Upadacitinib for Crohn’s Disease and Ulcerative Colitis Treatment: Hitting the Selective JAKpot

See "Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis," by Sandborn WJ, Ghosh S, Panes J, et al, on page 2139; and "Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn's disease," by Sandborn WJ, Feagan BG, Loftus Jr EV, et al, on page 2123; published in the June 2020 issue of Gastroenterology. See "Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis," by Sandborn WJ, Ghosh S, Panes J, et al, on page 2139; and "Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn's disease," by Sandborn WJ, Feagan BG, Loftus Jr EV, et al, on page 2123; published in the June 2020 issue of Gastroenterology. The current treatment options for patients with moderate-to-severe inflammatory bowel disease (IBD) have substantial limitations: many individuals are refractory to available therapies, develop drug resistance,1Roda 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 (260) Google Scholar or experience adverse effects that limit quality of life and/or treatment.2Shivaji U.N. Sharratt C.L. Thomas T. et al.Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease.Aliment Pharmacol Ther. 2019; 49: 664-680Crossref PubMed Scopus (49) Google Scholar Therefore, new therapeutic options are needed. This issue of Gastroenterology reports the results of 2 phase II trials of the selective Janus kinase-1 (JAK 1) inhibitor upadacitinib in patients with Crohn's disease and ulcerative colitis.3Sandborn W.J. Ghosh S. Panes J. et al.Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis.Gastroenterology. 2020; 158: 2139-2149Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,4Sandborn W.J. Feagan B.G. Loftus Jr., E.V. et al.Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn's disease.Gastroenterology. 2021; 160: 2123-2138Google Scholar Cytokine signaling plays a key role in the pathogenesis of IBD.5Marafini I. Sedda S. Dinallo V. et al.Inflammatory cytokines: from discoveries to therapies in IBD.Expert Opin Biol Ther. 2019; 19: 1207-1217Crossref PubMed Scopus (36) Google Scholar Such involvement is reflected in the biologics approved to treat these diseases, including monoclonal antibodies targeting the cytokines tumor necrosis factor and IL-12/IL-23. Yet a substantial proportion of patients either do not respond to these drugs, owing to the involvement of other, nontargeted cytokines, or lose response over time.1Roda 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 (260) Google Scholar Owing to their biologic origin,6Pérez-Jeldres T. Tyler C.J. Boyer J.D. et al.Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease: JAK inhibitors and S1PR agonists.Front Pharmacol. 2019; 10: 212Crossref PubMed Scopus (45) Google Scholar these agents often induce antidrug antibody responses7Vermeire S. Gils A. Accossato P. et al.Immunogenicity of biologics in inflammatory bowel disease.Therap Adv Gastroenterol. 2018; 11 (1756283X17750355)Crossref PubMed Scopus (106) Google Scholar and must be administered intravenously or subcutaneously—requiring drug storage costs, hospital visits, and causing substantial patient inconvenience. The past decade has seen the expansion of a pipeline of small molecule therapies for IBD, driven by the hope that the drawbacks of monoclonal antibody therapies can be avoided or mitigated.8Olivera P. Danese S. Peyrin-Biroulet L. Next generation of small molecules in inflammatory bowel disease.Gut. 2017; 66: 199-209Crossref PubMed Scopus (79) Google Scholar In particular, small molecules can be administered orally, have a rapid onset of action, and do not elicit antidrug antibodies.9Shivaji U.N. Nardone O.M. Cannatelli R. et al.Small molecule oral targeted therapies in ulcerative colitis.Lancet Gastroenterol Hepatol. 2020; 4: 850-851Abstract Full Text Full Text PDF Scopus (14) Google Scholar One promising target of these agents is the conserved JAK–signal transducers and activators of transcription (STAT) pathway, long recognized as a central mediator of inflammatory cytokine signalling.10Soendergaard C. Bergenheim F.H. Bjerrum J.T. et al.Targeting JAK-STAT signal transduction in IBD.Pharmacol Ther. 2018; 192: 100-111Crossref PubMed Scopus (43) Google Scholar Four JAK proteins exist: JAK1, JAK2, JAK3, and TYK2.11Banerjee S. Biehl A. Gadina M. et al.JAK–stat signaling as a target for inflammatory and autoimmune diseases: current and future prospects.Drugs. 2017; 77: 521-546Crossref PubMed Scopus (322) Google Scholar These proteins bind the intracellular membrane regions of cytokine receptor subunits, with different JAK isoforms exhibiting binding preference for different receptors. Receptor ligand binding induces activation of pairs of JAK monomers, which in turn activates STAT factors. STAT proteins subsequently regulate numerous important cellular functions, including adaptive and innate immunity, hematopoiesis, and cell growth, differentiation and migration.12Danese S. Argollo M. Le Berre C. et al.JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?.Gut. 2019; 68: 1893-1899Crossref PubMed Scopus (41) Google Scholar As each JAK isoform binds a number of distinct cytokine receptors, JAK inhibition presents the opportunity to modulate the effects of multiple cytokines.12Danese S. Argollo M. Le Berre C. et al.JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?.Gut. 2019; 68: 1893-1899Crossref PubMed Scopus (41) Google Scholar In addition, the cell-type–specific expression of JAK isoforms and cytokine receptors offers a chance of targeting effects to tissues of interest, albeit with the caveat that, to date, JAK inhibitor molecules are selective but not specific for JAK isoforms.12Danese S. Argollo M. Le Berre C. et al.JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?.Gut. 2019; 68: 1893-1899Crossref PubMed Scopus (41) Google Scholar Tofacitinib, a pan-JAK inhibitor, was the first JAK inhibitor approved for use in ulcerative colitis and an important addition to the IBD armamentarium.13Sandborn W.J. Su C. Sands B.E. et al.Tofacitinib as induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2017; 376: 1723-1736Crossref PubMed Scopus (609) Google Scholar However, an analysis of postmarketing safety data led the US Food and Drug Administration to issue warnings in 2019 about an increased risk of blood clots and death with the drug in patients with rheumatoid arthritis.14US Food and Drug AdministrationSafety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. 2019.www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-xrDate accessed: March 15, 2020Google Scholar Interestingly, in patients with IBD, an increased rate of thromboembolic events after treatment with small molecules was not found, but it remains unclear whether the risk of these adverse events is regulated by JAK selectivity or disease-related factors.15Olivera P. Lasa J. Bonovas S. et al.Safety of Janus Kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1554-1573.e12Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar A number of selective JAK inhibitors are at various stages of development, with the aim of improving the risk–benefit profile of pan-JAK inhibitors (Figure 1). Upadacitinib is an oral small molecule JAK inhibitor selective for JAK1, through which it modulates the signaling of key cytokines, including IL-2, IL-4 IL-7, IL-9, IL-15, IL-21, and type I and III interferons.11Banerjee S. Biehl A. Gadina M. et al.JAK–stat signaling as a target for inflammatory and autoimmune diseases: current and future prospects.Drugs. 2017; 77: 521-546Crossref PubMed Scopus (322) Google Scholar In the CELEST phase II double-blind trial, the efficacy and safety of upadacitinib were assessed in adult patients with moderate-to-severe active Crohn's disease refractory or intolerant to immunosuppressive or anti-tumor necrosis factor therapy. Patients (n = 220) were randomly assigned in a 1:1:1:1:1:1 ratio to placebo or upadacitinib: 3 mg twice-daily (BID), 6 mg BID, 12 mg BID, or 24 mg once-daily (QD) or BID. Those completing the 16-week induction phase were then rerandomized to 3 mg BID, 12 mg BID, or 24 mg QD for a 36-week maintenance phase. The 2 coprimary end points were clinical remission at week 16 and endoscopic remission at week 12 or week 16. Upadacitinib did not significantly improve clinical remission at week 16 at any dose (with the exception of 6 mg at the P < .1 level). However, endoscopic remission at week 12 of the 16-week trial was increased compared with placebo for doses of 3 mg (4/39; P < .1), 12 mg (3/36; P < .1), 24 mg BID (8/36; P < .01) and 24 mg QD (5/35; P < .05), in a dose-dependent manner. In the U-ACHIEVE phase II double-blind trial, patients with moderate-to-severe active ulcerative colitis and an inadequate response, loss of response, or intolerance to immunosuppressive or biologic agents were randomly assigned (1:1:1:1:1) to placebo or upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg) as induction therapy for 8 weeks. The primary end point, clinical remission according to a stringent Adapted Mayo score, was met in 0% of the placebo group compared with 8.5% (P = .052) of the 7.5 mg group, 14.3% (P = .013) of the 15 mg group, 13.5% (P = .011) of the 30 mg group, and 19.6% (P = .002) of the 45 mg group. Improvements compared with placebo in endoscopic response were observed at all 4 doses. Adverse events in both studies were generally consistent with prior reports, although neither trial was powered for safety analyses. Infections and viral reactivation have been previously reported with JAK inhibitors.13Sandborn W.J. Su C. Sands B.E. et al.Tofacitinib as induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2017; 376: 1723-1736Crossref PubMed Scopus (609) Google Scholar,16Genovese M.C. Smolen J.S. Weinblatt M.E. et al.Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate.Arthritis Rheumatol. 2016; 68: 2857-2866Crossref PubMed Scopus (129) Google Scholar In the CELEST induction phase, there were numerically more infections and serious infections in patients receiving upadacitinib (9 in total compared with 0 in the placebo group). In U-ACHIEVE, 2 patients in the placebo group, 1 patient in the 15 mg group, and 2 patients in the 45 mg group experienced serious infections. Herpes zoster infection was reported in 3 patients receiving upadacitinib in CELEST (1 patient in the induction phase and 2 patients in the maintenance phase), and in 1 patient in the 45 mg upadacitinib group in U-ACHIEVE. One patient with cardiovascular risk factors in the U-ACHIEVE 45 mg upadacitinib group experienced a pulmonary embolism and deep venous thrombosis. Ongoing phase III trials (Figure 1) will provide information on the rate of these important events. The efficacy demonstrated in refractory patient populations supports upadacitinib as a highly promising agent for the treatment of IBD, given the urgent need for alternative therapeutic options for these patients and increasing interest in precision IBD medicine.17Fiocchi C. Tailoring treatment to the individual patient - will inflammatory bowel disease medicine be personalized?.Dig Dis. 2015; 33: 82-89Crossref PubMed Scopus (9) Google Scholar The delivery and administration benefits of small molecule JAK inhibitors are also clear. Confirming the efficacy signals in these studies in ongoing phase III trials is now crucial, as is demonstrating safety in robust long-term postmarketing studies. Additional trials are needed to compare the small molecules' safety and to define the role of JAK selectivity in the onset of adverse events. Based on these premises, upadacitinib may be a "JAK"pot-winning therapy for the treatment of both Crohn's disease and ulcerative colitis. Ultimately, however, its sequence and positioning in the armamentarium will require head-to-head trials against the currently available drugs and competitive small molecules in development. Efficacy of Upadacitinib in a Randomized Trial of Patients With Active Ulcerative ColitisGastroenterologyVol. 158Issue 8PreviewWe evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC). Full-Text PDF Open AccessEfficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's DiseaseGastroenterologyVol. 158Issue 8PreviewWe evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). Full-Text PDF Open Access