The US Food and Drug Administration approval of tofacitinib (Xeljanz) in November 2012 represents a potential for significant change in the approach to the treatment of rheumatoid arthritis.
The US Food and Drug Administration (FDA) approval of tofacitinib (Xeljanz) in November 2012 represents a potential for significant change in the approach to the treatment of rheumatoid arthritis (RA). Now providers, patients and payers have an oral therapeutic option for patients who have not responded to traditional non-biologic disease-modifying anti-rheumatic drugs (DMARDS).
Tofacitinib is the first oral non-traditional DMARD to be approved by the FDA and it has been highly anticipated by both patients and physicians. This new RA agent belongs to a class of drugs known as Janus kinase (JAK) inhibitors. Tofacitinib blocks a signaling molecule that is released when a cytokine binds to the surface of a cell, thus inhibiting the activity of the cytokine. Based on the mechanism of action, the clinical features of this medication are very similar to those of the interleukin-6 receptor antagonists.
Because the FDA approved tofacitinib as a second-line agent for rheumatoid arthritis, it means that treatment with a biologic agent is not required before a physician may consider using this agent. Tofacitinib was approved at a dose of 5 mg taken orally twice daily and it is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
Tofacitinib can be used either as monotherapy or in combination with methotrexate or other non-biologic DMARDs. It is important to note that this drug was studied in a development program that involved approximately 5000 patients worldwide. It was studied at both the approved 5-mg dose and a 10-mg twice-daily dosing regimen in patients who had an inadequate response to non-biologic DMARDs or to anti-tumor necrosis factor (TNF) agents.
According to Badrul Chowdhury, MD, PhD of the FDA, "Xeljanz provides a new treatment option for adults suffering from the debilitating disease of RA who have had a poor response to methotrexate.1 "Most of the RA treatments that have come to market over the last two decades have been biologics, such as tumor necrosis factor (TNF) inhibitors (eg, Remicade, Humira, Symponi, Cimzia, and Enbrel). Unlike tofacitinib, these drugs must be administered subcutaneously or by infusion.
In 2 large studies published recently in The New England Journal of Medicine, 51.5% to 65.7% of patients receiving the active treatment met the American College of Rheumatology criteria of 20% (ACR-20) improvement endpoint compared with 26.7% to 28.3% of those given placebo.2 In all, efficacy and safety have been assessed in a total of seven trials of patients with active RA.
However, as with any new class of agents, there are safety concerns. The FDA advisory panel's safety concerns arising from those trials, included serious infections, seen at a rate of 3 per 100 patient-years, and there were 12 cases of tuberculosis among patients receiving tofacitinib. Additionally, cases of lymphoma and other cancers were reported, and the drug's labeling will carry a boxed warning about risks.
To further assess safety of this product as compared to other agents in the class, the FDA is requiring a post-marketing study to gather further data on potentially serious adverse events. There is also a REMS program that requires that patients be given a medication guide advising them on risks of the drug and how to communicate with their caregivers should problems arise.
Rheumatoid arthritis and its treatment is an area of significant interest for virtually all payers. The therapeutic category of biologic agents used to treat RA, including the anti-TNF drugs, typically represents the largest category of specialty drug spending for most payers, often approaching one-third of all specialty pharmacy spending. Anti-TNF agents for RA now typically cost plans about $25,000 per patient per year depending on the agent and the dosing. Tofacitinib is expected to be priced at about $2000 per month or $24,000 per year.
Because it is the first oral agent in the class, the introduction of tofacitinib into the RA market has the potential to change the way RA is treated in the future. However, there are a number of unanswered questions that will likely make plans and prescribing physicians take a conservative approach to this agent at first. Because it is a new agent, the long-term safety issues, especially when the drug is given to larger populations remain in question. Additionally because the FDA panel noted it was not possible to make conclusions about the effect of tofacitinib on the progression of structural damage in RA, both physicians and payers may take a cautious approach to the use of this agent at first. From my discussions with many payer thought leaders, it appears that tofacitinib will be made available, with a prior authorization, as an alternative to the anti-TNFs by some plans. However, a number of plans will continue to consider the anti-TNFs the mainstay of therapy and require the use of one or more of these agents before approval for tofacitinib is granted.
Therefore, the mainstay of therapy for those who fail traditional DMARD therapy will likely remain the injectable anti-TNF drugs in the near future. As both payers and physicians gain more experience with tofacitinib, there is likely to be a shift to increased use as an oral alternative to the anti-TNFs or even as a preferred next step after traditional DMARDs fail, but only time will tell.
1. Pfizer Oral RA Drug Gets FDA Approva. http://www.medpagetoday.com/Rheumatology/Arthritis/35799. Accessed January 11, 2013.
2. van Vollenhoven R, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508-519.