Professor El-Omar has chosen Professor Alexander Ford and Dr Brigida Barberio to do the next #GUTBlog. Professor Ford is from the Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, and the Leeds Institute of Medical Research, University of Leeds, Leeds, UK and Dr Brigida Barberio is from the Department of Surgery, Oncology and Gastroenterology (DISCOG), Gastroenterology Unit, University of Padova-Azienda Ospedaliera di Padova, Padova, Italy.  The #GUTBlog focusses on the paper “Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn’s disease: systematic review and network meta-analysis” which was published in paper copy in GUT in February 2023.

Professor Alexander Ford and Dr Brigida Barberio write:

“As is well known, many patients with Crohn’s disease (CD) require biological therapies to avoid the need for repeated courses of glucocorticosteroids and to prevent disease progression, with resulting gastrointestinal damage. Since the advent of infliximab, which demonstrated efficacy in clinical trials for luminal CD in the late 1990s, multiple novel biologic drugs have been developed and tested in CD. In addition, and more recently, small molecules administered orally, including the janus kinase inhibitors tofacitinib, filgotinib, and upadacitinib, have been evaluated. Therefore, given there are now a relatively large number of drugs available to treat luminal CD, comparing the efficacy of all these therapies with each other may be useful to help guide physicians’ choice of therapy in clinical practice.

However, most trials in CD only compare an active treatment with a placebo. It is, therefore, difficult to know whether a new treatment is any better than existing options, or whether a particular drug within a single drug class should be preferred. The best way to resolve this uncertainty would be to conduct high quality randomised controlled trials (RCTs) comparing different active treatments head-to-head. However, such trials are expensive and difficult to perform, as they need large numbers of patients to show a benefit of one treatment over another, and there is also the risk to pharmaceutical companies that their new drug may prove to be inferior to an older, existing drug. Network meta-analysis (NMA) is a technique that can bypass these issues, to some extent. In fact, the methodology employed allows indirect, as well as direct, comparisons of different drugs tested across multiple RCTs to be made where no or few head-to-head comparisons exist. Not only does this allow comparison of drugs that have not been evaluated side-by-side, but it also increases the number of participants’ data available for analysis, increasing the power to detect small, but potentially clinically important, differences in efficacy. In addition, this technique allows a credible ranking system of the likely relative efficacy of different drugs to be developed, which can aid clinical decision-making.

To explain this in simple terms, where two drugs, drug A and drug B, share a common comparator, for example a placebo, C, but have not themselves been compared directly in a trial, NMA enables us to estimate the treatment effect between drug A and drug B indirectly (Figure 1). This is because we already know the magnitude and direction of the effect between drug A and drug B and the shared comparator, placebo, C, from existing trial data. These data are referred to as direct evidence. If we then include another drug, drug D, (Figure 2) which has been compared with both drug A, and placebo, C, the connections of the network become more complex and, by considering all the direct and indirect treatment estimates together, we can examine the relative efficacy of all included treatments. Furthermore, we can use statistics to rank treatments based on the probability of which one is likely to be the most efficacious across the network.

Therefore, within our research group, which has a long-standing interest and experience in performing meta-analyses in this field, we conducted a recent NMA published in Gut evaluating the efficacy and safety of biological drugs and small molecules in luminal CD.¹ To be eligible, RCTs had to examine the efficacy of these drugs for induction or maintenance of remission in luminal CD at the doses taken through into phase 3 clinical trials. These therapies included anti-tumour necrosis factor-α antibodies (e.g., infliximab, adalimumab, or certolizumab), anti-integrin antibodies (e.g., vedolizumab or etrolizumab), anti-interleukin-12/23 antibodies (e.g., ustekinumab), anti-interleukin-23 antibodies (e.g., risankizumab) or janus kinase inhibitors (e.g., tofacitinib, filgotinib, or upadacitinib).

We included data from more than 8700 patients in 25 induction of remission trials. Our analysis suggested that infliximab 5mg/kg was the most efficacious drug for induction of remission of luminal CD, when data from all patients were pooled, with risankizumab 600mg and upadacitinib 45mg o.d. ranked second and third, respectively. All comparisons across this network were rated as either high or moderate confidence. However, when we analysed the data for biologic-naïve or exposed patients separately, risankizumab 600mg ranked first for both groups, suggesting that the ranking of infliximab 5mg/kg as first was driven mainly by its use in biologic-naïve patients in all trials in which it was studied. In biologic-naïve patients, infliximab 5mg/kg ranked second and risankizumab 1200mg third. In biologic-exposed patients, upadacitinib 45mg o.d. ranked second followed by risankizumab 1200mg. Analysing data from 15 maintenance of remission trials, recruiting over 4000 patients, upadacitinib 30mg o.d. ranked first for efficacy, followed by adalimumab 40mg weekly and infliximab 10mg/kg 8-weekly. When data were pooled according to previous biologic exposure, adalimumab 40mg weekly ranked first in biologic-naïve patients, and subcutaneous vedolizumab 108mg 2-weekly first in biologic-exposed. There was no significant increase in total numbers of adverse events, serious adverse events, or infections with any drug over placebo, although withdrawals due to adverse events were significantly more likely with infliximab 10mg/kg 8-weekly in maintenance of remission trials.

Although there have been previous network meta-analyses on this topic,^2,3we identified studies from the “grey” literature,^4,5(NCT00291668)incorporated recent trials of newer drugs, conducted maintenance of remission analyses according to previous biologic exposure and only included maintenance of remission trials that re-randomised patients, rather than including treat-through studies. We also performed all our analyses according to dose, and dosing schedule, of each of the drugs of interest, rather than pooling individual drugs together irrespective of these issues. Our network meta-analysis can, therefore, assist with selection of the optimal dose and treatment interval for each drug according to previous treatments received, as well as providing evidence that some novel drugs, which are likely to come to market soon, are potentially more efficacious than existing licensed therapies for both biologic-naïve and biologic-exposed individuals with luminal CD.

REFERENCES

1. Barberio B, Gracie DJ, Black CJ, Ford AC. Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn’s disease: systematic review and network meta-analysis. Gut 2022;doi:10.1136/gutjnl-2022-328052.
2. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: First- and second-line biologic therapies for moderate-severe Crohn’s disease. Aliment Pharmacol Ther 2018;48.4:394-409.
3. Singh S, Murad MH, Fumery M, Sedano R, Jairath V, Panaccione R, et al.Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn’s disease: A systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2021;6.12:1002-14.
4. Second phase 3 induction study confirms upadacitinib (RINVOQ®) improved Clinical and endoscopic outcomes in patients with Crohn’s disease. https://news.abbvie.com/news/press-releases/news-type/rd-news/second-phase-3-induction-study-confirms-upadacitinib-rinvoq-improved-clinical-and-endoscopic-outcomes-in-patients-with-crohns-disease.htm Accessed 27th May 2022.
5. Upadacitinib (RINVOQ®) achieved clinical remission and endoscopic response at one year in phase 3 maintenance study in patients with Crohn’s disease. https://www.benzinga.com/pressreleases/22/05/n27134213/upadacitinib-rinvoq-achieved-clinical-remission-and-endoscopic-response-at-one-year-in-phase-3-mai Accessed 27th May 2022.

SOCIAL MEDIA

Professor Alexander Ford @alex_ford12399

Dr Brigida Barberio @bribarberio