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Recent advances in basic science
JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?
  1. Silvio Danese1,2,
  2. Marjorie Argollo2,3,
  3. Catherine Le Berre4,
  4. Laurent Peyrin-Biroulet5,6
  1. 1 IBD Centre, Humanitas Clinical Research Centre, Rozzano, Milan, Italy
  2. 2 Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
  3. 3 Gastroenterology, Universidade Federal de São Paulo, São Paulo, Brazil
  4. 4 Gastroenterology, Nancy-Universite, Nancy, Lorraine, France
  5. 5 Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-lès-Nancy, France
  6. 6 Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France
  1. Correspondence to Prof Silvio Danese, Istituto Clinico Humanitas, Rozzano 20089, Italy; sdanese{at}hotmail.com

Abstract

The two major forms of inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated conditions characterised by an increased production of pro-inflammatory cytokines that act as critical drivers of intestinal inflammation. Anti-cytokine therapy has been shown to improve clinical outcomes in IBD. Janus kinases (JAKs) are tyrosine kinases that bind different intracellular cytokine receptors, leading to phosphorylation of signal transducer and activation of transcription molecules implicated on targeted gene transcription. Four isoforms of JAKs have been described: JAK1, JAK2, JAK3 and TYK2. Oral JAK inhibitors (JAKi) have been developed as synergic anti-cytokine therapy in IBD, showing different selectivity towards JAK isoforms. Tofacitinib, a pan-JAK inhibitor, has been recently approved for the treatment of moderate-to-severe UC. With the aim of improving the benefit: risk ratio of this drug class, several second-generation subtype-selective JAKi are under development. However, whether selective inhibition of JAK isoforms is associated with an increased clinical efficacy and/or a better safety profile remains debatable. The aim of this review is to critically review the preclinical and clinical data for the differential selectivity of JAK inhibitors and to summarise the potential clinical implications of the selective JAK inhibitors under development for UC and CD.

  • crohn’s disease
  • ulcerative colitis
  • inflammatory bowel disease
  • drug development
  • IBD clinical

https://doi.org/10.1136/gutjnl-2019-318448

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    Key messages

    • Tofacitinib is the first approved pan–Janus kinase inhibitor (JAKi) for the treatment of UC, but further novel subtype-selective JAKi are currently under development.

    • JAK selectivity is not absolute but relative.

    • JAK selectivity is dose and tissue dependent.

    • Comparative clinical effectiveness research and postmarketing studies will clarify the clinical implications of further JAK selectivity for patients with IBD.

    Introduction

    Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is progressive immune-mediated conditions of the gastrointestinal (GI) tract that require long-term treatment and close monitoring.1 Over the past decades, advances in the knowledge of the inflammatory cascade and the role of cytokines and cell adhesion molecules involved in the pathogenesis of the disease have expanded the pharmacological armamentarium in IBD. Until recently, anti-cytokine theraphy with only monoclonal antibodies, targeting only one or two single cytokines, such as anti-tumour necrosis factor (TNF) agents and ustekinumab, have been approved in IBD.2 However, a significant proportion of patients experience a lack of response to these drugs or lose response over time. Furthermore, monoclonal antibodies are associated with immunogenicity and require parenteral administration.3

    In this context, the development of new molecules targeting simultaneously multiple cytokines has been proven to be effective in IBD4 5 given that there are multiple cytokine-driven inflammatory pathways in the pathogenesis of the disease. The discovery of the Janus kinase (JAK) family of intracellular tyrosine kinases (TYKs) and elucidation of their role in cytokine signalling pathways have identified this class of molecules as potential therapeutic targets for the treatment of IBD.6

    Previous data from tofacitinib, a pan-JAK inhibitor (JAKi), approved since 2012, for the treatment of rheumatoid arthritis (RA) reported broadly similar efficacy to monoclonal antibodies,7 but higher rates of adverse events were observed, including infections, especially herpes zoster reactivation, decreased peripheral blood cell counts, and increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) concentrations.8 Due to concerns about the long-term safety profile of a pan-JAK inhibition, novel subtype-selective JAKi agents are currently being developed and tested as potential novel therapies for IBD including filgotinib (GLPG0634/GS-6034), upadacitinib (ABT-494), TD-1473, PF-06651600, PF-06700841 and BMS-986165.

    Here, we review the existing data and discuss the potential clinical implications of JAKi subtype selectivity in IBD.

    JAK–STAT signalling pathway: simultaneous inhibition of multiple inflammatory cytokine downstream effects

    Stimuli from the extracellular compartment must be transmitted to the intracellular space across the plasma membrane on receptor ligation by a cognate ligand. The transmission of signals from cytoplasm to the nucleus is based on the post-translational protein phosphorylation, catalysed by a group of enzymes, such as protein kinases, functioning as intracellular effectors. Their signalling activities are essential to transcribe external influx into effective cellular responses. Different positive and negative regulators are involved to ensure the accuracy of signals and to prevent aberrant signal activation, leading to proliferative diseases, such as cancer.9

    Cytokine receptors consist of two or more receptor subunits mainly each associated with a JAK monomer, and are classified as type 1 and type 2 according to the structure of their receptors. The first type shows specific characteristics in their extracellular amino acid domain, including the common gamma chain (eg, interleukine (IL)-2), the gp130 family (eg, IL-6), the p40 subunit (eg, IL-12 and IL-23) and the common beta chain cytokine receptors (haematopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF)). The second type constitutes members of the IL-10 and interferon (IFN) families. Both types of cytokine receptor families function by the activation of the JAK-signal transducers and activators of transcription (STAT) pathways.10

    The JAK family comprises four intracellular protein TYKs: JAK1, JAK2, JAK3 and TYK2. All are associated with the proximal intracellular membrane region of cytokine receptors that when activated by external stimuli undergoes conformational changes leading to phosphorylation of JAKs through the reciprocal interaction of two juxtapositioned JAKs. Hence, JAK activation requires two JAK isoforms either as homodimers or heterodimers to autophosphorylate. Consequently, different combinations of JAKs are associated with different cytokine receptors to recruit and phosphorylate other signalling molecules including members of the STAT family (STAT1, STAT2, STAT3, STAT4, STAT5 or STAT6) of DNA binding proteins. Phosphorylation of STATs promotes their translocation to the nucleus and further gene transcription, which ultimately alters aspects of cellular function, including growth, maturation, differentiation and survival, in addition to inflammatory and immune responses.11

    JAK isoforms: selectivity and functions

    JAKs are relatively large in size (ranging from 120 to 140 kDa), structurally composed of seven homologous domains (JH1–7). The JH5–7 regions are crucial for the JAK–cognate receptor binding. The JH1 kinase region is the active catalytic domain, considered essential for JAK activation that plays a crucial role in functional activity and is therefore the main target of JAKi. Because the JH1 domains of the JAK isoforms exhibit a high degree of homology, JAKs share a high sequence identity in their enzyme active regions: JAK3 shares 84% of the residues in its active site with JAK1, 87% with JAK2 and 80% with TYK2. Therefore, JAKi molecules are selective but not specific. JAKi selectivity is assessed by in vitro assay of cytokine release and/or pSTAT activation, and the results depend on the assay substrates/cell lines and measured cytokines. Furthermore, JAK1, JAK2 and TYK2 are ubiquitously expressed, in contrast to JAK3, mainly expressed by haematopoietic cells and affects different cell function (figure 1).11 12

    Figure 1
    Figure 1

    Cell-type expression and activity of the Janus kinase (JAK) family. DC, dendritic cell; HSC, haematopoietic stem cell; NK, natural killer; RBC, red blood cell.

    Mutations in all four isoforms of the JAK family have been described to be associated with human diseases. Inherited mutations in JAK alleles result in the inactivation of JAK3 and TYK2 in human immune deficiency syndromes, while somatic mutations in JAK1, JAK2 and JAK3 lead to myeloproliferative disorders, leukaemia and lymphomas.9 JAK1 somatic activating mutations have been identified in up to 20% of adult T-cell acute lymphoblastic leukaemia while JAK2 somatic activating mutations are associated with myeloproliferative neoplasms.13 14 Furthermore, JAK3 activating mutations have been detected in 7%–15% of patients with severe combined immunodeficiency lacking natural killer (NK) and T cells.15

    The JAK family plays different roles in general cellular functions such as cell growth, maturation, differentiation and haematopoiesis, and its inhibition could lead to deleterious effects, such as increased risk of infections and other adverse events. JAK2 inhibition could lead to neutropenia and anaemia due to its involvement in erythropoiesis. JAK3 is associated with a single cytokine receptor γ-chain, presenting with the most limited function on haematopoietic cells. Therefore, JAK3 selective inhibition may be preferable for the suppression of the inflammatory response associated with the γ-common cytokines.16

    JAK isoform selectivity is dose dependent

    Although increasing dose with a JAKi generally increases its clinical efficacy in multiple diseases, dose-dependent changes in clinical laboratory parameters may also occur.17 The concentration needed to inhibit 50% of activation (half maximal inhibitory concentration, IC50) varies widely from one JAKi to another. A low IC50 value implies a higher potency. JAK isoform selectivity is determined by the ratio and difference between IC50s for different JAK isoforms, considered as the ‘JAK selectivity dose window’. Even though pharmacology efforts aim to develop molecules with a high potency, in the case of JAKi, potency may affect the ‘selectivity dose window’. Therefore, highly potent compounds show a narrow selectivity window while low potent molecules have a larger selectivity window. Thus, the clinical impact of JAK isoform selectivity depends on the dose, cell type, tissue penetration and individual genetic background.18

    As an example of clinical implication of selectivity and dose, it has been reported a smaller increase in haemoglobin (Hb) levels with 10 mg (0.28 g/dL) than with 5 mg of tofacitinib (0.47 g/dL) in patients with RA, as tofacitinib is selective for JAK1 and JAK3 at 5 mg. However, this selectivity is reduced at a higher dose and JAK2 becomes inhibited with consequent reduced erythropoiesis19–21  (table 1).

    View this table:
    Table 1

    JAK selectivity and changes in laboratory parameters

    Correlation of JAK selectivity with clinical data: lessons learnt from RA

    As compared with gastroenterologists, rheumatologists have more experience with the use of JAKi since tofacitinib, a pan-JAKi, was first approved by the Food and Drug Administration (FDA) in 2012 for the treatment of RA. In Europe, tofacitinib received approval by the European Medicines Agency (EMA) in 2017 for the treatment of RA, as well as another JAKi, baricitinib, a selective JAK1 and JAK2 inhibitor. Four additional selective JAKi are currently being developed for the treatment of RA: upadacitinib and filgotinib (both JAK1i), and peficitinib (JAK1 and JAK2i).22–27

    In terms of clinical efficacy, both tofacitinib and baricitinib have been examined in large phase III and IV trials. Until then, there are no head-to-head trials comparing the efficacy between both agents, but tofacitinib and baricitinib seem to have overall similar efficacy.28–31

    JAK isoform selectivity may be particularly relevant regarding the safety profile of JAKi. In patients with RA, safety data are mostly based on randomised controlled trials and extension studies. For tofacitinib, limited real-world data are available from a worldwide, 3-year, postmarketing surveillance32 showing an incidence rate (IR) of serious infections of 2.7/100 and 2.9/100 patient years for tofacitinib and baricitinib, respectively. Both tofacitinib and baricitinib were associated with increased incidence of reactivation of herpes zoster (for every 10 patients each treated for 10 years, 3–4 suffered from zoster reactivation) and similar IR of malignancies (0.9/100 and 0.8/100 patient years for tofacitinib and baricitinib, respectively). As regards laboratory abnormalities, baricitinib induced a mean decrease in Hb level (−0.17 g/dL), while a small increase in Hb level was observed in patients treated with tofacitinib (+0.47 g/dL and +0.28 g/dL at 5 mg and 10 mg dose, respectively). Decrease in neutrophil count has been observed with both agents (−1.09, –0.49 and −1.08×103/mm3 for 5 mg, 10 mg tofacitinib and baricitinib, respectively) as well as lymphocyte count but to a much higher extent with tofacitinib (−0.24, –0.36 and −0.05×103/mm3 for 5 mg, 10 mg tofacitinib and baricitinib, respectively). Platelet count decreased with tofacitinib whereas baricitinib was associated with thrombocytosis. Increase in both HDL and LDL cholesterol occurred after treatment with both drugs as well as increase in liver transaminases, serum creatinine and creatine phosphokinase.33 34 Recently, the FDA alerted the public that a safety clinical trial found an increased risk of blood clots in the lungs and death when a 10 mg twice daily (B.I.D) dose of tofacitinib was used in patients with RA, even though this dosing regimen is only approved for patients with UC. Caution should be taken when extrapolating these findings since the inflammatory burden profile and combination therapy are considerably different among these patient populations. This ongoing trial is expected to be completed by the end of 2019; meanwhile, physicians should follow the recommendations in the tofacitinib prescribing information for the specific condition they are treating and monitor patients for the signs and symptoms of pulmonary embolism.35

    In addition, recently EMA recommended that tofacitinib 10mg B.I.D should not be indicated for patients under additional risk factors for thrombotic events such as current use of oral contraceptive or hormonal therapy, decompensated heart disease, history of any previous venous thromboembolism event (deep or pulmonary), hereditary coagulopathy, cancer and patients with recent major surgical intervention. Other risk factors that should be carefully considered before prescribing tofacitinib are age, obesity, active smoking status and immobilization. In those patients with higher risk for developing any thromboembolic event, other treatment approach should be considered rather than tofacitinib 10mg B.I.D. Moreover, close-monitoring and suspension of the drug are recommended in patients treated with tofacitinib showing any signs or symptoms of pulmonary embolism. (https://www.ema.europa.eu/en/news/restrictions-use-xeljanz-while-ema-reviews-risk-blood-clots-lungs).

    Overall, the clinical significance of selective JAK inhibition remains to be further explored in patients with RA through effectiveness research based on observational studies in order to obtain long-term comparative safety and efficacy data across JAK inhibitors.

    JAK isoforms as therapeutic targets in IBD

    IFN-γ plays an important role in the intestinal response against bacterial pathogens and activates the JAK1/JAK2 combination. The γ-common cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21) signal through the activation of JAK1/JAK3 combination involved in the modulation of the adaptive immune function, including B-cell maturation and Th1, Th2 and Th17 differentiation. IL-13, described as a crucial effector cytokine for an impaired barrier function in IBD, signals through JAK1, JAK2 or TYK2.9

    The partial and reversible inhibition of multiple cytokine pathways with a small molecule, compared with inhibition of a single cytokine pathway with biologics, could offer an alternative therapeutic profile of this new class of drugs. The already approved tofacitinib and the other JAKi currently tested in IBD all have a significant effect on the JAK1 isoform. JAK1 activation is involved in the signal transduction of IL-6, IFN and the common γ-chain cytokines including IL-2 and IL-15. It remains unclear if IFN suppression is an important contributor to the therapeutic benefit of JAK1 inhibitors. However, IFN is crucial for anti-viral immunity, which could explain the association between the use of tofacitinib and herpes zoster reactivation observed in previous studies. Current evidence suggests that JAK1 is an important therapeutic target in IBD.2 36

    Whether JAK2 is a key therapeutic target in IBD is less clear. Pro-inflammatory cytokines such as GM-CSF signal via JAK2. Hence, JAK1 and JAK2 inhibition could lead to a greater anti-inflammatory effect. However, inhibition of JAK2 is potentially related to unfavourable side effects on haematopoietic cytokine inhibition such as erythropoietin, IL-3 and IL-5, and hormones (prolactin and growth hormone). Long-term clinical inhibition of JAK2 has not been assessed yet. In vitro experimentation has shown that JAK2 is involved in platelet activation.34 Furthermore, JAK2 inhibition increases platelet count and rare cases of deep vein thrombosis and pulmonary embolism have been reported.37

    Few available data suggest that TYK2 may be a potential therapeutic target in IBD. Even though there has been an increased interest in the study of TYK2 inhibition for the treatment of immune-mediated diseases in recent years, to date no TYK2-selective inhibitor is available and approved for use.38 Previous data showed that catalytic activity of TYK2 was implicated on downregulation of IL-12, IL-13 and IFN-1, but did not significantly interfere with signalling downstream of IFN-α, IL-6, IL-10 and IL-22, mostly dependent on the JAK1 catalytic activity. Moreover, activation of JAK2 contributed to IL-23, but not to IL-12 signalling, suggesting that IL-12 might be the most appropriate stimulus for evaluating TYK2 coding variation. Therefore, the potential selective inhibition of TYK2 mainly regulating IL-12, IL-23 and IFN signalling, with limited effect on transducing signalling for other cytokines, could lead to less systemic side effects.38

    As regards JAK3, a selective tricyclic JAK3 inhibitor has been developed in vitro. This molecule is characterised by an ATP competitive compound, through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909), which irreversibly inhibits the JAK3 enzyme activity (IC50 <100 nM) with a high selectivity against other kinases. Further studies are ongoing to assess the potential efficacy of selective JAK3 inhibitors for the treatment of patients with IBD (figure 2).12

    Figure 2
    Figure 2

    Janus kinase (JAK) family isoform selectivity: characteristics and dose correlation. BID, twice a day; CNTF, ciliary neutrophic factor; EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; HWB, human whole blood; IC50, half maximal inhibitory concentration; IFN, interferon; IL, interleukin; LIF, leukaemia inhibitory factor; N/A, not applicable; OSM, oncostatin M; QD, once a day; TPO, thrombopoietin.

    JAK selectivity in IBD: correlation with clinical data

    Tofacitinib (Pfizer, New York City, New York, USA)

    Even though tofacitinib, with a 3-hour half-life, was originally developed as a JAK3-specific inhibitor, further studies showed an additional binding affinity for JAK1 and JAK2, thus making tofacitinib a pan-JAKi, targeting both the innate and adaptive immunity.5

    Ulcerative colitis

    Tofacitinib is currently the only JAKi approved by the FDA and the EMA for the treatment of patients with moderate-to-severe UC, based on three phase III OCTAVE trials that demonstrated the superiority of tofacitinib over placebo in inducing and maintaining clinical remission, clinical response and mucosal healing.39

    A recent meta-analysis including 1220 patients showed that tofacitinib had a favourable effect on quality of life with no significant differences in the safety profile compared with placebo. The risk for infections was increased (OR 1.51, 95% CI 1.05 to 2.19), but the incidence of serious infections did not differ between tofacitinib and placebo.40 In the OCTAVE trial, herpes zoster reactivation was more frequent among patients under tofacitinib 10 mg twice a day (5.1%) compared with other treatment groups (1.5% and 0.5% across tofacitinib 5 mg twice a day and placebo, respectively). Regarding other side effects, a dose-dependent elevation of LDL and HDL cholesterol levels has been reported. However, this was reversible after treatment cessation. Few cases of tofacitinib-induced leucopenia (absolute neutrophil count <1500/mm3) were observed. A dose-dependent elevation of LDL and HDL cholesterol levels has been reported. However, this was reversible after treatment cessation. The potential significance of this elevation of LDL cholesterol in the relatively younger population of patients with IBD compared with patients with RA remains to be further explored. The lack of increased cardiovascular events in RA may relate to that age confounder and the known association of active RA with major adverse cardiovascular events.39

    Long-term real-life experience with the use of tofacitinib for the treatment of 58 patients with anti–TNF-resistant moderate-to-severe IBD (53 UC, 4 CD and 1 pouchitis) has been reported recently demonstrating that tofacitinib may be a potential therapeutic alternative for this challenging patient population. At week 8, 36% and 33% of patients achieved clinical response and remission, respectively, with steroid-free remission observed in 26%. Among patients followed until week 52, 27% showed clinical steroid-free remission. The safety profile of the drug was also assessed during follow-up reporting 12 cases of systemic infections, mostly associated with the use of concomitant steroids, and 1 case of herpes zoster reactivation.6

    Regarding the potential increased risk of venous thromboembolism, a recent safety review of post-marketing FDA’s Adverse Event Reporting System (FAERS) reports associated with three JAK inhibitors (tofacitinib, baricitinib and ruloxitinib) did not find elevated reporting rates for deep venous thrombosis and pulmonary embolism. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. These data need to be confirmed by future adverse events reporting trends and clinical trials.41

    Crohn’s disease

    Phase II trials assessing the use of tofacitinib in patients with moderate-to-severe CD failed to induce a significant clinical benefit, even though reductions of C-reactive protein and faecal calprotectin levels indicate it may be biologically active.42 43

    However, results from the phase II open-label 48-week extension study reported worsening disease as the most frequently occurring adverse event, thus supporting the lack of clinical efficacy in CD.44 Based on these results, further development of tofacitinib for CD was discontinued.

    Novel generation of subtype-selective JAKi

    Filgotinib (GLPG0634; Galapagos NV, Mechelen, Belgium)

    Filgotinib is an oral selective JAK1 inhibitor with a 6-hour half-life and maximal pharmacodynamic effects achieved with once-daily dosing. Filgotinib has a 50-fold greater selectivity for JAK1 over JAK3 inhibition and a 30-fold selectivity for JAK1 over JAK2 inhibition. The FITZROY study, a 20-week phase II double-blind, placebo-controlled trial evaluated the efficacy and safety of filgotinib in both naïve and anti-TNF-experienced patients with active moderate-to-severe CD. At week 10, clinical remission was achieved in 47% of patients receiving filgotinib compared with 23% in the placebo group (p=0.0077). The difference in remission rates found in the filgotinib and placebo groups revealed that previous exposure to anti-TNF agents appears to be a surrogate marker of disease severity possibly related with lower rates of response to filgotinib.45 Regarding safety at week 20, serious treatment-related adverse effects were reported in 9% of patients treated with filgotinib and 4% of those treated with placebo. In contrast to tofacitinib, no significant changes in lymphocyte or neutrophil counts were reported. Higher doses of filgotinib increased by 11% and 12% HDL and LDL levels, respectively. However, a similar effect was observed in the placebo group with a mean rise of 4% in HDL and 13% in LDL. Phase III trials are ongoing in both UC and CD.

    Upadacitinib (ABT-494; AbbVie, Chicago, Illinois, USA)

    Upadacitinib, another selective JAK1 inhibitor, was evaluated in the phase II CELEST study for the treatment of patients with moderate-to-severe CD who either failed to respond or were intolerant to conventional therapy. This trial evaluated the efficacy and safety of multiple doses of upadacitinib as an induction treatment until week 16, followed by blinded extension therapy for 36 weeks. Significantly more patients on 6 mg twice a day achieved clinical remission compared with placebo (27% vs 11%). A significant dose–response relationship was observed with upadacitinib versus placebo for endoscopic remission. In the extension phase of this study, rates of clinical and endoscopic responses were generally higher in the 6 and 12 mg twice-daily arms. Even though overall adverse events and infections were numerically higher in the upadacitinib-exposed population, these events did not appear to be dose related.46 47 Similar to filgotinib, phase III trials are ongoing in both UC and CD.

    TD-1473 (Theravance Biopharma, San Francisco, California, USA)

    TD-1473 is a pan-JAK inhibitor with a high affinity for each member of the JAK family of enzymes (JAK1, JAK2, JAK3 and TYK2), which is specifically designed to distribute adequately and exclusively to the intestinal tract, thus minimising systemic exposure (gut selectivity). In vitro and in vivo studies demonstrated that TD-1473 and tofacitinib had similar inhibitory potencies in cellular assays.48

    The safety, tolerability and pharmacodynamics of TD-1473 were evaluated in a double-blind placebo-controlled phase Ib trial including 40 patients with moderate-to-severe UC. All TD-1473 doses (20 mg, 80 mg and 270 mg) were well tolerated over 4 weeks, without serious or opportunistic infections or signals for adverse abnormalities in laboratory parameters. There was evidence of gut selectivity, with low plasma exposures and higher colonic tissue concentrations, and trends for higher rates of clinical response, mucosal healing and biomarker decrease compared with placebo.49 Phase II and phase III trials are ongoing to assess TD-1473 as a potential alternative for the treatment of both CD and UC.

    PF-06700841 and PF-06651600 (Pfizer)

    Since JAK2 uniquely forms a homodimer, which is important in haematopoiesis via signal transduction associated with erythropoietin, thrombopoietin and IL-3, it has been hypothesised that dual JAK1/TYK2 inhibition could provide additional efficacy, while managing the risk of driven haematopoietic changes by optimising selectivity over JAK2, leading to further development of a new molecule PF-06700841. This novel subtype of selective JAKi was designed to inhibit cytokines mediated by the TYK2 isoform, in particular IL-12 and IL-23, as well as those mediated by JAK1, thus establishing potency and selectivity to achieve clinical efficacy and safety (eg, erythropoietin modulation).17

    Moreover, until now, no truly selective JAK3 inhibitor had reached clinical stages. PF-06651600 is a new potent selective JAK3 inhibitor, described to be highly effective in inhibiting γc-cytokine signalling, yet preserving the JAK1-dependent anti-inflammatory signalling (eg, IL-10 suppressive functions and the suppression of TNF-α and IL-1β production). In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Thus, JAK3-selective inhibition differs from pan-JAK or JAK1 inhibition in several immune-cellular responses, possibly leading to advantageous clinical outcomes in immune-mediated diseases.50 51

    These two new generations of selective JAKi, PF-06700841 and PF-06651600, are currently under study in phase II trials enrolling patients with moderate-to-severe CD and UC.

    BMS-986165 (Bristol-Myers Squibb, New York City, New York, USA)

    BMS-986165 inhibits TYK2, required for signal transduction downstream of IL-12 and IL-23, through a novel mechanism by binding selectively not to the active catalytic site of TYK2 but instead to the JH2 pseudokinase domain. Pseudokinase domain binders stabilise the TYK2 pseudokinase domain in a conformational state preventing receptor-mediated activation and activity of the catalytic domain.52

    A phase II trial evaluating the use of BMS-986165 for the treatment of psoriasis resulted in significantly greater clearing of psoriasis compared with placebo. As regards the safety profile, three serious adverse events and one case of malignant melanoma were reported in patients receiving the active drug, 96 days after the start of treatment.53 These promising results led to further research in the IBD field with a phase II multidosing interventional study (the LATTICE trial) still recruiting to evaluate the safety and efficacy of BMS-986165 in subjects with moderate-to-severe CD. Figure 3 summarises all JAKi currently approved or in development in patients with IBD.

    Figure 3
    Figure 3

    Janus kinase (JAK) inhibitors in IBD. CNTF, ciliary neutrophic factor; EMA, European Medicines Agency; Epo, erythropoietin; FDA, Food and Drug Administration; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; LIF, leukaemia inhibitory factor; OSM, oncostatin M; Tpo, thrombopoietin.

    Conclusions

    Small-molecule drugs represent a new generation of drugs in IBD following two decades of monoclonal antibodies (anti-TNF, vedolizumab, ustekinumab). Tofacitinib is currently the only JAKi approved for use in patients with active moderate-to-severe UC, as it has proven to be effective in inducing and maintaining clinical remission and mucosal healing in these patients, regardless of any previous anti-TNF treatment. Tofacitinib was not effective in a phase II trial in CD. Similar to previous findings in patients with RA treated with tofacitinib, a higher risk of herpes zoster reactivation was demonstrated and vaccination of patients treated with tofacitinib is currently advised. Shingrix is the first approved recombinant vaccine for the prevention of herpes zoster (EU, USA, Japan, Canada and Australia) highly effective in adults aged ≥50 years, not contraindicated in immunocompromised individuals, and preferred over a live attenuated herpes zoster vaccine in immunocompetent individuals.

    Several novel selective oral JAKi are currently under development and should expand the therapeutic armamentarium for the management of patients with IBD within the next 2–3 years. Selective JAK1 inhibitors, filgotinib and upadacitinib, were evaluated in phase II trials FITZROY and CELEST, respectively, for the treatment of patients with moderate-to-severe CD and yielded promising results with encouraging clinical response and mucosal healing rates, while no significant adverse effects were identified versus placebo. Phase III studies are ongoing and will help to determine whether filgotinib and upadacitinib are effective options in the treatment of CD. No cases of herpes zoster reactivation were identified, corroborating with the hypothesis of a possible class effect on NK cells through a combined JAK1 and JAK3 inhibition of tofacitinib.

    Gut selectivity for orally administered JAKi has been described with TD-1473 and could be an approach to minimise systemic drug exposure. TD-1473 exposure in patients with moderate-to-severe UC was well tolerated and showed trends for higher rates of clinical response, mucosal healing and biomarker decrease compared with placebo. Systemic TD-1473 levels were very low in plasma, but exceeded that needed for JAK inhibition in colonic tissue.

    In the near future, many new orally administrated small molecules will be available, leading to some new dilemmas as regards drug positioning, escalation and de-escalation strategies, as well as combination therapy. Hence, comparative effectiveness research and head-to-head trials between biological drugs and new small molecules are eagerly awaited to define which drug to use as first-line therapy in patients with IBD. Whether JAK selectivity will lead to improved risk–benefit profile of JAKi in patients with RA and IBD will require further assessment in ongoing phase III trials and postmarketing studies. At the moment, JAK selectivity seems mainly a ‘bench’ exercise, and whether this will truly translate into clinical benefit remains to be proven.

    Acknowledgments

    The authors thank Materia Prima via Gilead for the editorial support and Dr J Gale for critical review of the paper.

    References

    1. ↵
      2. Cosnes J ,
      3. Gower-Rousseau C ,
      4. Seksik P , et al
      . Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology2011;140:1785–94.doi:10.1053/j.gastro.2011.01.055
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      2. Danese S ,
      3. Grisham M ,
      4. Hodge J , et al
      . JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol2016;310:G155–62.doi:10.1152/ajpgi.00311.2015
      OpenUrlCrossRefPubMed
    3. ↵
      2. Olivera P ,
      3. Danese S ,
      4. Peyrin-Biroulet L
      . Next generation of small molecules in inflammatory bowel disease. Gut2017;66:199–209.doi:10.1136/gutjnl-2016-312912
      OpenUrlFREE Full Text
    4. ↵
      2. Danese S ,
      3. Allez M ,
      4. van Bodegraven AA , et al
      . Unmet medical needs in ulcerative colitis: an expert group consensus. Dig Dis2019;37:266–83.doi:10.1159/000496739
      OpenUrl
    5. ↵
      2. D’Amico F ,
      3. Fiorino G ,
      4. Furfaro F , et al
      . Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin Investig Drugs2018;27:595–9.doi:10.1080/13543784.2018.1492547
      OpenUrl
    6. ↵
      2. Weisshof R ,
      3. Aharoni Golan M ,
      4. Sossenheimer PH , et al
      . Real-world experience with tofacitinib in IBD at a tertiary center. Dig Dis Sci2019 (Epub ahead of print 7 Feb 2019).doi:10.1007/s10620-019-05492-y
    7. ↵
      2. Bonovas S ,
      3. Lytras T ,
      4. Nikolopoulos G , et al
      . Editorial: tofacitinib and biologics for moderate-to-severe ulcerative colitis—what is best in class? Authors' reply. Aliment Pharmacol Ther2018;47:540–1.doi:10.1111/apt.14486
      OpenUrl
    8. ↵
      2. Harigai M
      . Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology2019;58(Supplement_1):i34–42.doi:10.1093/rheumatology/key287
      OpenUrl
    9. ↵
      2. Babon JJ ,
      3. Lucet IS ,
      4. Murphy JM , et al
      . The molecular regulation of Janus kinase (JAK) activation. Biochem J2014;462:1–13.doi:10.1042/BJ20140712
      OpenUrlAbstract/FREE Full Text
    10. ↵
      2. Rawlings JS ,
      3. Rosler KM ,
      4. Harrison DA
      . The JAK/STAT signaling pathway. J Cell Sci2004;117(Pt 8):1281–3.doi:10.1242/jcs.00963
      OpenUrlFREE Full Text
    11. ↵
      2. Choy EH
      . Clinical significance of Janus Kinase inhibitor selectivity. Rheumatology2018;10:1.
      OpenUrl
    12. ↵
      2. Goedken ER ,
      3. Argiriadi MA ,
      4. Banach DL , et al
      . Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. J Biol Chem2015;290:4573–89.doi:10.1074/jbc.M114.595181
      OpenUrlAbstract/FREE Full Text
    13. ↵
      2. Jeong EG ,
      3. Kim MS ,
      4. Nam HK , et al
      . Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res2008;14:3716–21.doi:10.1158/1078-0432.CCR-07-4839
      OpenUrlAbstract/FREE Full Text
    14. ↵
      2. Baxter EJ ,
      3. Scott LM ,
      4. Campbell PJ , et al
      . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet2005;365:1054–61.doi:10.1016/S0140-6736(05)74230-6
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      2. O’Shea JJ ,
      3. Husa M ,
      4. Li D , et al
      . Jak3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol2004;41:727–37.doi:10.1016/j.molimm.2004.04.014
      OpenUrlCrossRefPubMed
    16. ↵
      2. Fiorino G ,
      3. D’Amico F ,
      4. Italia A , et al
      . JAK inhibitors: novel developments in management of ulcerative colitis. Best Pract Res Clin Gastroenterol2018;32-33:89–93.doi:10.1016/j.bpg.2018.05.015
      OpenUrl
    17. ↵
      2. Fensome A ,
      3. Ambler CM ,
      4. Arnold E , et al
      . Dual inhibition of TYK2 and JAK1 for the treatment of autoimmune diseases: discovery of ((S)-2,2-difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841). J Med Chem2018;61:8597–612.doi:10.1021/acs.jmedchem.8b00917
      OpenUrl
    18. ↵
      2. Riese RJ ,
      3. Krishnaswami S ,
      4. Kremer J
      . Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol2010;24:513–26.doi:10.1016/j.berh.2010.02.003
      OpenUrlCrossRefPubMed
    19. ↵
      2. Schulze-Koops H ,
      3. Strand V ,
      4. Nduaka C , et al
      . Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. Rheumatology2017;56:46–57.doi:10.1093/rheumatology/kew329
      OpenUrlCrossRefPubMed
    20. ↵
      Tofacitinib. Summary of product characteristics. London, UK: European Medicine Agency, 2017.
    21. ↵
      2. Winthrop KL
      . The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol2017;13:234–43.doi:10.1038/nrrheum.2017.23
      OpenUrlPubMed
    22. ↵
      2. Kremer JM ,
      3. Emery P ,
      4. Camp HS , et al
      . A phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy. Arthritis Rheumatol2016;68:2867–77.doi:10.1002/art.39801
      OpenUrl
    23. ↵
      2. Westhovens R ,
      3. Taylor PC ,
      4. Alten R , et al
      . Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis2017;76:998–1008.doi:10.1136/annrheumdis-2016-210104
      OpenUrlAbstract/FREE Full Text
    24. ↵
      2. Kavanaugh A ,
      3. Kremer J ,
      4. Ponce L , et al
      . Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis2017;76:1009–19.doi:10.1136/annrheumdis-2016-210105
      OpenUrlAbstract/FREE Full Text
    25. ↵
      2. Kivitz AJ ,
      3. Gutierrez-Ureña SR ,
      4. Poiley J , et al
      . Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatol2017;69:709–19.doi:10.1002/art.39955
      OpenUrl
    26. ↵
      2. Fleischmann RM ,
      3. Damjanov NS ,
      4. Kivitz AJ , et al
      . A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis. Arthritis Rheumatol2015;67:334–43.doi:10.1002/art.38949
      OpenUrl
    27. ↵
      2. Genovese MC ,
      3. van Vollenhoven RF ,
      4. Pacheco-Tena C , et al
      . VX-509 (decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheumatol2016;68:46–55.doi:10.1002/art.39473
      OpenUrl
    28. ↵
      2. van Vollenhoven RF ,
      3. Fleischmann R ,
      4. Cohen S , et al
      . Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med2012;367:508–19.doi:10.1056/NEJMoa1112072
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      2. Taylor PC ,
      3. Keystone EC ,
      4. van der Heijde D , et al
      . Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med2017;376:652–62.doi:10.1056/NEJMoa1608345
      OpenUrl
    30. ↵
      2. Dougados M ,
      3. van der Heijde D ,
      4. Chen YC , et al
      . Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis2017;76:88–95.doi:10.1136/annrheumdis-2016-210094
      OpenUrlAbstract/FREE Full Text
    31. ↵
      2. Genovese MC ,
      3. Kremer J ,
      4. Zamani O , et al
      . Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med2016;374:1243–52.doi:10.1056/NEJMoa1507247
      OpenUrlCrossRefPubMed
    32. ↵
      2. Cohen S ,
      3. Curtis JR ,
      4. DeMasi R , et al
      . Worldwide, 3-year, post-marketing surveillance experience with tofacitinib in rheumatoid arthritis. Rheumatol Ther2018;5:283–91.doi:10.1007/s40744-018-0097-3
      OpenUrl
    33. ↵
      2. Cohen SB ,
      3. Tanaka Y ,
      4. Mariette X , et al
      . Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis2017;76:1253–62.doi:10.1136/annrheumdis-2016-210457
      OpenUrlAbstract/FREE Full Text
    34. ↵
      2. Choy EHS ,
      3. Miceli-Richard C ,
      4. González-Gay MA , et al
      . The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib. Clin Exp Rheumatol2019.
    35. ↵
      Safety 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. https://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-xr.
    36. ↵
      2. Hodge JA ,
      3. Kawabata TT ,
      4. Krishnaswami S , et al
      . The mechanism of action of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol2016;34:318–28.
      OpenUrlPubMed
    37. ↵
      2. De VLCS ,
      3. Wildenberg ME ,
      4. De JWJ , et al
      . The future of Janus kinase inhibitors in inflammatory bowel disease. 2017:885–93.
    38. ↵
      2. Sohn SJ ,
      3. Barrett K ,
      4. Van Abbema A , et al
      . A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol2013;191:2205–16.doi:10.4049/jimmunol.1202859
      OpenUrlAbstract/FREE Full Text
    39. ↵
      2. Sandborn WJ ,
      3. Su C ,
      4. Sands BE , et al
      . Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med2017;376:1723–36.doi:10.1056/NEJMoa1606910
      OpenUrl
    40. ↵
      2. Paschos P ,
      3. Katsoula A ,
      4. Giouleme O , et al
      . Tofacitinib for induction of remission in ulcerative colitis: systematic review and meta-analysis. Ann Gastroenterol2018;31:572–82.doi:10.20524/aog.2018.0276
      OpenUrl
    41. ↵
      2. Verden A ,
      3. Dimbil M ,
      4. Kyle R , et al
      . Analysis of spontaneous postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors. Drug Saf2018;41:357–61.doi:10.1007/s40264-017-0622-2
      OpenUrl
    42. ↵
      2. Panés J ,
      3. Sandborn WJ ,
      4. Schreiber S , et al
      . Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut2017;66:1049–59.doi:10.1136/gutjnl-2016-312735
      OpenUrlAbstract/FREE Full Text
    43. ↵
      2. Sandborn WJ ,
      3. Ghosh S ,
      4. Panes J , et al
      . A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol2014;12:1485–93.doi:10.1016/j.cgh.2014.01.029
      OpenUrlCrossRefPubMed
    44. ↵
      2. Panés J ,
      3. D’Haens GR ,
      4. Higgins PDR , et al
      . Long-term safety and tolerability of oral tofacitinib in patients with Crohn’s disease: results from a phase 2, open-label, 48-week extension study. Aliment Pharmacol Ther2019;49:265–76.doi:10.1111/apt.15072
      OpenUrl
    45. ↵
      2. Vermeire S ,
      3. Schreiber S ,
      4. Petryka R , et al
      . Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet2017;389:266–75.doi:10.1016/S0140-6736(16)32537-5
      OpenUrl
    46. ↵
      2. Sanborn WJ ,
      3. Feagan B ,
      4. Panes J , et al
      . OP007 Safety and efficacy of upadacitinib (ABT-494), an oral JAK1 inhibitor, as induction therapy in patients with Crohn’s disease: results from CELEST. United Eur Gastroenterol J2017;5:A1–A.
      OpenUrl
    47. ↵
      2. Panes J ,
      3. Sandborn WJ ,
      4. Loftus EV , et al
      . P273 Efficacy and safety of upadacitinib maintenance treatment for moderate to severe Crohn’s disease: results from the CELEST study. Eur Crohn’s Colitis Organ2018.
    48. ↵
      2. Beattie D ,
      3. Tsuruda P ,
      4. Shen F , et al
      . TD-1473, a novel, potent, and orally administered, GI-targeted, pan-Janus kinase (JAK) inhibitor. Eur Crohn’s colitis Organ2016.
    49. ↵
      2. Sandborn W ,
      3. Bhandari R ,
      4. Leighton JA , et al
      . Pan-JAK inhibitor TD-1473 demonstrates favorable safety, tolerability, pharmacokinetics, and signal for clinical activity in subjects with moderately-to-severely active ulcerative colitis. Poster Present Crohn’s Colitis Congr Las Vegas2019.
    50. ↵
      2. Thorarensen A ,
      3. Dowty ME ,
      4. Banker ME , et al
      . Design of a Janus kinase 3 (JAK3) specific inhibitor 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) allowing for the interrogation of JAK3 signaling in humans. J Med Chem2017;60:1971–93.doi:10.1021/acs.jmedchem.6b01694
      OpenUrl
    51. ↵
      2. Telliez JB ,
      3. Dowty ME ,
      4. Wang L , et al
      . Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem Biol2016;11:3442–51.doi:10.1021/acschembio.6b00677
      OpenUrl
    52. ↵
      2. Tokarski JS ,
      3. Zupa-Fernandez A ,
      4. Tredup JA , et al
      . Tyrosine kinase 2-mediated signal transduction in T lymphocytes is blocked by pharmacological stabilization of its pseudokinase domain. J Biol Chem2015;290:11061–74.doi:10.1074/jbc.M114.619502
      OpenUrlAbstract/FREE Full Text
    53. ↵
      2. Papp K ,
      3. Gordon K ,
      4. Thaçi D , et al
      . Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med2018;379:1313–21.doi:10.1056/NEJMoa1806382
      OpenUrl

    Footnotes

    • Contributors All authors contributed to this manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it published Online First. The acknowledgement statement has been updated.

    • Patient consent for publication Not required.