Janus kinase inhibitors for autoimmune disorders

Transcription

1 THERAY REVIEW Janus kinase inhibitors for autoimmune disorders STEVE CHALIN Three janus kinase () inhibitors baricitinib (Olumiant) and tofacitinib (Xeljanz) for rheumatoid arthritis, and ruxolitinib (Jakavi) for myelofibrosis have already been launched in the UK and others are currently being evaluated in a diverse range of autoimmune disorders and cancers. This article provides an overview of the properties and potential of this new class of drugs. Understanding of the mechanisms by which cytokines alter cellular behaviour as part of the immune response has been evolving since the 19s. The kernel of this complex multistranded system is reversible protein phosphorylation, a function executed within the cell that activates or deactivates pathways that change gene expression. Several hundred protein kinases have been identified. Recognition that they are major drivers of pro- and anti-inflammatory pathways has opened a fruitful avenue of research, culminating in the development of new classes of drugs with a potentially profound therapeutic impact. 1 rotein kinase inhibitors have been available for the treatment of various cancers since the early s examples include imatinib for leukaemia and gastrointestinal tumours, sorafenib for hepatic and renal cell cancer, sunitinib for gastrointestinal and renal cell cancer, and trametinib for melanoma and non-small cell lung cancer (NSCLC). One pathway in particular, the janus kinase-signal transducer and activator of transcription (-STAT) pathway, has been the target of intense research effort in recent years and novel drugs are now in the final stages of development or have been introduced for the treatment of autoimmune disorders including rheumatoid arthritis, psoriasis and inflammatory bowel disease. cytokine 2 1 plasma membrane receptor nucleus DNA Figure 1. Simplified overview of the -STAT signalling pathway Cytokine binds to receptor 2. Receptor dimerisation activates phosphorylation of receptor 3. STAT binds phosphorylated receptor 4. phosphorylates STAT 5. STAT dimer is formed 6. STAT dimer travels to the nucleus 7. STAT dimer binds DNA and activates gene transcription 7 6 STAT 4 STAT dimer STAT activation of transcription Janus kinases and the -STAT signalling pathway Cytokines are a large and diverse group of proteins that influence cellular activity. They are secreted by many cell types and include the interleukins (IL), interferons (IFN), tumour necrosis factors (TNF) and growth factors. In general, cytokines bind with cell surface receptors to activate intracellular pathways. Again, there is a multiplicity of pathways, each responsive to specific cytokines, that lead to changes in intracellular targets. rescriber December 17 33

2 THERAY REVIEW l Janus kinase inhibitors Cytokine STAT Functional/role IL-2 1, 3 3, 5 Enhances effector and regulatory responses IL-9 1, 3 1, 3, 5 Atopic disease, inflammatory bowel disease IL-3 2 3, 5, 6 Differentiation of multipotent haematopoietic stem cells, proliferation of myeloid cells IL-5 2 3, 5, 6 Allergies, asthma, eosinophilic disease IL-6 1, 2, 1, 3 rototypic proinflammatory cytokine implicated in many autoimmune disorders Erythropoietin 2 5 Erythropoiesis IFN-gamma 1, 2 1 Enhanced immunity against infection, drives autoimmunity IL-19 1, 2, 3 B cell activation, antibody production Table 1. Examples of cytokines, the s and STATs involved in their signalling pathways, and their functions 2 The protein kinases include four s 1, 2, 3 and tyrosine kinase 2 () each associated with different cytokine receptors. The STATS, of which there are seven, bind to the phosphorylated cytokine-receptor complex and, after phosphorylation by a, they translocate to the nucleus, bind DNA and activate target gene transcription (see Figure 1). Table 1 includes examples of cytokines, the s and STATs involved in their signalling pathways, and their functional roles. The -STAT signalling pathway is important for cytokines that regulate the cellular immune response (type I cytokines such as IL-2 and related interleukins) and the antibody-mediated response (type II cytokines such as the interferons, IL-1 and related interleukins). However, some other cytokines with a major role in inflammatory disorders do not use the -STAT pathway; examples include TNF, IL-1 and IL Gene mutations that affect or STAT function have been implicated in several disorders. Examples include severe combined immunodeficiency (3), systemic lupus erythematosus (, STAT4), rheumatoid arthritis (STAT4), atopy (STAT6), Crohn s disease (, STAT3) and Behcet s disease (2, STAT3). 2 roperties of inhibitors The inhibitors (also known as jakinibs) are small molecules; they are orally active and have a straightforward daily dosing regimen. For many people, this will be an advantage over the biological disease-modifying drugs, many of which are monoclonal antibodies that require subcutaneous injection or intravenous infusion (albeit much less frequently, at intervals of weeks or months). inhibitors will therefore avoid the need to train patients or carers to administer the dose, or for patients to attend a clinic for treatment. Imatinib and other early protein kinase inhibitors introduced for the treatment of cancer were not selective for a single class of protein kinases. Similarly, the inhibitors available to date are selective but not specific for a single. Given the overlap between s in their interactions with STATs and their association with more than one cytokine (see Table 1), it is evident that each agent is likely to affect several immunological pathways. Furthermore, a inhibitor can block mediators of cytokines not dependent on the -STAT signalling pathway for example, indirectly affecting TNF by blocking interferons. And not all cytokines are pro-inflammatory some interleukins, such as IL-2 and IL-1, have anti-inflammatory actions so the wider impact of inhibition may be complex. The immunological effects of inhibitors are influenced by their selectivity for subtypes 3 but whether such differences will be associated with clinically significant differences in efficacy or safety is not yet clear. Adverse effects that are potentially associated with inhibition of each are summarised in Table 2. 4 inhibitors are currently being evaluated in a diverse range of disorders (see of which rheumatoid arthritis, psoriasis, inflammatory bowel disease and myeloproliferative disorders account for the greatest number. Many more trials are underway in other autoimmune disorders (juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus, Sjögren s syndrome), chronic kidney disease and diabetic nephropathy, breast cancer, lymphoma and the prevention of graft rejection. Rheumatoid arthritis Two inhibitors, baricitinib (Olumiant) and tofacitinib (Xeljanz), have been introduced in the UK for the treatment of rheumatoid arthritis. Baricitinib is selective for 1 and 2 and tofacitinib preferentially inhibits 1 and 3. Both are licensed as monotherapy or in combination with methotrexate for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to, one or more disease-modifying antirheumatic drug (DMARDs). Several other inhibitors are undergoing clinical trials for similar indications, including the 1-selective filgotinib and upadacitinib. There is strong evidence that inhibitors, combined with methotrexate, improve the symptoms of rheumatoid arthritis in patients who did not experience benefit from treatment with a biological DMARD plus methotrexate. Defining a response as the ACR (a % improvement in tender and swollen joint counts, plus a % improvement in at least three of: visual analogue pain scale, disability, acute phase reactants, and patient and physician global assessment), a key phase 3 trial of baricitinib reported response rates of 55% compared with 27% with placebo after 12 weeks in patients with refractory disease (see Figure 2); 5 similar response rates have been reported for tofacitinib. 6 After failure of methotrexate therapy (but before 34 rescriber December 17

3 Janus kinase inhibitors l THERAY REVIEW Function impaired otential adverse effect Severely impaired lymphoid development Defective cytokine signalling Impaired erythropoiesis, myelopoiesis Impaired response to gamma chain receptor family of interleukins (eg IL-2) Impaired helper T cell (Th)1 responses Reduction in pathogenic Th17 cells Blockade of IFN actions Infection, hyperlipidaemia Anaemia, neutropenia Natural killer cell lymphopenia Diminished function of CD8 T cells Infection, possibly opportunistic infection Infection Table 2. otential adverse effects associated with inhibition 4 treatment with a biological DMARD), tofacitinib and baricitinib have been shown to be non-inferior 7 or superior 8 to the TNF inhibitor adalimumab and to slow disease progression. 8,9 Because long-term safety is currently uncertain, European management guidance recommends that inhibitors should be reserved for use when a biological DMARD proves unsatisfactory. 1 NICE has now appraised both baricitinib and tofacitinib, and recommends them for use only when disease is severe and has responded inadequately to a combination of conventional DMARDs, or if the patient has responded inadequately to or cannot take a biological DMARD. 11,12 A month s treatment with tofacitinib or baricitinib costs 69 or 85, which is close to the cost of biological DMARDs. Dermatology inhibitors are being evaluated as treatments for psoriasis, alopecia areata, vitiligo and atopic dermatitis. 13 NICE recommends systemic biological agents as an alternative to the DE4 inhibitor apremilast for the treatment of severe psoriasis when phototherapy, methotrexate and ciclosporin have proved unsuccessful. 14 The options are the TNF inhibitors adalimumab and etanercept, the interleukin (IL)-12 and IL-23 inhibitor ustekinumab, the IL-17A inhibitors secukinumab and ixekizumab, and (for very severe psoriasis) the TNF inhibitor infliximab. Most clinical trials of inhibitors for psoriasis have been of tofacitinib. 13 In patients with moderate to severe plaque psoriasis who were eligible for conventional systemic therapy, who had not responded to it, or in whom it was contraindicated or poorly tolerated, the proportion of patients with a ASI 75 response ( 75% reduction in soriasis Area and Severity Index score) was 46% with 5mg tofacitinib twice daily and 59 % with 1mg tofacitinib twice daily compared with 6 11% with placebo after 16 weeks (see Figure 3). 15 The higher dose of tofacitinib was non-inferior to etanercept 5mg twice weekly. 16 In one trial that included 12 patients with psoriatic arthritis, all met the ACR response criterion after 12 weeks treatment with tofacitinib and this improvement was maintained in most patients after one year, with the 1mg twice daily dosage possibly superior to 5mg twice daily. 17 A phase 2 trial suggests that baricitinib may offer similar efficacy in patients with moderate to severe plaque psoriasis. 18 Topical formulations of inhibitors have also been evaluated; early trials suggest that ruxolitinib compares well with established topical treatments but trials of topical tofacitinib have been inconclusive. 13 Other early trials suggest that inhibitors show promise in the treatment of vitiligo and atopic dermatitis. Animal models suggest that inhibitors can activate hair follicles and restore hair growth; several trials indicate that tofacitinib in particular may improve alopecia areata in 3 % of patients, though definitive evidence is needed. 13 In one retrospective study, symptom score improved by more than 5% in % of patients treated for 4 18 months. 19 Inflammatory bowel disease NICE recommends the alpha-4 beta-7 integrin inhibitor vedolizumab for moderate to severe active ulcerative colitis, TNF inhibitors when treatment with steroids and immunosuppressants has failed, and infliximab for acute exacerbations of ulcerative coli- % patients lacebo Baricitinib 2mg daily Baricitinib 4mg daily ACR ACR5 ACR7 ACR ACR5 ACR7 p value vs placebo p<.1 p<.1 *p<.5 Week 12 Week 24 Figure 2. American College of Rheumatology (ACR) response rates to baricitinib 2mg or 4mg daily or placebo, plus a conventional disease-modifying antirheumatic drug (DMARD), in patients with moderate to severe active rheumatoid arthritis and an inadequate response to a biological DMARD 3 ACR (primary endpoint), ACR5, ACR7 = a %, 5% or 7% improvement in tender and swollen joint counts, plus a %, 5% or 7% improvement in at least three of: visual analogue pain scale, disability, acute phase reactants, and patient and physician global assessments * rescriber December 17 35

4 THERAY REVIEW l Janus kinase inhibitors ercentage patients achieving ASI 75 ± SE ercentage patients achieving ASI 75 ± SE tis. Similar guidance applies to the treatment of severe active Crohn s disease that is unresponsive to conventional agents and immunosuppressants, and vedolizumab is a further option if biological agents are unsuitable or ineffective. 21,22 Early experience with inhibitors in patients with ulcerative colitis has been encouraging. In patients with active ulcerative colitis despite treatment with conventional and biological agents, treatment with tofacitinib induced remission in 17 19% of patients after eight weeks (vs 4 8% with placebo); by 52 weeks, 34% of patients taking a dosage of 5mg twice daily and 41% of those taking 1mg twice daily were in remission (vs 11% with placebo). 23 By contrast, results in patients with Crohn s disease has been disappointing: one phase 2 trial showed that, after eight weeks, tofacitinib did not significantly increase the proportion of patients with moderate to severe disease in remission (43% vs 38% with placebo), with no significant difference in the proportion of patients with response or remission Tofacitinib 5mg twice daily Tofacitinib 1mg twice daily lacebo Week Week ASI 75 = 75% reduction in the soriasis Area and Severity Index (ASI) score. *p.5, p<.1, p<.1 vs placebo Figure 3. ASI 75 response rates in two randomised trials of tofacitinib in patients with moderate to severe chronic psoriasis who were candidates for systemic therapy 15 at six months (56% with 1mg tofacitinib twice daily, % with 5mg twice daily) compared with placebo (38%). 24 Filgotinib is currently undergoing evaluation as a treatment for ulcerative colitis and Crohn s disease in several trials, none of which have been published to date. Myeloproliferative disorders The 1- and 2-selective inhibitor ruxolitinib (Jakavi) is indicated for the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis, either as a primary disease or after polycythaemia vera or essential thrombocythaemia, and is recommended by NICE for intermediate- or high-risk disease. 25 Treatment reduces splenomegaly, itch and fatigue and improves survival but the newer agents now in phase 3 trials, such as momelotinib and pacritinib, may offer similar efficacy with a lower risk of myelosuppression (though they may have other adverse effects such as, in the case of momelotinib, peripheral neuropathy). 26 Adverse effects It is presently uncertain how great the differences in tolerability and toxicity are between the inhibitors. These agents vary in their selectivity for subtypes for example, baricitinib and ruxolitinib exert greatest inhibition on 1 and 2 whereas tofacitinib preferentially inhibits 1 and 3. To what extent these effects selectively induce the potential adverse effects listed in Table 2 is unclear. As with the biological DMARDs, there are concerns about the risk of serious infection with the inhibitors. A meta-analysis of 66 randomised trials and 22 long-term extension studies in patients with rheumatoid arthritis who had not responded to a biological DMARD found that the risk of serious infection with tofacitinib was similar to that of the biological DMARDs. 27 A second meta-analysis of 45 studies concluded that the rate of treatment discontinuation in clinical trials was similar for tofacitinib and biological DMARDs in patients with rheumatoid arthritis who had not responded to treatment with a conventional DMARD. 28 Tofacitinib and baricitinib are associated with an increased risk of herpes zoster, and upper respiratory tract infections were the most frequent adverse events in clinical trials. 15,29,3 Based on premarketing experience, there is no evidence that either of these agents is associated with an increased risk of malignancy in patients with rheumatoid arthritis. Both tofacitinib and baricitinib raise LDL cholesterol in patients with rheumatoid arthritis but this appears to be at least partly attributable to correction of the low levels caused by inflammation associated with rheumatoid arthritis This effect is more frequent than with methotrexate or adalimumab but is not associated with a change in the LDL/HDL ratio or, so far (up to eight years for tofacitinib), an increase in cardiovascular events; similar findings have been reported in patients with psoriasis treated with tofacitinib. 29,31,32 Tofacitinib and baricitinib have been associated with anaemia, lymphopenia or neutropenia (and with thrombocytopenia in patients with myelofibrosis treated with ruxolitinib), 33 and with abnormal liver function tests; prescribing cautions require 36 rescriber December 17

5 Janus kinase inhibitors l THERAY REVIEW monitoring during treatment and interruption of treatment if minimum thresholds are reached. Summary The inhibitors offer a new pharmacological strategy for the treatment of a range of autoimmune disorders. Most of the published data are for tofacitinib and baricitinib in the treatment of rheumatoid arthritis. inhibitors have been shown to be effective in the treatment of rheumatoid arthritis, myeloproliferative disease, psoriasis and ulcerative colitis when other treatments have failed. However, a substantial proportion of patients who are running out of other treatment options do not respond to these agents. The inhibitors appear to be as safe as biological DMARDs though less is known about their long-term effects and about the risk of blood disorders and malignancy in particular. They are currently recommended for the treatment of severe rheumatoid arthritis when established therapies fail; as clinical experience grows, it may be possible to target these agents to improve outcomes further. References 1. atterson H, et al. rotein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin Exp Immunol 14;176: Schwartz DM, et al. Type I/II cytokines, s, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 16;12: Telliez JB, et al. Discovery of a 3-Selective Inhibitor: Functional Differentiation of 3-Selective Inhibition over pan- or 1- Selective Inhibition. ACS Chem Biol 16;11: Kontzias A, et al. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin harmacol 12;12: Genovese MC, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 16;374: Fleischmann R, et al. lacebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 12;367: van Vollenhoven RF, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 12;367: Taylor C, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 17;376: van der Heijde D, et al. Tofacitinib (C-69,55) in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum 13;65: Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 16 update. Ann Rheum Dis 17;76: National Institute for Health and Care Excellence. Baricitinib for moderate to severe rheumatoid arthritis. TA466. August 17. Available from: National Institute for Health and Care Excellence. Tofacitinib for moderate to severe rheumatoid arthritis. TA48. October 17. Available from: Shreberk-Hassidim R, et al. Janus kinase inhibitors in dermatology: a systematic review. J Am Acad Dermatol 17;76: National Institute of Health and Care Excellence. soriasis interactive flowchart. Updated May 17. Available from: nice.org.uk/pathways/psoriasis [accessed May 17]. 15. app K, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol 15;173: Bachelez H, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet 15;386: Asahina A, et al. Oral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized, double-blind, phase 3 study. J Dermatol 16;43: app KA, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase () 1/2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol 16;174: Liu LY, et al. Tofacitinib for the treatment of severe alopecia areata and variants: A study of 9 patients. J Am Acad Dermatol 17;76: National Institute for Health and Care Excellence. Ulcerative colitis interactive flowchart. Updated March 17. Available from: pathways.nice.org.uk/pathways/ulcerative-colitis [accessed May 17]. 21. National Institute for Health and Care Excellence. Crohn s disease: management. CG152. October 12 (updated May 16). Available from: National Institute for Health and Care Excellence. Vedolizumab for treating moderately to severely active Crohn s disease after prior therapy. TA352. August 15. Available from: Sandborn WJ, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 17;376: anés J, et al. Tofacitinib for induction and maintenance therapy of Crohn s disease: results of two phase IIb randomised placebo-controlled trials. Gut 17;66: National Institute for Health and Care Excellence. Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. TA386. March 16. Available from: uk/guidance/ta atel AB, et al. New strategies in myeloproliferative neoplasms: the evolving genetic and therapeutic landscape. Clin Cancer Res 16;22: Strand V, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther 15;17:362. doi: /s Bergrath E, et al. Tofacitinib versus biologic treatments in moderate-to-severe rheumatoid arthritis patients who have had an inadequate response to nonbiologic DMARDs: systematic literature review and network meta-analysis. Int J Rheumatol 17; doi:1.1155/17/ European Medicines Agency. Tofacitinib (Xeljanz) ublic Assessment Report. January European Medicines Agency. Baricitinib (Olumiant) ublic Assessment Report. December Charles-Schoeman C, et al. otential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol 15;67: Wu JJ, et al. Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis. J Am Acad Dermatol 16;75: Cervantes F, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 13;122: Declaration of interests None to declare. Steve Chaplin is a medical writer specialising in therapeutics rescriber December 17 37