Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis

Sandborn, William J.; Peyrin–Biroulet, Laurent; Zhang, Jinkun; Michael, Chiorean; Vermeire, Séverine; Lee, Scott D.; Kühbacher, Tanja; Yacyshyn, Bruce; Cabell, Christopher H.; Naik, Snehal; Klassen, Preston S.; Panés, Julián

doi:10.1053/j.gastro.2019.10.035

Cited by 178 publications

(130 citation statements)

References 40 publications

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“…Conversely, administration of DOP or THI decreased inflammation, T cell recruitment, and Crohn’s disease-like pathology in mice that overexpress TNFα in intestinal epithelium ( TNF iΔARE ) [ 256 , 260 ]. Results from studies of SPL in colitis models corroborate the hypothesis of a key role for S1P in the numerous clinical studies assessing the efficacy of S1PR modulating drugs etrasimod (APD334), ozanimod (RPC-1063), and amiselimod (MT-1303) in ulcerative colitis (UC) and Crohn’s disease [ 125 , 261 – 263 ].…”

Section: S1p Metabolismsupporting

confidence: 55%

“…The S1PR agonist etrasimod activates S1P 1 > S1P 5 > S1P 4 with no activity at S1P 2 or S1P 3 and decreased inflammation in a T cell transfer model of colitis [ 124 ]. Etrasimod has also shown efficacy at a dose of 2 mg in clinical trials for treatment of moderate to severe active ulcerative colitis (UC), including histologic remission [ 125 ].…”

Section: Introductionmentioning

confidence: 99%

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Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Blaho

2020

Druggable Lipid Signaling Pathways

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Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

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Section: S1p Metabolismsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Blaho

2020

Druggable Lipid Signaling Pathways

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“…In this regard, S1P 4 , as discussed previously in this review, is predominantly expressed in lymphoid tissues [88,95], and ligation and its subsequent signaling are involved in marking time regarding proliferation [286,287], a reduction of effector cytokines secreted [286,287], and migration of lymphocytes [288,289]. It is worth noting that amiselimod displays a very safe risk profile [290][291][292], while it is too early to consistently assess this for etrasimod [293]. Their application and/or investigation regarding their future therapeutic exploitability in neurological conditions should find due consideration soon.…”

Section: Insights Into Current and Future Therapeutic Perspectivesmentioning

confidence: 84%

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

Lucaciu

Brunkhorst

Pfeilschifter

et al. 2020

Cells

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Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

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“…Etrasimod, a S1Pr1, S1pR3, and S1Pr5 antagonist, has also been investigated in patients with moderately to severely active UC. At the dose of 2 mg etrasimod was found more effective than placebo in producing clinical and endoscopic improvement, suggesting that further investigations are warranted [178]. Both ozanimod and etrasimod inhibit various S1PRs but not S1PR2; therefore, the role of S1PR2 in IBD remains to be proven.…”

Section: Sphingosin1-phosphate Receptor 2 (S1pr2)mentioning

confidence: 99%

Bile Acid Signaling in Inflammatory Bowel Diseases

et al. 2020

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Bile acids are a group of chemically different steroids generated at the host/microbial interface. Indeed, while primary bile acids are the end-product of cholesterol breakdown in the host liver, secondary bile acids are the products of microbial metabolism. Primary and secondary bile acids along with their oxo derivatives have been identified as signaling molecules acting on a family of cell membrane and nuclear receptors collectively known as “bile acid-activated receptors.” Members of this group of receptors are highly expressed throughout the gastrointestinal tract and mediate the bilateral communications of the intestinal microbiota with the host immune system. The expression and function of bile acid-activated receptors FXR, GPBAR1, PXR, VDR, and RORγt are highly dependent on the structure of the intestinal microbiota and negatively regulated by intestinal inflammation. Studies from gene ablated mice have demonstrated that FXR and GPBAR1 are essential to maintain a tolerogenic phenotype in the intestine, and their ablation promotes the polarization of intestinal T cells and macrophages toward a pro-inflammatory phenotype. RORγt inhibition by oxo -bile acids is essential to constrain Th17 polarization of intestinal lymphocytes. Gene-wide association studies and functional characterizations suggest a potential role for impaired bile acid signaling in development inflammatory bowel diseases (IBD). In this review, we will focus on how bile acids and their receptors mediate communications of intestinal microbiota with the intestinal immune system, describing dynamic changes of bile acid metabolism in IBD and the potential therapeutic application of targeting bile acid signaling in these disorders.

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Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis

Cited by 178 publications

References 40 publications

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

Bile Acid Signaling in Inflammatory Bowel Diseases

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