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Review
. 2024 Dec 19:17:17562848241303651.
doi: 10.1177/17562848241303651. eCollection 2024.

Advancing therapeutic frontiers: a pipeline of novel drugs for luminal and perianal Crohn's disease management

Luisa Bertin  1 , Martina Crepaldi  1 , Miriana Zanconato  1 , Greta Lorenzon  1 , Daria Maniero  1 , Caterina de Barba  1 , Erica Bonazzi  1 , Sonia Facchin  1 , Marco Scarpa  2 , Cesare Ruffolo  2 , Imerio Angriman  2 , Andrea Buda  3 , Fabiana Zingone  1 , Brigida Barberio  1 , Edoardo Vincenzo Savarino  4
Affiliations
Review

Advancing therapeutic frontiers: a pipeline of novel drugs for luminal and perianal Crohn's disease management

Luisa Bertin et al. Therap Adv Gastroenterol. .

Abstract

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria. Emerging therapies that target novel pathways offer promise in overcoming these limitations. This review explores the latest investigational drugs in phases I, II, and III clinical trials for treating both luminal and perianal CD. We highlight promising therapies that target known mechanisms, including selective Janus kinase inhibitors, anti-adhesion molecules, tumor necrosis factor inhibitors, and IL-23 selective inhibitors. In addition, we delve into novel therapeutic strategies such as sphingosine-1-phosphate receptor modulators, miR-124 upregulators, anti-fractalkine (CX3CL1), anti-TL1A, peroxisome proliferator-activated receptor gamma agonists, TGFBRI/ALK5 inhibitors, anti-CCR9 agents, and other innovative small molecules, as well as combination therapies. These emerging approaches, by addressing new pathways and mechanisms of action, have the potential to surpass the limitations of existing treatments and significantly improve CD management. However, the path to developing new therapies for inflammatory bowel disease (IBD) is fraught with challenges, including complex trial designs, ethical concerns regarding placebo use, recruitment difficulties, and escalating costs. The landscape of IBD clinical trials is shifting toward greater inclusivity, improved patient diversity, and innovative trial designs, such as adaptive and Bayesian approaches, to address these challenges. By overcoming these obstacles, the drug development pipeline can advance more effective, accessible, and timely treatments for CD.

Keywords: Crohn’s disease; biologic therapies; challenges; clinical trials; mechanism of action; perianal Crohn’s disease; placebo; small molecules; trial design.

Plain language summary

Crohn’s disease: hope on the horizon with new therapies in development Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that affects millions of people worldwide. Many people with CD do not respond well to current treatments, and researchers are looking for new options. Clinical trials are research studies that test new drugs and treatments. They are carefully designed to protect the safety of participants. Several new approaches to treating CD are currently undergoing clinical trials. These include drug candidates in various stages of development, from early research to large-scale phase III trials. Cellular therapies are also being tested, involving the injection of cells locally or intravenously to promote healing. Crohn’s disease (CD) is a long-term condition that causes inflammation in the digestive tract. It can be difficult to treat, as current medications don’t always work for everyone, and some people experience side effects or stop responding to treatment over time. Even in clinical trials, where new treatments are tested, less than 60% of patients show positive responses. Researchers are working on new treatments that target different pathways involved in Crohn’s disease. This review looks at drugs being tested in early to late-stage clinical trials. Some of these drugs target well-known pathways, like JAK inhibitors and IL-23 blockers, while others focus on newer areas, such as specific receptors or molecules involved in inflammation. These emerging therapies aim to provide better, longer-lasting relief for patients. However, developing new treatments isn’t easy. Clinical trials for Crohn’s disease face many challenges, including complicated trial designs, ethical concerns about using placebos, difficulties in recruiting enough patients, and high costs. To overcome these issues, researchers are exploring more flexible and inclusive trial methods, which could help bring new treatments to patients more quickly and efficiently.

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Conflict of interest statement

Edoardo Vincenzo Savarino has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Unifarco; has served as a consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, DiademaFarmaceutici, Dr Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co., Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Fabiana Zingone has served as a speaker for EG Stada Group, Fresenius Kabi, Janssen, Pfizer, Takeda, Unifarco, Malesci, and Kedrion and has served as a consultant for Galapagos. Brigida Barberio has served as a speaker for Abbvie, Agave, Alfasigma, AGpharma, Janssen, Lilly, MSD, Pfizer, Sofar, Takeda, and Unifarco. Sonia Facchin has served as a consultant for SILA, Unifarco, and Zeta Farmaceutici and has served as a speaker for Unifarco and SILA. The other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Timeline of FDA approvals for Crohn’s disease, and new drugs entering the scene. ALK5, activin receptor-like kinase 5, also known as the transforming growth factor (TGF-β) type 1 receptor; CCR9, C-C motif chemokine receptor 9; FKN, fractalkine; JAK, Janus kinase; miR-124, microRNA-124; PPARγ, peroxisome proliferator-activated receptor gamma; MOA, mechanism of action; S1PR, sphingosine-1-phosphate receptor; TL1A, TNF-like ligand 1A; TNF, tumor necrosis factor. Source: Created with Biorender.com (accessed 21 September 2024).
Figure 2.
Figure 2.
Mechanisms of action of emerging therapies for Crohn’s disease. ALK5, activin receptor-like kinase 5; CCR9, C-C chemokine receptor 9; CX3CL1, chemokine (C-X3-C motif) ligand 1; IL-23, interleukin-23; JAK, Janus kinase; MiR-124, microRNA-124; NCT, National Clinical Trial (Identifier); PPARγ, peroxisome proliferator-activated receptor gamma; SC, subcutaneous; S1P, sphingosine-1-phosphate; TL1A, tumor necrosis factor-like cytokine 1A; TNF, tumor necrosis factor; α4β7, alpha4 beta7 integrin receptor. Source: Created with Biorender.com (accessed 12 November 2024).
Figure 3.
Figure 3.
Drugs in phase II and III clinical trials for the treatment of luminal Crohn’s disease. ALK5, activin receptor-like kinase 5, also known as the transforming growth factor (TGF-β) type 1 receptor; CCR9, C-C motif chemokine receptor 9; FKN, fractalkine; JAK, Janus kinase; miR-124, microRNA-124; PPARγ, peroxisome proliferator-activated receptor gamma; MOA, mechanism of action; S1PR, sphingosine-1-phosphate receptor; TL1A, TNF-like ligand 1A; TNF, tumor necrosis factor. Source: Created with Biorender.com (accessed 12 November 2024).
Figure 4.
Figure 4.
Drugs and cellular therapies in phase I, II, and III clinical trials for the treatment of luminal Crohn’s disease. ALK5, activin receptor-like kinase 5, also known as the transforming growth factor (TGF-β) type 1 receptor; CAR-T, chimeric antigen receptor T-cell therapy; CCR9, C-C motif chemokine receptor 9; FKN, fractalkine; HSCT, hematopoietic stem cell transplantation; JAK, Janus kinase; miR-124, microRNA-124; MOA, mechanism of action; PPARγ, peroxisome proliferator-activated receptor gamma; S1PR, sphingosine-1-phosphate receptor; TL1A, TNF-like ligand 1A; TNF, tumor necrosis factor; UPA, upadacitinib; UST, ustekinumab; Vedo, vedolizumab. Source: Created with Biorender.com (accessed 12 November 2024).
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