Rheumatoid Arthritis: A New Class, a New Approval, a New Approach

Jonathan Kay, MD; Ronald F. Van Vollenhoven, MD, PhD


November 29, 2012

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Jonathan Kay, MD: Hello. I am Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at the University of Massachusetts Medical School and UMass Memorial Medical Center, both in Worcester, Massachusetts. Welcome to this Medscape peer-to-peer discussion.

I am in Washington, DC, at the American College of Rheumatology and Association of Rheumatology Health Professionals (ACR/ARHP) 2012 Annual Scientific Meeting. Joining me today is Ronald Van Vollenhoven, Professor of Therapeutic Medicine at the Karolinska Institute and Chief of the Clinical Trials Unit in the Department of Rheumatology at Karolinska University Hospital in Stockholm, Sweden. Welcome, Ron.

Ronald F. Van Vollenhoven, MD, PhD: Thank you, Jon.

Dr. Kay: Today we are going to discuss highlights and advances in rheumatoid arthritis. As of this past week, tofacitinib has been approved in the United States as Xeljanz® at a dose of 5 mg taken by mouth twice daily, the first oral agent in the new class of JAK (Janus kinase) inhibitors.

At this meeting, there is a very important trial, the ORAL Start trial, that is being presented. There are also data from other trials of tofacitinib and other oral JAK inhibitors.

Dr. Van Vollenhoven: Yes, that is correct. This is a big story right now. It is a very recent approval for a new drug against rheumatoid arthritis that is available as a tablet, so it distinguishes itself from the biologics, which are always given as injections or infusions. This is indeed one of the JAK inhibitors.

Tofacitinib has already gone through a phase 3 trial program, but now there is a new trial with tofacitinib being presented here at the ACR/ARHP meeting.[1] It is a trial conducted in patients who were not previously treated with methotrexate. Usually, that means that they are pretty early in the disease. They were randomly assigned to receive either methotrexate or tofacitinib at 5 mg twice daily or tofacitinib 10 mg twice daily. In the analysis after the first year of this trial, it turned out that all 3 treatments work very well. We knew that methotrexate was a very good treatment, but tofacitinib had the edge. It was better than methotrexate, both in terms of clinical outcomes (ie, ACR20, ACR50, ACR70, and the EULAR outcomes) as well as radiologic outcomes. If you look at the degree to which radiologic damage was prevented, tofacitinib did a little bit better at both of the dosages than methotrexate, which in early rheumatoid arthritis is very important.

Dr. Kay: Tofacitinib is dosed at 5 mg twice daily, which requires the patient to take a pill in the morning and in the evening or at some other time during the day. For methotrexate, we dose once a week. Are we dosing methotrexate too infrequently? Perhaps, if we dosed methotrexate more often, the pharmacokinetics of the medication might be more equivalent to tofacitinib. Also, are patients going to be willing to accept twice-daily dosing rather than once-weekly oral dosing?

Dr. Van Vollenhoven: Those are good questions. The dosing of methotrexate has been worked out many years ago, and dosing once weekly is not just for convenience. It is also the safest. If you were to give it daily, the patient would have many more side effects.

Tofacitinib has to be dosed twice daily because of the half-life. It is a little more work for the patient, but it is an alternative that has been approved for patients who have already failed methotrexate. If they tried methotrexate and it did not work well, they could take tofacitinib, and only at the lower of the 2 dosages. Taking 5 mg twice daily has been approved, but the other dosage has not.

Dr. Kay: What is important in this study is that radiographic progression is slowed significantly more with tofacitinib than with methotrexate. Being an oral medication is a real advantage when starting a patient on DMARD (disease-modifying antirheumatic drug) therapy and the reason why this medication might take an earlier place in the therapeutic pathway.

Dr. Van Vollenhoven: I think the future will tell us if the story is going to develop further in that direction or if physicians are going to continue to think of methotrexate as the first-line treatment for most patients with rheumatoid arthritis. But if it fails, we have a number of options. Many drugs have been approved in that setting, and now they include tofacitinib.

Dr. Kay: Tofacitinib is a JAK3 inhibitor, but there is also an inhibitor of JAK1 and JAK2.

Dr. Van Vollenhoven: That is correct. There are several other JAK inhibitors being developed right now. One of them is baricitinib, which blocks JAK1 and JAK2. As you mentioned, tofacitinib blocks JAK3 but also JAK1. There are 3 JAKs, and the combination in which they are blocked could make a difference clinically or in the side effects.

Baricitinib has been in a phase 2 trial, and there is another phase 2 trial that was presented here at this meeting.[2] It shows that you can look at the different dosages and define which dosage would be most appropriate, and that is going to go to phase 3. In the large trials, we will see if the efficacy holds up. Certainly at this point for baricitinib, it looks to be in the playing field of the oral molecules that are JAK inhibitors and have the convenience of oral dosing, but issues with side effects still need to be resolved in larger trials.

Dr. Kay: Tofacitinib is the beginning of a new paradigm. We have the TNF (tumor necrosis factor) inhibitors, which revolutionized the treatment of rheumatoid arthritis. Over the past decade, we have had a number of other mechanisms of action of parenteral medications. But now we have oral medications that specifically target signal transduction molecules and block cytokine signaling -- perhaps several cytokines at once -- through a different approach that can be administered orally. A number of older trials are being presented with additional information at this meeting.

Dr. Van Vollenhoven: Yes, the biologics have been around for many years. We have learned how to use them. Now we are getting to the point where we are discovering interesting new things, and several of these are being presented here. One finding is that if you have patients who are doing very well on a biologic agent -- in most cases it is a TNF inhibitor -- you may be able to continue with a lower dosage or less frequent dosing.

A study from France, presented by Dr. Fautrel, shows that if you have a very good result with either etanercept or adalimumab -- the 2 most widely used TNF inhibitors -- you can administer the drug less frequently but keep the good effects.[3] You can taper it and continue using the treatment. You don't stop treatment completely. Stopping completely would also be interesting, but it only works in very few patients.

Dr. Kay: The cost of biologic agents and some of these JAK inhibitors is significant to patients. We have lower-cost alternatives such as methotrexate, albeit not quite as effective as tofacitinib in the ORAL Start trial.

Inducing a remission or controlling disease activity with the more expensive biologic agents and then maintaining the patient on methotrexate is an approach that you and your colleagues have investigated. You presented some very interesting and intriguing data at the EULAR (European League Against Rheumatism) meeting in Berlin. What is going on in that area?

Dr. Van Vollenhoven: Induction maintenance is a little bit of a dream for rheumatoid arthritis treatment. You come in with strong treatments, but there are cost issues and more side effects. Then, you maintain a good result with a simpler treatment, maybe just methotrexate once a week.

The data that are being presented here at the meeting showed that, mostly, it is not so easy to do that. Sometimes you can stop the treatment. If you start very early, as in the OPTIMA clinical trial,[4] which was also presented at previous meetings, then you might be able to maintain the good result with a simpler treatment. If you have a patient with established disease on a biologic agent, you may be able to reduce the dosage or frequency of treatment. Again, it may not be possible to stop completely in most patients.

Dr. Kay: Those are interesting approaches, and the use of JAK inhibitors as maintenance therapy may be a successful approach in the future. There are many different strategies that are yet to be studied and interesting data to come.

Thank you very much for joining us here in Washington, DC, and I look forward to speaking with you in Madrid at EULAR next spring.

Dr. Van Vollenhoven: Thank you.

Dr. Kay: Thank you very much for your attention. We look forward to seeing you again on Medscape.