The Research
Dr. Kremer focused the majority of his talk on his own and others’ investigative and clinical experience with oral tofacitinib, formerly known as CP-690, 550, and the first JAK inhibitor to reach clinical trials. In kinase assays, tofacitinib inhibits JAK1, -2 and -3 and, to a lesser extent, TyK2; however, in cellular settings, it more specifically inhibits signaling associated with JAK3, and to a lesser extent, JAK1 and JAK2. Dr. Kremer also covered JAKs in development, including baricitinib, GLPG0634 and VX-509. He contrasted their target JAK molecules with the clinical and side effect profiles of these agents.
Tofacitinib was approved by the FDA for use in RA for patients who have had an inadequate response or intolerance to other therapies. Dr. Kremer has investigated its use in RA patients as a monotherapy and in combination with background methotrexate (MTX). Early on during Phase IIB trials, efficacious ACR20 responses were demonstrated.1,2
“We expected these drugs to work, and they do,” Dr. Kremer reiterated.
He then explained drawbacks for which clinicians should be prepared. As patients get better, he said, clinicians may also see changes in laboratory parameters, such as increases in low-density lipoprotein (LDL) cholesterol. “So what are we doing,” he asked rhetorically, “giving a drug [that] increases LDL, [which is] implicated in one of the most common comorbidities that we treat—cardiovascular disease? Well, like a lot of things we do, it’s a very complex story.”
In fact, working with baricitinib, Dr. Kremer found it necessary to more closely analyze the total cholesterol picture. “If the LDL changes are now [increases in] large LDL molecules, which are less atherogenic, and if the HDL changes are now [increases in] smaller HDL molecules, the evolution of these lipid changes seems to be in the direction that would not be atherogenic.”
“If you’re just measuring LDL, it and serum creatinine will increase,” Dr. Kremer said. These effects were also noted in the largest Phase III trial to date, an international randomized radiographic study led by Désirée van der Heijde, one-year results of which were presented at the ACR Annual Meeting in November 2011.3 Authors demonstrated that tofacitinib inhibited progression of structural damage and improved disease activity in patients with RA who are also receiving MTX.
Monitoring laboratory assays is important, but, as Dr. Kremer noted, “The question is, do we treat the patient or do we treat the lab results?” He advised his audience to “Keep in mind that the enzyme assays really don’t tell the whole story. You really need full blood assays and you need to look back, as my friend John O’Shea has said, and see what happens in human beings.”
The specificity of JAK inhibition remains a complex question, noted Dr. Kremer. Somatic mutations of the JAK2 gene, for example, stimulate the production of red blood cells, “so if you have a JAK2 inhibitor or a pan-JAK inhibitor, one of the things that you might expect, even as inflammation decreases and your patient gets better, are IL-6 inhibition types of effects.” There is also no doubt, said Dr. Kremer, that there are TNF-downstream effects of JAK inhibition. These effects were foreshadowed nearly 20 years ago in a seminal 1995 paper in Science, which identified the role of JAK3 in lymphoid development in a patient with severe combined immunodeficiency syndrome (SCID) who had lost function of JAK3. According to the Science authors, “The current study further suggests that any agents that inactivate JAK 3 function may be potent immunosuppressants.”4
Dr. Kremer has seen occasional development of infections and said that he recommends giving Zovirax vaccine prophylactically before starting tofacitinib; if the patient has recurrent herpes zoster infection, he might not use tofacitinib at all.
Mono- vs. Combination Therapy
Some preliminary data suggest a case for utilization of monotherapy; however, Dr. Kremer said, the decision about monotherapy with a JAK inhibitor will most likely need to be seen in a societal as well as economic context.
In conclusion, Dr. Kremer noted that the ideal JAK target for the best efficacy/toxicity profile has not yet been determined. “We are waiting for more insights,” he said.
Gretchen Henkel is a medical journalist based in California.
NOTE: Updated July 29, 2014, to correct usage of tofacitinib, which is not approved for the treatment of psoriasis. XELJANZ (tofacitinib citrate) 5 mg tablets are indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX). XELJANZ may be used alone or in combination with methotrexate or other non-biologic, disease-modifying antirheumatic drugs (DMARDs). Use of XELJANZ in combination with biologic DMARDs or potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended. Please click the direct link to the full prescribing information for XELJANZ, including boxed warning and Medication Guide: http://labeling.pfizer.com/ShowLabeling.aspx?id=959.
References
- Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690, 550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012 Mar;64(3):617–629.
- Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690, 550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012 Apr;64(4):970–981.
- van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690, 550) in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum. 2013 Mar;65(3):559–570.
- Russell SM, Tayebi N, Nakajima H, et al. Mutation of Jak3 in a patient with SCID: Essential role of Jak3 in lymphoid development. Science. 1995 Nov;270(5237):797–800.
