JAK inhibitors: The next generation of drugs for treating rheumatoid arthritis?
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Janus kinase (JAK) inhibitors, or “Jakinibs,” have been proposed as “an encouraging next-generation treatment tool” for rheumatoid arthritis (RA) that could “meaningfully contribute” to the therapeutic landscape .
With tofacitinib now approved for use in the USA and the EU, and a number of JAK inhibitors currently undergoing testing in clinical trials, medwireNews takes a look at the current regulatory status of the various JAK inhibitors, outlines their efficacy and safety profiles, and addresses some common questions about the use of these small-molecule therapies for the treatment of RA.
What are JAK inhibitors?
JAKs are intracellular enzymes that transmit signals from cytokines binding to receptors on the cell surface to signal transducers and activators of transcription (STATs), which drive pro-inflammatory cellular responses . The JAK–STAT pathway, outlined in Figure 1, contributes to the pathophysiological processes in RA [3, 4, 5, 6].
There are four JAKs in humans, JAK1, JAK2, JAK3, and tyrosine kinase 2. A number of JAK inhibitors have been developed over the past decade, with some compounds having greater specificity for certain JAKs over others. For example, tofacitinib targets JAK1 and JAK3, whereas baricitinib targets JAK 1 and JAK2.
While traditional biologic therapies – including etanercept, adalimumab, rituximab, and infliximab – act outside cells to suppress inflammation and are given by injections or infusions, JAK inhibitors work inside cells and are taken orally .
Why is there a need for JAK inhibitors in the RA treatment landscape?
Although treatment with biologic agents results in disease suppression for many patients with RA, only approximately 30% achieve complete remission, and the majority of patients treated with biologics experience disease exacerbation following cessation of treatment [1, 8, 9]. The route of administration is also an important consideration, with the results of two studies suggesting that patients with RA may prefer therapies that can be taken orally over those with other routes of administration [10, 11].
Given the important role played by JAK–STAT signaling in the development of RA and other autoimmune conditions, small-molecule JAK inhibitors have been proposed to “offer an important alternative to biological therapies for the treatment of inflammatory diseases” .
Which JAK inhibitors are approved for treating RA, and what are the data supporting their use?
Tofacitinib was the first JAK inhibitor approved for the treatment of RA, and a number of related compounds are currently being tested in phase II and III trials. Figure 2 outlines the key regulatory events for JAK inhibitors in RA following the approval of tofacitinib by the US Food and Drug Administration (FDA) in 2012 , and Table 1 summarizes the different JAK inhibitors that are currently approved or in clinical development.
|Drug/Compound||Current stage of development|
||Approved by EMA and FDA
||Approved by EMA
||Phase II (currently on hold)
Table 1. JAK inhibitors that are currently approved or in clinical development. EMA, European Medicines agency; FDA, US Food and Drug Administration.
Tofacitinib was approved by the FDA in June 2012 at a dose of up to 5 mg administered twice daily for the treatment of moderate-to-severe RA with an inadequate response to methotrexate . Subsequently, in March 2017, the European Medicines Agency (EMA) approved the agent at a dose of 5 mg twice daily for use in combination with methotrexate for the treatment of moderate-to-severe RA with inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs) .
The approval of tofacitinib was based on the results of several studies demonstrating its efficacy both alone and in combination with methotrexate. In the ORAL Solo study, Roy Fleischmann (Metroplex Clinical Research Center, Dallas, Texas, USA) and fellow researchers found that a significantly higher proportion of patients treated with either 5 or 10 mg tofacitinib twice daily achieved at least a 20% improvement in ACR criteria (ACR20) after 3 months when compared with placebo, at 59.8% and 65.7% versus 26.7% . Patients included in ORAL Solo had an inadequate response to at least one nonbiologic or biologic DMARD at baseline.
Similarly, Richard Riese and colleagues (Pfizer Inc., Groton, Connecticut, USA) showed that adding tofacitinib to nonbiologic DMARD treatment – primarily methotrexate – improved disease control relative to placebo among patients with active disease despite prior to treatment . The researchers demonstrated significant improvements in ACR20 response rates after 6 months among patients receiving 5 or 10 mg tofacitinib versus placebo (52.1 and 56.6 vs 30.8%), both given alongside nonbiologic DMARD treatment.
The results of these clinical trials demonstrated the efficacy of tofacitinib “from early phases (starting from approximately 1–2 weeks after initiation), and the compound was effective in both patients who had inadequate response to [DMARDs] as well as in patients who had inadequate response to tumor necrosis factor (TNF) inhibitors,” summarizes Kunihiro Yamaoka (Keio University School of Medicine, Tokyo, Japan) in a review article .
“Importantly, tofacitinib had similar efficacy to adalimumab in RA patients with inadequate response to [methotrexate],” he adds.
Indeed, in the ORAL Standard trial, which investigated the efficacy of tocilizumab or the anti-TNF biologic adalimumab versus placebo in RA patients receiving background methotrexate therapy, 6-month ACR20 rates were 51.5% for patients receiving 5 mg tofacitinib, 52.6% for the 10 mg tofacitinib group, 47.2% for the adalimumab group, and 28.3% for those receiving placebo .
Furthermore, tofacitinib was shown to reduce the signs and symptoms of RA and improve physical functioning relative to methotrexate in the ORAL Start study .
And in a post-hoc analysis of this study, Fleischmann and colleagues identified “generally similar” improvements in disease control with tofacitinib between patients with early versus established RA. However, the improvements in the signs and symptoms of disease with tofacitinib 5 mg at month 24 were significantly greater for patients with early compared with established RA, reinforcing that “diagnosis of RA should be made, and treatment started, as early as possible after the development of symptoms” .
Yamaoka summarizes: “Tofacitinib has demonstrated efficacy in RA patients as a monotherapy as well as in conjunction with methotrexate in a number of clinical trials” .
Baricitinib was approved in Europe at doses of 2 mg and 4 mg for the treatment of moderate-to-severe active RA in adults with an inadequate response to one or more DMARDs in February 2017 . The agent is not currently approved for use in the USA; according to a company press release, as the FDA requires additional data to determine the most appropriate doses of the drug and to further characterize its safety profile .
The European approval of baricitinib was based on the results of studies demonstrating that the drug improves symptoms of RA when previous treatment with DMARDs did not work well enough, or they could not be tolerated. The EMA Committee for Medicinal Products for Human Use (CHMP) also took into account “the lack of treatment options for these patients,” and the convenience of taking baricitinib orally .
Two phase III clinical trials, RA-BEACON and RA-BUILD, demonstrated that treatment with once-daily baricitinib improved RA symptoms relative to placebo. In RA-BEACON, a study of 527 RA patients with inadequate response to TNF inhibitors, other biologic DMARDs, or both, Mark Genovese (Stanford University School of Medicine, Palo Alto, California, USA) and colleagues found that a significantly higher proportion of patients receiving 4 mg baricitinib had an ACR20 response after 12 weeks than their counterparts given placebo (55 vs 27%) .
Similarly, the RA-BUILD trial demonstrated that patients with inadequate response to conventional DMARDs who were treated with baricitinib 4 mg were more likely to experience an ACR20 response and improvements in disease activity and disability scores at week 12 compared with placebo-treated patients . Unlike the patients in RA-BEACON, however, the 684 participants in RA-BUILD were biologic-naïve.
The results of the RA-BEAM trial, published in early 2017, demonstrated that baricitinib may improve clinical outcomes relative to placebo and adalimumab among patients with an inadequate response to methotrexate . Seventy percent of 487 patients receiving baricitinib experienced an ACR20 response at 12 weeks, compared with 40% of 488 patients receiving placebo and 61% of 330 patients taking adalimumab, a significant difference in both cases.
This latter finding suggests that baricitinib is associated with “significant clinical improvements” compared with “a current standard-of-care treatment in this patient population,” say study author Peter Taylor (University of Oxford, UK) and colleagues.
Participants received the study drug in addition to background treatment with methotrexate, “a context in which adalimumab has proved to be most efficacious,” they add.
While Yamaoka believes that “baricitinib is an extremely promising agent, given these findings,” he cautions that studies with longer-term follow-up are necessary to validate the current trial results .
Accordingly, the European product information for baricitinib carries a black triangle label for additional monitoring, meaning that the effects of its long-term use will be more closely scrutinized than those of other medicines .
Filgotinib (GLPG0634) – a selective JAK1 inhibitor – is an investigational drug for RA. The results of two phase IIb studies have demonstrated its efficacy in combination with methotrexate and as a monotherapy.
In the DARWIN 1 trial, a significantly higher proportion of patients receiving stable methotrexate treatment who were randomly assigned to filgotinib at a dose of either 100 or 200 mg daily experienced an ACR20 response at week 12 compared with those assigned to placebo .
These improvements were sustained up to week 24 and “support the future development of filgotinib for the treatment of active RA in patients receiving [methotrexate] treatment,” say Rene Westhovens (University Hospitals Leuven, Belgium) and study co-authors.
Furthermore, the results of the DARWIN 2 trial suggest that filgotinib monotherapy could improve the signs and symptoms of RA relative to placebo, with 12-week ACR20 responses of 67%, 66%, 73%, and 29% in the filgotinib 50, 100, or 200 mg per day, and placebo groups, respectively .
These “encouraging” results support the development of filgotinib monotherapy for the treatment of patients who do not respond adequately to methotrexate, say the study authors.
According to a company press release, phase III trials of filgotinib for the treatment of RA are currently underway .
The JAK1/3 inhibitor peficitinib (ASP015K), another investigational drug, has been shown to improve RA outcomes in two phase IIb placebo-controlled trials.
These studies were the first to demonstrate that peficitinib monotherapy, at daily doses of 25, 50, 100, and 150 mg, resulted in dose-dependent improvements in ACR20 response rates compared with placebo among Japanese patients with moderate-to-severe RA .
The second study was conducted across 41 sites in six countries (USA, Poland, Hungary, Czech Republic, Mexico, and Bulgaria), and also found that peficitinib treatment, at the same doses, resulted in dose-dependent improvements in ACR20 responses relative to placebo among patients with moderate-to-severe RA. Study participants could take a limited number of conventional DMARDs alongside the study drug – hydroxychloroquine, chloroquine, or sulfasalazine – but other DMARDs and biologic treatments were not permitted .
“To fully assess the efficacy and safety of this novel JAK inhibitor, longer-term and larger-scale phase III studies of peficitinib 100 mg and 150 mg are currently ongoing,” say the study authors.
ABT-494 is an investigational JAK-1 selective inhibitor that has also demonstrated efficacy in phase IIb studies.
In the placebo-controlled BALANCE I trial, Joel Kremer (Albany Medical College, New York, USA) and colleagues found that treatment with ABT-494 up to doses of 18 mg twice a day or 24 mg once a day resulted in dose-dependent improvements in ACR20 response rates among patients with an inadequate response or intolerance to one or more anti-TNF agents .
And in BALANCE II, Mark Genovese and study co-authors observed dose-dependent improvements in ACR20 responses with ABT-494 relative to placebo among patients with an inadequate response to methotrexate .
Together, the results of the BALANCE studies “informed the selection of doses with optimal balance of efficacy and safety for further evaluation in phase III trials,” say Kremer and colleagues.
And they conclude: “Larger phase III trials are underway to confirm the selectivity of ABT-494 against JAK-1 and to determine whether this translates to an improved benefit–risk profile across a wide spectrum of RA patients.”
The JAK3 inhibitor decernotinib was shown to be superior to placebo in a phase IIa trial involving patients who had been unsuccessfully treated with at least one DMARD , and a subsequent dose-escalating phase IIb study found that decernotinib significantly improved ACR20 response rates at weeks 12 and 24 compared with placebo . However, the clinical development of decernotinib is thought to be discontinued at present .
Taken together, clinical trial data from the JAK inhibitors that are currently in phase II or III of development show that the drugs “seem to be effective in RA, with a favorable tolerance profile, regardless of their different JAK specificity,” say Marie-Christophe Boissier (Inserm UMR 1125, Bobigny, France) and colleagues in an editorial .
“It is then reasonable to say that several new jakinibs will be marketed in a near future,” they comment.
Which patients are JAK inhibitors suitable for?
Tofacitinib is approved for use by adult patients with moderate-to-severe RA in both the US and Europe. The US label specifies that the drug should be given to those who have had an inadequate response or intolerance to methotrexate , whereas the European label states that tofacitinib is suitable for those who responded inadequately to or are intolerant to one or more DMARDs .
Similarly, baricitinib is approved in Europe for the treatment of moderate-to-severe active RA among adult patients with an inadequate response or intolerance to at least one DMARD.
Boissier and colleagues note that clinical trials support similar positioning for the other JAK inhibitors in clinical development .
Although head-to-head trials have demonstrated the superiority of both tofacitinib and baricitinib to methotrexate in early RA, they believe that “it is unlikely that these drugs may replace [methotrexate] as first line of intervention.” Accordingly, they point out that “in the latest ACR recommendations for the treatment of RA, there is a conditional suggestion to prioritize agents with longer postmarketing experience”.
What side effects are associated with JAK inhibitors?
As JAK inhibitors are a relatively new addition to the RA treatment landscape, extensive data on their long-term safety are not yet available.
“With one JAK inhibitor currently used in the clinic for the treatment of RA [in the USA], and several others in phase III clinical trials, the safety of these compounds is just beginning to be understood,” writes Kevin Winthrop (Oregon Health & Science University, Portland, USA) in a review article . However, he notes that “a characteristic safety profile is emerging for some JAK inhibitors.”
The US prescribing information for tofacitinib includes a boxed warning for serious infections, including tuberculosis and other opportunistic infections, with similar precautions included in the European label [12, 13]. Winthrop observes that an increased risk for viral infections, particularly herpes zoster, appears to distinguish the safety profile of tofacitinib and other JAK inhibitors from that of other biologic treatments for RA .
Indeed, the most common serious infections that have been reported with tofacitinib include pneumonia, cellulitis, herpes zoster, and urinary tract infection, and the prescribing information recommends that patients should be monitored for the development of any signs or symptoms of infection, or laboratory abnormalities that could lead to early identification of infection, during treatment with tofacitinib [12, 13].
Similarly, the European label for baricitinib includes a warning for infection risk, and recommends screening for tuberculosis and viral hepatitis before commencing therapy.
The tofacitinib label also includes a boxed warning for lymphoma and other malignancies; the most common malignancies observed in the clinical studies were lung and breast cancer, followed by gastric, colorectal, renal cell and prostate cancer, lymphoma, and malignant melanoma .
Although Winthrop observes that the malignancy risk among patients treated with tofacitinib “seems to be similar to that observed with biological therapies,” and “the current picture is reassuring,” he cautions that “many more years of exposure and time are needed to characterize the risk associated with these compounds.”
Winthrop summarizes that with the exception of tofacitinib, “safety data on JAK inhibitors are limited,” but “differences between individual agents might emerge on the basis of distinct potency against their molecular targets.”
And he concludes that “[f]or now, JAK inhibitors remain a promising class of oral therapeutics for which many adverse events, like those associated with use of biologic agents, are preventable through screening, vaccination or laboratory monitoring.”
Are there any patient populations that cannot take these drugs?
The prescribing information for tofacitinib specifies that the drug should not be given to patients with severe hepatic impairment, or those with lymphocyte counts below 500 cells/mm3, an absolute neutrophil count of less than 100 cells/mm3, or hemoglobin levels below 9 g/dL. Dose reduction to 5 mg once daily is recommended for patients with severe renal impairment (<30 mL per minute) or moderate hepatic impairment [12, 13].
Similarly, baricitinib is not recommended for patients with severe hepatic or renal impairment .
For both drugs, the FDA and EMA stress that no data are available on their safety and efficacy in pediatric populations, and there are “limited data” on clinical experience among patients aged 75 years or older.
Winthrop notes that there is also “little information” regarding the use of JAK inhibitors during pregnancy, as pregnant women were excluded from the clinical trials . Data from preclinical studies demonstrated that tofacitinib and baricitinib were teratogenic in rats and rabbits, and their use during pregnancy is contraindicated as a precautionary measure. A pregnancy registry has been set up to monitor the outcomes of pregnancy among women exposed to tofacitinib .
Taking the current efficacy and safety data into account, Yamaoka believes that JAK inhibitors “represent an intriguing recent innovation in the rheumatology field, and as with biologics, Jakinibs are expected to meaningfully contribute to RA treatment.” However, he notes that while their efficacy is promising, “potential side-effects should be monitored carefully through further study” before the compounds can be established as a next-generation treatment tool. 
And Boissier and co-authors conclude that “[t]he creation of patient registries is part of the research agenda to monitor outcomes and optimize practices with these new agents” .
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