JAK inhibitors in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by inflammation, synovitis and progressive destruction of the articular cartilage and underlying bone, along with various extra-articular manifestations. Cytokines act as soluble mediators responsible for the inflammatory process, activating endothelial cells and attracting immune cells to accumulate within the synovial compartment.¹

 

The basis of RA treatment is the use of disease-modifying anti-rheumatic drugs (DMARDs). There are two major classes of DMARDs: synthetic (sDMARDs) and biological (bDMARDs). Furthermore, sDMARDs are divided into conventional synthetic (csDMARDs) and targeted synthetic (tsDMARDs).² This classification is based on the development process. The use of csDMARDs has evolved empirically, as their modes of action are largely unknown. By contrast, tsDMARDs have been developed to target specific molecules that are known to play a role in RA pathogenesis. This is the case of the subjects of this review, being designed to inhibit molecules of the Janus kinase (JAK) transduction pathway.

 

The JAK inhibitors are a recent class of drugs for the treatment of RA. Unlike previous therapies that were based on blocking different cytokines outside the cell, JAK inhibitors act by disrupting signalling pathways within the cell. In recent years, intracellular signalling proteins, as kinases, have emerged as potential targets for regulating the immune system in arthritis. JAKs are intracellular transducers of signals from many extracellular cytokines. There are four types of JAKs: JAK1; JAK2; JAK3; and non-receptor tyrosine protein kinase, TYK2. Distinct cytokine receptors are paired with different JAKs, which are activated upon cytokine binding. This triggers the regulation of gene expression through activation of various signalling molecules.³ Suppressing the cytokine effect through JAK inhibition seems a feasible approach to treat RA. Each JAK inhibitor has specific affinities to different JAKs; therefore distinctive cytokines and other soluble factors are blocked and particular effects are expected.

 

Present recommendations for the treatment of RA suggest that therapy should be initiated with a csDMARD, methotrexate (MTX) being the most commonly used. Until the advent of tsDMARDs, bDMARDs were the single available option in patients who failed to respond to csDMARDs. 

 

The arrival of bDMARDs meant a dramatic step forward in the treatment of RA and made it possible to increase the level of demand, supporting a ‘treat to target’ strategy aimed at lowering disease activity or remission. However, up to one third of patients do not adequately respond to bDMARDs and more lose response over time or experience adverse events.⁵ Thus there is a demand for new therapies to fill the gap and that is where tsDMARDs, specifically JAK inhibitors, come into play. Presently, tsDMARDs are recommended for the treatment of patients who failed with csDMARD added to the csDMARD in a similar way than bDMARDs.4 Interestingly, if the use of csDMARD as comedication is contraindicated, tsDMARDs are preferred over all bDMARDs, because JAK inhibitors have shown better efficacy on monotherapy compared with MTX.^6,7

 

A large number of clinical trials have already demonstrated the efficacy of different JAK inhibitors; To date, tofacitinib and baricitinib have been approved by the European Medicines Agency (EMA) and by the Food and Drug Administration (FDA). Tofacitinib has been marketed in a number of countries, including the USA, in the last five years. Many JAK inhibitors with different specificities are being developed, and a number of these are expected to be launched in the coming years.

 

Tofacitinib is a selective inhibitor with a high affinity for JAK1 and 3 and for JAK2, to a lesser extent. Phase III trials have shown efficacy for tofacitinib in RA patients who have failed DMARDs, both as monotherapy⁶ and in combination with MTX.⁸ A study has demonstrated that tofacitinib plus MTX was non-inferior to adalimumab plus MTX, and that tofacitinib monotherapy was not non-inferior relative to the two combination groups.⁹ Tofacitinib also demonstrated higher rates of response when compared with placebo in patients with insufficient response to bDMARDs.¹⁰

 

Tofacitinib was the first JAK inhibitor to reach the market, being approved in the USA and 44 other countries in 2012. It took longer to obtain approval from the EMA, and this was granted in March 2017. The reasons behind this delay were unresolved safety concerns (mainly infections) and doubts about reduction of structural progression. Pooled data from studies of tofacitinib in patients with RA showed that the overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib were similar to those observed in RA patients treated with biologic agents.¹¹ Regarding joint damage, a subsequent trial showed that tofacitinib monotherapy was superior to MTX in preventing radiological progression.¹² The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure and were in line with what is expected in patients with moderate to severe RA.¹³

 

The EMA approved tofacitinib at a dose of 5mg twice daily, being indicated in combination with MTX for the treatment of moderate to severe active RA in adult patients who have had an inadequate response to MTX. It also can be used as monotherapy in cases of intolerance to MTX or when continued treatment with MTX is inappropriate. 

 

Baricitinib is a JAK1/2 inhibitor with moderate activity on TYK2 and no influence on JAK3. Phase III studies demonstrated that baricitinib alone or in combination with MTX had superior efficacy to MTX monotherapy as initial treatment for patients with active RA.⁷ In patients with inadequate response to MTX, baricitinib was superior when compared with placebo and adalimumab.¹⁴ It also demonstrated clinical improvement and inhibition of progression of radiographic joint damage in patients who failed to respond to csDMARDs¹⁵ and clinical improvement in patients with inadequate response to bDMARDs.¹⁶

 

Baricitinib was approved by the EMA in March 2017 at a dose of 4 or 2mg once daily. It is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs. It may be used as monotherapy or in combination with MTX. 

 

Baricitinib approval was initially rejected by the FDA, on the basis that additional clinical data were needed to determine the most appropriate doses and to further characterise safety concerns across treatment arms. A major reason behind this decision was the presence of thromboembolic events in five patients receiving baricitinib in clinical trials. It just has been approved by the FDA at a dose of 2mg once daily in adult patients with moderately-to-severely active RA who have had an inadequate response to one or more tumor necrosis factor (TNF) inhibitor therapies. It may be used as monotherapy or in combination with MTX or other csDMARDs. Baricitinib was approved with a Boxed Warning for the risk of serious infections, malignancies and thrombosis. As part of the approval, the sponsor has agreed to conduct a randomised controlled clinical trial to evaluate the long-term safety of baricitinib in patients with RA.

 

Filgotinib is a selective inhibitor of JAK1 over JAK2, JAK3 and TYK2. The rationale for the development of more selective inhibitors such as filgotinib is that less selective JAK inhibitors lead to pan-JAK inhibition that might generate dose-limiting side effects.

 

Published results of Phase II studies in patients with insufficient response to MTX showed that filgotinib was superior to placebo with an acceptable safety profile.^17,18 It has also shown efficacy as monotherapy.¹⁹

 

Upadacitinib is another selective inhibitor of JAK1. It has also demonstrated efficacy in Phase II trials, with a favorable safety and tolerability profile in patients with inadequate response to MTX and to bDMARDs.^20,21 Phase III clinical trials are currently ongoing.

 

Decernotinib selectively inhibits JAK3 over the other JAKs. Taking this into account it would be expected that some of the side effects seen with less specific JAK inhibitors might be avoided. Decernotinib has shown superiority compared with placebo in a Phase II study.²² Development is currently on hold.

 

Peficitinib inhibits all of the JAKs, having a moderate selectivity for JAK3. Its milder effect on JAK2 suggests that effects on red blood cells and platelets caused by JAK2 inhibition might be less intense. Results from Phase II trials have demonstrated an acceptable response in patients with inadequate response to csDMARDs.^23,24 Phase III trials are underway.

 

Information from clinical trials is creating a characteristic safety profile for this new class of molecules. What is difficult to answer at this moment is whether the different selectivities of each JAK inhibitor will establish distinctions between them. To date, it seems that there is a large overlap between JAK inhibitors despite their various specifities. Infections and changes in laboratory parameters seem to be common issues with JAK inhibitors.²⁵

 

Most of the safety information for this class of drugs comes from the tofacitinib development programme and post-marketing experience. Some of the changes in laboratory parameters resemble those seen with the bDMARD, tocilizumab, reflecting the inhibition of IL-6. Changes seen with tofacitinib include a decrease in lymphocytes, neutrophils, natural killer cells and platelets, increased levels of transaminases and lipids, and a small increase in serum creatinine. During the development process, only a small percentage of patients developed serious adverse events related to these; further work in necessary to completely understand the consequences of these changes.²⁵

 

Baricitinib showed similar laboratory changes but differences were detected in relation to lymphocyte and platelet counts, which mostly remained unchanged, and levels of haemoglobin, which were reduced. Special concern regarding thrombotic risk is raised. Further information is needed to clarify this issue. Data for other JAK inhibitors are preliminary but it seems that differences in laboratory parameters observed between JAK inhibitors are difficult to explain looking at only their different effect on JAKs. It has to be considered that information of these newer molecules comes from phase II studies where different doses are used, losing JAK inhibitors’ specificity at higher doses.

 

There are limited data on the malignancy risk associated with the use of JAK inhibitors. Information comes from tofacitinib and baricitinib long-term extension studies and the risk of cancer seems to be similar to that observed with bDMARDs.^13,26 There are no long-term data for other JAK inhibitors. Even though preliminary data are encouraging, many more years of exposure are needed to profile the malignancy risk of this class of drugs.

 

Serious infection rates with tofacitinib and baricitinib are similar to those observed with bDMARDs.^11,26 Particular reference to varicella zoster virus has to be made. There is an increase in the risk of herpes zoster in patients receiving JAK inhibitors that seems to be a class effect because it is described with most of them.²⁵ Treatment with tofacitinib showed an increase of the risk in clinical trials²⁷ that was confirmed with real-world data.²⁸ Most of the cases were localised infections, no visceral disease or deaths were reported and the concomitant use of steroids or methotrexate considerably influenced the risk.²⁹ Patients receiving tofacitinib as monotherapy had a significant reduced risk of herpes zoster. 

 

Studies with baricitinib and other JAK inhibitors, even though less consistent because of reduced years of exposure, show similar results. There is a live vaccine to prevent herpes zoster but attenuated live vaccines are contraindicated in patients receiving JAK inhibitors. The exact interval that is required between vaccination and the start of JAK inhibitor treatment needs to be determined.

 

To date, the safety profile of JAK inhibitors seems to be similar to that of bDMARDs, with the exception of herpes zoster.²⁵ Apart from tofacitinib and, to a lesser extent, baricitinib, safety data on JAK inhibitors are limited and further studies are needed but it seems that the safety profiles of JAK inhibitors will be difficult to predict on the basis of their selectivity.

 

1 Feldmann M, Maini SR. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev 2008;223:7–19.

2 Smolen JS et al. Proposal for a new nomenclature of disease-modifying antirrheumatic drugs. Ann Rheum Dis 2014;73:3–5.

3 O’Shea JJ et al. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 2013;72:111–15.

4 Smolen JS et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirrheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960–77.

5 Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther 2009;11:S1.

6 Fleischmann R et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495–507.

7 Fleischmann R et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 2017;69:506–17.

8 Van Vollenhoven RF et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508–19.

9 Fleischmann R et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 2017;S0140-6736(17)31618-5.

10 Burmester GR et al. Tofacitinib (CP-690-550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomized phase 3 trial. Lancet 2013;381:451–60.

11 Cohen S et al. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol 2014;66:2924–37.

12 Lee EB et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014;370:2377–86.

13 Curtis JR et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis 2016;75:831–41.

14 Taylor PC et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017;376:652–62.

15 Dougados M. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDS: results from the RA-BUILD study. Ann Rheum Dis 2017;76:88–95.

16 Genovese MC et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016;374:1243–52.

17 Vanhoutte F et al. Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective Janus kinase 1 inhibitor, after short-term treatment of rheumatoid arthritis: Results of two randomized Phase IIA trials. Arthritis Rheumatol 2017;69(10):1949–59.

18 Westhovens 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 Dis 2017;76:998–1008.

19 Kavanaugh A 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 Dis 2017;76:1009–19.

20 Genovese MC 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;68:2857–66.

21 Kremer JM 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 Rheumatol 2016;2867–77.

22 Genovese MC et al. VX-509 (decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheumatol 2016;68:46–55.

23 Kivitz AJ et al. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatol 2017;69:709–19.

24 Genovese MC et al. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease.modifying antirrheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis Rheumatol 2017;69:932–42.

25 Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nature Rev 2017;13(4):234–43.

26 Smolen J et al. Safety profile of baricitinib in patients with active RA: an integrated analysis. Ann Rheum Dis 2016;75:243–4.

27 Winthrop KL et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol 2014;66:2675–84.

28 Curtis JR et al. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis 2016;75:1843–7.

29 Winthrop KL et al. Herpes zoster and tofacitinib: the risk of concomitant nonbiologic therapy. Ann Rheum Dis 2015;74:741.