Kinase inhibitors for the treatment of rheumatoid arthritis.
Abstract: Kinase inhibitors have now been shown to work in various types of patients and have potential to be additional weapons in our armamentarium in rheumatoid arthritis treatment. This review will go over the currently available data and discuss potential uses for these new agents.
Subject: Rheumatoid arthritis (Drug therapy)
Methotrexate
Rheumatoid factor
Authors: Yazici, Yusuf
Steiger, Benjamin
Pub Date: 07/01/2012
Publication: Name: Bulletin of the NYU Hospital for Joint Diseases Publisher: J. Michael Ryan Publishing Co. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 J. Michael Ryan Publishing Co. ISSN: 1936-9719
Issue: Date: July, 2012 Source Volume: 70 Source Issue: 3
Accession Number: 311498771
Full Text: There have been major changes in the way rheumatoid arthritis (RA) is treated in the last two decades. Early and aggressive approach to treatment using methotrexate (MTX), the use of disease activity measures to guide this approach and to define targets of low disease activity, and finally the availability of biologic agents in addition to the traditional disease modifying antirheumatic drugs (DMARDS) in patients who have an inadequate response to DMARDs alone, have been the main components of this change. (1)

Despite these advances, improved long-term outcomes, and a larger proportion of RA patients in remission or with low disease activity, 30% to 40% of RA patients are still not adequately controlled with the available drugs and at least half of RA patients who were previously responding to a biologic or a biologic/DMARD combination lose the efficacy of this regimen over 5 years and need new agents for treatment. (1,2)

Currently nine biologic agents are approved in the United States with five different mechanisms of action (MOA): cytokine inhibitors of TNF alpha, IL-6, and IL-1, or cell modulators targeting T and B cells. These are all administered by either intravenous (IV) infusion or intramuscular (IM) injection. For the last decade, the possibility of having oral biologic agents has been studied and discussed, and now increasing data and applications for approval for these small molecules are in progress. Two targets, janus kinase (JAK) and spleen tyrosine kinase (Syk), are promising at this time and have good data to possibly support their use.

In this review, we will present the data collected so far for these two agents in the treatment of RA.

Tofacitinib

The JAK family of kinases plays an important role in cytokine induced signal transduction. There are four JAK proteins (JAK 1, JAK 2, JAK 3 and tyrosine kinase 2) and 7 STAT (signal transducer and activator of transcription) molecules that work together to affect intracellular signals that originate when the cytokine binds a receptor.

Tofacitinib (initially called tasocitinib before the name was changed) is a selective JAK inhibitor with functional selectivity for JAK 1 and JAK 3 over JAK 2. Following proof of concept in animal models, it has been studied in clinical trials for patients with rheumatoid arthritis in phase II and phase III trials. (3)

In a 6-week phase IIA dose ranging trial, the drug exhibited robust ACR responses across a range of dosages up to 30 mg twice a day. At week 6, the ACR20 response rate was 70.5, 81.2, 76.8, and 29.2% for 5, 15, 30 mg and placebo, respectively (p < 0.001 for all treatment groups). Patients receiving tofacitinib showed a rapid response, and an ACR20 improvement was observed from the first week across all groups receiving tofacitinib. The ACR50 and ACR70 responses were statistically significant at week 2 in the 30 mg group and from week 4 in all treatment groups (p < 0.05). All doses showed a significant improvement in pain and disability as measured by a HAQ. (4)

This trial was followed by another dose ranging phase IIB, placebo and active comparator trial of 24 weeks duration in which tofacitinib (maximum dose 15 mg BID) was studied in MTX failures, in 509 RA patients. At 3 months, all doses above 3 mg showed clinical efficacy. However, doses 5 mg or greater showed more sustainable improvement in ACR20, 50, and 70 responses as compared to placebo. (5)

A similar IIB study in DMARD-failures had an active comparator arm, adalimumab 40 mg BID, in addition to a placebo arm. (6) At 12 weeks, all doses greater than 3 mg showed significant improvement compared to placebo; when results were assessed at 6 months, doses greater than 5 mg twice day had better ACR20, 50, and 70 responses. The adalimumab arm did not do as well as previous studies of adalimumab in this population; however, the reasons for this are not clear.

Another published phase IIB study was conducted in Japanese patients who were MTX IR. (7) In this 12-week, double-blind study, a total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice daily or the placebo. The primary efficacy end point was ACR20 at week 12. All patients remained on background methotrexate. At week 12, ACR20 response rates at were significant (p < 0.0001) for all groups treated with tofacitinib and a significant (p < 0.0001) dose-response relationship was observed. The percentage of patients achieving ACR20 response was for the 1 mg twice daily dose 64.3%; 3 mg twice daily dose 77.8%; 5 mg twice daily dose 96.3%; and 10 mg twice daily, dose 80.8% compared to the placebo, 14.3%. The most commonly reported AEs were nasopharyngitis and increased alanine aminotransferase and aspartate aminotransferase levels. Tofacitinib was rapidly effective, with clinically significant change from baseline seen as early as week 1 in ACR20 response rates, DAS28-3 (CRP), DAS28-4 (ESR), HAQ DI score, patient and physician global assessment, swollen joint counts, and pain. It was concluded that tofacitinib in combination with methotrexate is efficacious and generally well tolerated over 12 weeks in Japanese patients with active RA with an inadequate response to methotrexate alone.

Earlier this year, two reports of the phase III program were published. (8,9) Fleischmann and colleagues (8) studied patients with RA who had failed at least one biologic or nonbiologic DMARD. Patients stopped all their medications and were randomized to 5 or 10 mg of tofacitinib or placebo for 3 months after which all patients received active medication. There were three primary outcomes; ACR20 at 3 months, change from baseline of function as measured by HAQ and remission defined by DAS28 score. At 3 months, patients achieving an ACR 20 response 59.8% for 5mg tofacitinib, 65.7% for 10 mg tofacitinib, and only 26.7% for the placebo patients, (p < 0.001). Similarly HAQ scores were also significantly improved in the treatment arms compared to placebo (-0.5 and -0.57 for tofacitinib 5 and 10 mg and -0.19 for placebo, p < 0.001). However, the third primary outcome, patients achieving remission by DAS28, was not significantly different between active treatment arms and the placebo group.

As for safety, there was more serious infection with tofacitinib compared to placebo, with the 10 mg group having more than the 5 mg tofacitinib group. The same pattern was seen for decreases in neutrophil counts and elevation in total cholesterol levels, with the 10 mg tofacitinib groups having more compared to 5 mg group.

In the other study reported in the same issue, (9) investigators randomized RA patients who had an inadequate response to MTX to tofacitinib 5 mg, adalimumab 10 mg or 40 mg, or placebo, for 3 months after which the placebo patients were randomized to one of the tofacitinib doses for the remainder of the study if they did not achieve a 20% response at 3 months; the rest were switched at 6 months. The study duration was 12 months. There were three primary outcomes; ACR20 at 3 months, change from baseline of function as measured by HAQ and remission defined by DAS28 score. At 6 months the ACR20 responses were higher among patients getting 5 mg or 10 mg of tofacitinib and adalimumab, compared to placebo, 51.5%, 52.6%, 47.2%, and 28.3%, respectively. The improvement in functional scores was 0.55, 0.61, 0.49 with the treatment arms and 0.24 with placebo, again significantly better with active treatment compared to placebo. Percentage of patients achieving DAS28 remission were significantly higher with tofacitinib 5mg (6.2%), 10 mg tofacitinib (12.5%) and adalimumab (6.7%), compared to placebo (1.1%).

Adverse events were again higher with the tofacitinib groups and so were total cholesterol elevations and neutrophil count decreases. Liver function tests elevations were also seen more commonly in the tofacitinib arms.

Another phase III study of tofacitinib in RA patients who had an inadequate response to traditional DMARDs was presented at a EULAR meeting. (10) The objective of this study was to compare the efficacy and safety of tofacitinib as compared to a placebo over 12 months in patients with active RA who also had inadequate prior response to at least one DMARD. All patients remained on non-biologic background DMARDs. Patients were randomized to two doses of tofacitinib, 5 or 10 mg twice daily, or placebo. There were escape opportunities at months 3 and 6 for patients on placebo. The primary endpoint at month 3 was change in HAQ-DI. The primary endpoints at month 6 were ACR20 and DAS28 remission. Tofacitinib was statistically superior to placebo for the primary efficacy endpoints, HAQDI change (5 mg BID, -0.46; 10 mg BID, -0.56; placebo, -0.21; p < 0.0001 for both dosages versus placebo), ACR20 (5 mg BID, 52.7%; 10 mg BID 58.3%; placebo, 31.2%; p < 0.0001 for both dosages versus placebo), and DAS28 remission responses (5 mg BID, 11%; 10 mg BID, 14.8%; placebo, 2.7%; p < 0.001 for 5 mg BID and p < 0.0001 for 10 mg BID versus placebo). Significant ACR20, ACR50, and HAQ-DI responses were seen versus placebo as early as the second week. Most adverse events were mild, with the most frequently reported being infections and infestations. There were four deaths (acute heart failure, respiratory failure, traumatic brain injury, and RA) and four opportunistic infections. Also noted were decreases in neutrophils, increases in LDL and HDL, and small increases in serum creatinine.

The ORAL Scan trial examined the radiographic progression of patients on tofacitinib. (11) Patient with an inadequate response to MTX were randomized to tofacitinib 5 and 10 mg. The primary outcome was change in total Sharp-van der Heijde score over 6 months for radiographic progression. At 6 months, tofacitinib 5 mg group had 0.12 units, 10 mg group 0.06 unit, and placebo had 0.47 unit worsening in radiographic scores, but only the 10 mg tofacitinib groups was significantly different than placebo. However, when percentages of non-progressors were analyzed, there was no difference between 5 and 10 mg tofacitinib groups and both were significantly better than the placebo group. This brings up a concern about how radiographic data are interpreted as the progression in either arm were better than placebo yet unlikely to be important in clinical decision making as the amount of progression, even in the placebo arms, was very small.

In conclusion, the efficacy of tofacitinib in all reported trials to date is significant when compared to a placebo group with ACR20 and promise of improvements has been seen in other areas measuring disease activity, such as HAQ and DAS scores, as well as radiographic progression. Adverse events were seen more commonly in tofacitinib arms compared to placebo, and the true impact of these in everyday clinical care will need to be assessed once it is used by a lot more patients in routine care.

Fostamatinib

Syk is a cytoplasmic tyrosine kinase involved in signaling and the activation of Fc gamma receptors on macrophages, neutrophils, and mast cells; it leads to up regulation of TNF alpha, IL-6, and MMP synthesis. Inhibitors of Syk kinase may have a role in the treatment of RA. Fostamatinib is an oral inhibitor that is converted to an active drug, which is a potent inhibitor of Syk kinase, in the body. (12) Two major studies, one in MTX inadequate responders (IR) and one in TNF IR have been published.

The first study in MTX IR RA patients (13) was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 64 sites in six countries. Criteria for inclusion required that patients had active arthritis for at least 6 months and had been receiving a stable dose of methotrexate (between 7.5 and 25 mg per week) for a minimum of 3 months. A total of 457 patients were randomly assigned in a 2:2:1:1 ratio, to one of four arms: Fostamatinib at a dose of 100 mg twice a day, a dose of 150 mg once a day, placebo twice daily, or placebo once daily. The primary outcome was the proportion of patients achieving the ACR20 response rate at 6 months.

The results indicated that significantly more patients in the fostamatinib groups than in the combined placebo group met the criteria for ACR 20 response (100 mg twice daily, 67%; 150 mg one daily, 57%; placebo, 35%; p < 0.001 for both doses versus placebo). The percentage of patients achieving ACR 20 response increased over time, but the predominant effect was seen quite early with the effects of fostamatinib being seen as early as 1 week after initiation of treatment. It was noted that ACR 20 response rates in both the placebo and active drug groups were higher among patients in Latin America and in Eastern Europe than among patients in the United States, but the investigators offered no reasoning for this in the publication of their findings. Inhibition of Syk with fostamatinib also produced a significant effect in ACR 50 (43 and 32% versus 19%; p < 0.001 for 100 mg twice daily versus placebo, p = 0.007 for 150 mg once daily versus placebo) and ACR 70 (28% and 14% versus 10%; p < 0.001 for 100 mg twice daily versus placebo, p = 0.34 for 150 mg once daily versus placebo) response rates, and in rates of DAS28 remission (31% and 21% versus 7%; p < 0.001 for 100 mg twice daily versus placebo, p = 0.003 for 150 mg once daily versus placebo), with a higher response observed in the group that received fostamatinib at a dose of 100 mg twice a day than in the group that received the drug at a dose of 150 mg once a day.

Adverse events arising during the study included diarrhea, upper respiratory infections, and neutropenia. Fostamatinib was also associated with an increase in systolic blood pressure. It was concluded that, in this phase 2 study involving patients who had active RA despite treatment with methotrexate, the addition of a Syk inhibitor led to reduced disease activity.

One issue related to the difference in response in this study among sites from different geographic areas is that the mean or median dose of MTX before patients were considered "failures" was not reported. This factor alone may explain the differential response rates and may even change the conclusions of the study. Most recent clinical trials that involve new biologic agents, particularly from the United States, have involved MTX use at higher doses of 20 to 25 mg per week in most patients. If United States patients were enrolled in the discussed study after failing a higher dose than Eastern European or Latin American patients, as even trying a dose as low as 7.5 mg MTX for 3 months was enough to be considered a failure by the protocol, then the results seen would not be unexplainable but rather expected. Neglecting to report this information, as was also suggested in a letter, (14) does not allow us to draw the conclusion that fostamatinib works in MTX IR, but instead that fostamatinib maybe works in patients with milder disease, those who had been treated with lower doses of MTX before being called a "failure."

A second study with fostamatinib studied the responses in biologic IR with RA. (15) Patient inclusion criteria required that patients had active RA for at least 12 months and had disease that was currently not responding or had previously failed to respond to treatment with a biologic agent at an approved label dose for more than 3 months. DMARDs, including methotrexate, leflunomide, sulfasalazine, chloroquine, hydroxychloroquine, NSAIDs, and oral corticosteroids were permitted if dosages were stable for 30 days prior to randomization.

A total of 219 patients were randomly assigned in a 2:1 ratio to either fostamatinib 100 mg twice a day or placebo. The primary end point was the percentage of patients meeting the ACR20 response at month 3.The results showed no significant differences between the fostamatinib group and the placebo group in the ACR20 (38% in fostamatinib versus 37% in placebo), ACR50 (22% versus 12%), or ACR70 (9% versus 5%) response or change from baseline in DAS28 (-1.62 versus 1.27) at month 3. These data are not that unexpected when the data from the MTX IR is also taken into consideration, where lack of a robust response was suggested when the dose of MTX used in different geographic areas is considered.

In conclusion, small oral molecules for the treatment of RA are viable candidates at this time. However, tofacitinib seems more effective than fostamatinib based on the data available so far. Further studies will be needed to better define the role of these agents in the treatment of RA in the future. Especially the question of using these drugs alone or in combination with MTX, before or after a biologic has been tried, will need to be studied and will help physicians with their decision making.

Disclosure Statement

Yusuf Yazici, M.D., has served as a consultant and had research support from Abbott, BMS, Celgene, Janssen, Genentech, Pfizer, Merck, UCB, Horizon, Takeda. Benjamin Steiger has no conflicts of interest.

References

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(11.) van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, in Combination with Methotrexate Reduced the Progression of Structural Damage in Patients with Rheumatoid Arthritis: a 24-Month Phase 3 Study [#2592]. Presented at the 75th Scientific Meeting of the American College of Rheumatology, Chicago, Illinois, 2011.

(12.) Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008.

(13.) Weinblatt ME, Kavanaugh A, Genovese MC, et al. An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis. N Engl J Med. 2010 Sep;363(14):14:1303-12.

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Yusuf Yazici, M.D., and Benjamin Steiger in the Division of Rheumatology and Medicine, NYU Hospital for Joint Diseases, New York, New York.

Correspondence: Yusuf Yazici, M.D., Seligman Center, Department of Rheumatology and Medicine, NYU Hospital for Joint Diseases, 246 East 20th Street, Suite 101, New York, New York 10003; yusuf.yazici@nyumc.org.
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