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Review
. 2022 Apr 1;102(2):605-652.
doi: 10.1152/physrev.00005.2021. Epub 2021 Sep 27.

Development of antifibrotic therapy for stricturing Crohn's disease: lessons from randomized trials in other fibrotic diseases

Si-Nan Lin  1   2   3 , Ren Mao  1   2   3 , Chenchen Qian  4 , Dominik Bettenworth  5 , Jie Wang  2   3   6 , Jiannan Li  2   3 , David H Bruining  7 , Vipul Jairath  8   9   10 , Brian G Feagan  8   9   10 , Min-Hu Chen  1 ; Stenosis Therapy and Antifibrotic Research (STAR) Consortium  2 ; Florian Rieder  2   3
Affiliations
Review

Development of antifibrotic therapy for stricturing Crohn's disease: lessons from randomized trials in other fibrotic diseases

Si-Nan Lin et al. Physiol Rev. .

Abstract

Intestinal fibrosis is considered an inevitable complication of Crohn's disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Keywords: Crohn’s disease; clinical trials; end point; stricture.

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Conflict of interest statement

D.B. is on the advisory board of or is a consultant for AbbVie, Amgen, Arena, BNG Service, Celltrion, Dr. Falk Foundation, Ferring, Galapagos Janssen-Cilag, Medical Tribune, MSD, Pfizer, Pharmacosmos, Roche, Takeda, Thieme, Tillotts Pharma, and Vifor. V.J. has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Alimentiv Inc., Topivert, and Celltrion and speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie, and Pfizer. B.G.F. has received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, and UCB, consulting fees from Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestle, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., and Zyngenia, and speaker’s bureau fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, and UCB Pharma; is a scientific advisory board member for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestle, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma; and is the Senior Scientific Officer of Alimentiv Inc. F.R. is a consultant to Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jannsen, Koutif, Metacrine, Morphic, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Takeda, Techlab, Thetis, and UCB and receives funding from the Crohn’s and Colitis Foundation of America, the Helmsley Charitable Trust, Kenneth Rainin Foundation, and the National Institutes of Health. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

Figures

None
Graphical abstract
FIGURE 1.
FIGURE 1.
Overview of all clinical studies included. A: clinical trials grouped by status and mechanisms. B: chart for proportion of clinical trials with antifibrotic therapies based on organ of interest. C: number of clinical trials over time formatted based on the type of investigated drugs. ECM, extracellular matrix; HMG-CoA, 5-hydroxy-3-methylglutaryl-coenzyme A; RAS, renin-angiotensin system.
FIGURE 2.
FIGURE 2.
Completed clinical trials with potential antifibrotics grouped by mechanism of action, phase of development, and mode of administration. ECM, extracellular matrix; HMG-CoA, 5-hydroxy-3-methylglutaryl-coenzyme A; RAS, renin-angiotensin system.
FIGURE 3.
FIGURE 3.
Imbalance of extracellular matrix (ECM) degradation and deposition in fibrosis. MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.
FIGURE 4.
FIGURE 4.
Major cellular sources of myofibroblast in intestinal fibrosis: mesenchymal cells, epithelial cells, endothelial cells, and bone marrow-derived cells.
FIGURE 5.
FIGURE 5.
Core pathological mechanisms of wound healing that are shared across organs. IL, interleukin; TGF, transforming growth factor; Th, T helper.
FIGURE 6.
FIGURE 6.
Potential mechanisms of action of antifibrotic therapies from organs other than the gut. Available therapies modulate growth factor and cytokine signaling, intracellular kinases, and extracellular matrix (ECM) remodeling. AKT, protein kinase B; ASK, apoptosis signal-regulating kinase; CASP, caspase; CTGF, connective tissue growth factor; EMT, epithelial-to-mesenchymal transition; ET, endothelin; ETR, endothelin receptor; FGF, fibroblast growth factor; FGFR, FGF receptor; HIMF, human intestinal myofibroblast; IL12, interleukin-12; IL12R, IL12 receptor; JAK, Janus kinase; JNK, c-Jun NH2-terminal kinase; MKK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphoinositide 3-kinase; PPAR, peroxisome proliferator-activated receptor; Rho, Ras homolog family member; RIP, receptor-interacting serine/threonine protein; RXR, retinoid X receptor; STAT, signal transducer and activator of transcription protein; TAK, transforming growth factor-β activated kinase; TGF, transforming growth factor; TGFR, TGF receptor; Th, T helper cells; TNF, tumor necrosis factor; TNFR, TNF receptor; TRADD, TNFR1-associated signal transducer; TRAP, TNFR-associated factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
FIGURE 7.
FIGURE 7.
Overview of canonical and noncanonical pathways of transforming growth factor (TGF)-β signaling in fibrosis. AKT, protein kinase B; ECM, extracellular matrix; LIMK, LMK kinase; PI3K, phosphoinositide 3-kinase; Rho, Ras homolog family member; SMA, smooth muscle actin; TGFR, TGF receptor.
FIGURE 8.
FIGURE 8.
Challenges and solutions for development of antifibrotic therapy for intestinal fibrosis.
FIGURE 9.
FIGURE 9.
Ultimate success for antifibrotic drug development will be achieved by combining the pipelines for preclinical targets and the development of validated clinical trial end points with partnerships with industry to properly test novel compounds. IBD, inflammatory bowel disease.
See this image and copyright information in PMC

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