New Drugs in the Ulcerative Colitis Pipeline: Prometheus Unbound
2019; Elsevier BV; Volume: 158; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2019.12.011
ISSN1528-0012
Autores Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoSee "Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis," by Sandborn WJ, Ferrante M, Bhandari BR, et al, on page 537; and "Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis," by Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al, on page 550. See "Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis," by Sandborn WJ, Ferrante M, Bhandari BR, et al, on page 537; and "Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis," by Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al, on page 550. Like Prometheus, who gave fire to humans and paid with the price of eternal torment, so the gift of new drugs in ulcerative colitis (UC) brings the consequence of patients with heterogeneous disease being cycled indiscriminately through similarly modestly effective agents. In this issue of Gastroenterology, Sandborn et al1Sandborn W.J. Peyrin-Biroulet L. Zhang J. et al.Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis.Gastroenterology. 2020; 158: 550-561Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar report positive results from the phase 2 trial of etrasimod, a small molecule selective sphingosine-1-phosphate (S1P) receptor modulator, in patients with UC. Although this success should be welcomed, the benefits of UC novel therapies can be realized only with personalized treatment strategies enabled by expanded research on biomarkers predicting response. UC was for many years viewed as the Cinderella of inflammatory bowel disease (IBD): whereas extensive research in Crohn's disease (CD) yielded many substantial advances in the understanding of disease genetics and pathophysiology, UC received comparatively little attention.2Danese S. Ulcerative colitis: a Cinderella story.Curr Drug Targets. 2011; 12: 1372Crossref PubMed Scopus (7) Google Scholar Consequently, therapeutic options for UC lagged behind those for CD. In the past few years this trend has shifted. A number of novel drugs, targeting an array of pathways, have proven positive in trials in patients with UC, and still more are in the pipeline3Sabino J. Verstockt B. Vermeire S. et al.New biologics and small molecules in inflammatory bowel disease: an update.Ther Adv Gastroenterol. 2019; 12 (1756284819853208)Crossref PubMed Scopus (63) Google Scholar (Figure 1). Notably, these include new small molecules that bring potential benefits over biologics widely clinically available, including oral delivery, the absence of antidrug antibody responses, and the opportunity for different mechanisms of action.4Olivera P. Danese S. Peyrin-Biroulet L. Next generation of small molecules in inflammatory bowel disease.Gut. 2017; 66: 199Crossref PubMed Scopus (90) Google Scholar The positive results reported with etrasimod mean that another agent with a novel mechanism of action might soon be added to the UC armamentarium. S1P receptor agonism has a number of immunomodulatory effects, including reducing S1P-mediated lymphocyte egress from lymph nodes, thus decreasing circulating lymphocyte levels.3Sabino J. Verstockt B. Vermeire S. et al.New biologics and small molecules in inflammatory bowel disease: an update.Ther Adv Gastroenterol. 2019; 12 (1756284819853208)Crossref PubMed Scopus (63) Google Scholar By contrast with earlier, nonselective S1P modulators, etrasimod selectively targets S1P1, S1P4, and S1P5 receptors, which might contribute to reduced off-target effects.1Sandborn W.J. Peyrin-Biroulet L. Zhang J. et al.Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis.Gastroenterology. 2020; 158: 550-561Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar In the double-blind placebo-controlled trial, adult patients with UC with modified Mayo Clinic scores of 4–9 were randomly assigned to etrasimod 1 mg once daily (n = 52), etrasimod 2 mg once daily (n = 50) or placebo (n = 54) for 12 weeks. The etrasimod 2 mg group met the primary end point of improved Mayo Clinic scores from baseline (mean difference from placebo 0.99 points; 90% confidence interval, 0.30–1.68; P = .009). Promising results for a second agent targeting another pathway in moderate to severe active UC have also recently been published in this journal. Mirikizumab is a monoclonal antibody against the p19 IL23 subunit, a specificity suggested to increase efficacy versus therapies targeting the p40 subunit shared by IL12 and IL23, such as ustekinumab.5Sandborn W.J. Ferrante M. Bhandari B.R. et al.Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis.Gastroenterology. 2020; 158: 537-549Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar In a phase 3 trial, mirikizumab did not meet the primary end point of greater clinical remission in the 600 mg group than placebo after 12 weeks. However, clinical responses were significantly greater than placebo at all doses, and these positive results have supported phase 3 trials in maintenance (NCT03518086) and induction (NCT03518086) settings in UC.5Sandborn W.J. Ferrante M. Bhandari B.R. et al.Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis.Gastroenterology. 2020; 158: 537-549Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar A wealth of other agents are in development or await late-phase results (Figure 1). These include other S1P receptor modulators (ozanimod, phase 3; NCT02435992), monoclonal antibodies targeting IL23 signaling (including guselkumab [phase 2/3; NCT04033445], brazikumab [phase 2; NCT03616821] and risankisumab [phase 2/3; NCT03398148]), small molecule JAK inhibitors (filgotinib [phase 3, NCT02914522] and upadacitinib [phase 3, NCT03653026]), and monoclonal antibodies targeting leukocyte adhesion (etrolizumab [phase 3, NCT02163759, NCT02171429] and ontamalimab [phase 3, NCT03259308, NCT03259334]). Although the emergence of these promising drugs should be welcomed, it also highlights a key hurdle in UC management: tailoring treatment to complement the heterogeneous UC pathophysiologic mechanisms specific to each patient.6Fiocchi C. Tailoring treatment to the individual patient - will inflammatory bowel disease medicine be personalized?.Dig Dis. 2015; 33: 82-89Crossref PubMed Scopus (11) Google Scholar Given the frequent primary nonresponse and loss of response with current and new therapies,7Roda G. Jharap B. Neeraj N. et al.Loss of response to anti-TNFs: definition, epidemiology, and management.Clin Transl Gastroenterol. 2016; 7: e135Crossref PubMed Scopus (353) Google Scholar predictive biomarkers are needed to enable earlier treatment and reduce patient exposure to ineffective and potentially harmful therapies. At present, no such biomarkers exist, and the complex interactions between genomic, environmental, microbial, and immunologic factors in IBD represent a significant challenge.8Souza HSP de Fiocchi C. Immunopathogenesis of IBD: current state of the art.Nat Rev Gastroenterol Hepatol. 2016; 13: 13-27Crossref PubMed Scopus (835) Google Scholar This complexity could explain the lack of robust genetic markers that predict UC therapy response. However, some small studies have derived tissue gene expression profiles associated with nonresponse to individual agents. In an early study published in 2009, Arijs et al9Arijs I. Li K. Toedter G. et al.Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis.Gut. 2009; 58: 1612-1619Crossref PubMed Scopus (286) Google Scholar reported a mucosal gene signature that predicted primary nonresponse to infliximab in patients with refractory UC, yet this signature has not seen clinical adoption.9Arijs I. Li K. Toedter G. et al.Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis.Gut. 2009; 58: 1612-1619Crossref PubMed Scopus (286) Google Scholar West et al10West N.R. Hegazy A.N. Owens B.M.J. et al.Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease.Nat Med. 2017; 23: 579-589Crossref PubMed Scopus (14) Google Scholar showed that oncostatin M promotes inflammation in patients with UC and CD, and demonstrated that higher pretreatment oncostatin M levels in colonic tissue from patients with UC predicted nonresponse to infliximab and golimumab.10West N.R. Hegazy A.N. Owens B.M.J. et al.Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease.Nat Med. 2017; 23: 579-589Crossref PubMed Scopus (14) Google Scholar Using samples collected during a phase 2 placebo-controlled trial of etrolizumab, Tew et al11Tew G.W. Hackney J.A. Gibbons D. et al.Association between response to etrolizumab and expression of integrin αE and granzyme A in colon biopsies of patients with ulcerative colitis.Gastroenterology. 2016; 150: 477-487.e9Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar found that increased colonic expression of granzyme A and integrin αE was associated with likelihood of clinical remission. Rapidly evolving single-cell techniques have yielded cell subpopulation signatures associated with clinically relevant phenotypes. In patients with ileal CD, Martin et al12Martin J.C. Chang C. Boschetti G. et al.Single-cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy.Cell. 2019; 178: 1493-1508.e20Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar used single-cell sequencing to identify a unique module of cells associated with anti-tumor necrosis factor resistance. Predictive signals have also been obtained from the gut microbiota—in a small prospective study, stool metagenomic information predicted vedolizumab response in UC and CD patients.13Ananthakrishnan A.N. Luo C. Yajnik V. et al.Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases.Cell Host Microbe. 2017; 21: 603-610.e3Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar How can we build on the early, modest successes in IBD precision medicine? The rapid maturation of new –omics characterization technologies,14Lloyd-Price J. Arze C. Ananthakrishnan A.N. et al.Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.Nature. 2019; 569: 655-662Crossref PubMed Scopus (969) Google Scholar high-resolution approaches such as single-cell sequencing,15Huang B. Chen Z. Geng L. et al.Mucosal profiling of pediatric-onset colitis and IBD reveals common pathogenics and therapeutic pathways.Cell. 2019; 179: 1160-1176.e24Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar and systems biology platforms to integrate big data16Olivera P. Danese S. Jay N. et al.Big data in IBD: a look into the future.Nat Rev Gastroenterol Hepatol. 2019; 16: 312-321Crossref PubMed Scopus (74) Google Scholar means that researchers now have the tools to comprehensively interrogate patient samples. Hence, the creation of standardized biobanks of patient tissue, obtained before and after an intervention, in responders and nonresponders, and at different disease stages, will be a critical step in advancing the field. A further complication is the need to objectively define therapeutic response—in the future, deep molecular phenotyping could offer a more precise readout of treatment effectiveness than currently used subjective activity scoring systems.17Furey T.S. Sethupathy P. Sheikh S.Z. Redefining the IBDs using genome-scale molecular phenotyping.Nat Rev Gastroenterol Hepatol. 2019; 16: 296-311Crossref PubMed Scopus (38) Google Scholar Finally, to be clinically useful the biomarker should be derived from easily obtainable samples (such as blood or stool), cost effective, and simple to interpret. In cancer, tumor phenotyping has advanced rapidly and clinical precision medicine is becoming reality.18Arnedos M. Vicier C. Loi S. et al.Precision medicine for metastatic breast cancer—limitations and solutions.Nat Rev Clin Oncol. 2015; 12: 693-704Crossref PubMed Scopus (218) Google Scholar The implementation of precision medicine in IBD will be costly, both in terms of research and the additional phenotyping required of patients, yet the potential benefits, including earlier and more effective treatment, decreased cycling of costly ineffective therapies, and fewer adverse events, make ongoing advances and investment a necessity. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative ColitisGastroenterologyVol. 158Issue 3PreviewInterleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. Full-Text PDF Open AccessEfficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative ColitisGastroenterologyVol. 158Issue 3PreviewEtrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). Full-Text PDF Open Access
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