, the authors show promising results for combination of advanced therapies in early CD. The authors importantly underline the need for future research studies to be performed on combination advanced therapies and for this research to be conducted in the context of clinical trials.

References

1. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–95.
2. Stalgis C, Deepak P, Mehandru S, Colombel JF. Rational combination therapy to overcome the plateau of drug efficacy in inflammatory bowel disease. Gastroenterology 2021;161:394–9.
3. Löwenberg M, Vermeire S, Mostafavi N, et al. Vedolizumab induces endoscopic and histologic remission in patients with Crohn’s disease. Gastroenterology 2019;157:997–1006.e6.
4. Danese S, Sandborn WJ, Colombel JF, et al. Endoscopic, radiologic, and histologic healing with vedolizumab in patients with active Crohn’s disease. Gastroenterology 2019;157:1007–1018.e7.
5. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology 2018;155:337–346.e10.
6. Rutgeerts P, Van Assche G, Sandborn WJ, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 2012;142:1102–1111.e2
7. Feagan BG, Sands BE, Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol 2023;8:307–20.
8. Sands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis 2007;13:2–11.
9. Guillo L, Flachaire B, Avouac J, et al. Efficacy and safety of combination targeted therapies in immune-mediated inflammatory disease: the COMBIO study. Dig Liver Dis 2023;55:61–8.

Nathan Grellier - Short Biography

Nathan Grellier works as a Senior Clinical Fellow at Poitiers University Hospital in France. Nathan has a specific interest in host–gut microbiota interactions in IBD and has been working in the lab of Professor Philippe Seksik to better understand the crosstalk between bacteria and the intestinal barrier.