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The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment)
  1. Silvio Danese1,
  2. Virginia Solitano2,
  3. Vipul Jairath3,4,
  4. Laurent Peyrin-Biroulet5
  1. 1 Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy
  2. 2 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
  3. 3 Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
  4. 4 Alimentiv, London, Ontario, Canada
  5. 5 University of Lorraine, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
  1. Correspondence to Dr Silvio Danese, Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Lombardia, Italy; sdanese{at}hotmail.com

https://doi.org/10.1136/gutjnl-2022-327025

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    Introduction

    The expanding therapeutic armamentarium available for inflammatory bowel disease (IBD) as well as multiple compounds in clinical development inevitably raises questions as to their impact on patient outcomes at the dawn of 2022.

    We must be cautious in making direct efficacy comparisons between clinical trials conducted today vs 20 years ago; patients in clinical trials now are generally more refractory to treat, with multiple prior drug exposures, longer disease duration and subject to more stringent trial endpoints. Notwithstanding the aforementioned caveats, it is a reasonable assumption that we have not observed transformational efficacy with the advent of newer agents over the last 10 years. Most advanced treatments report clinical remission rates at 1 year ranging between 30% and 50%,1–4 suggesting we may have reached a therapeutic ceiling through use of single agents. Multiple pathways drive the immune-mediated inflammatory process and agents effective for luminal disease may not be effective for extraintestinal manifestations or concomitant immune-mediated disease (IMID), necessitating the use of additional agents.5 6 Furthermore, using cumulative surgical resection rates as a surrogate for bowel damage, some studies report that these rates are similar in the prebiological versus postbiological era.7

    Several different inflammatory pathways orchestrate the development and progression of IBD and other IMIDs, and the existence of more than one cytokine pattern is one explanation of why we may have reached a therapeutic ceiling.8 The concept of targeting multiple-cytokines which act on shared disease pathways among IMID is well described by the reduction of entheseal inflammation in patients with IBD and concomitant psoriatic arthritis receiving the interleukin-12 and interleukin-23 inhibitor ustekinumab.9 Furthermore, Janus kinase (JAK) inhibitors, such as tofacitinib, targeting a wide range of cytokine hubs are effective in reducing the deregulated trafficking of immune effectors involving both the joints and the gut.10

    With …

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    Footnotes

    • Contributors All authors participated in writing the manuscript and approved the final, submitted version.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests SD has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. VJ has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, Celltrion; speakers’ fees from Takeda, Janssen, Shire, Ferring, Abbvie, Pfizer. LP-B has served as a speaker, consultant and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma, Celgene, Biogen, Lycera, Samsung Bioepis, Theravance.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.