In August, the Food and Drug Administration approved the oral once-daily JAK inhibitor upadacitinib (Rinvoq, AbbVie) for adults with moderate to severe active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. In this Q&A, we talk with Roy M. Fleischmann, M.D., the primary investigator for SELECT-COMPARE, the phase three clinical trial of Rinvoq. Dr. Fleischmann is also a clinical professor at the University of Texas Southwestern Medical Center in Dalls.
How have JAK inhibitors performed in clinical trials as compared to treatments with TNF or IL inhibitors?
"They have performed quite well. TNF inhibitors have been shown to be similar to methotrexate (MTX) in methotrexate naïve patients, effective in MTX-IR and effective in csDMARD-IR. Several have been shown to be effective in TNFi-IR. All TNFi are more effective in combination with methotrexate although they have some efficacy as monotherapy. IL-6 inhibitors have been shown to effective as monotherapy or combination therapy (more so in combination with methotrexate), more effective than methotrexate; effective in methotrexate-IR and TNF-IR and more effective as monotherapy than TNF inhibitors in methotrexate-IR. JAK inhibitors are effective as monotherapy or in combination with methotrexate, more effective than methotrexate as monotherapy, effective in methotrexate-IR, csDMARD-IR and TNF-IR patients in combination with methotrexate. Tofacitinib has been shown to be non-inferior to adalimumab in methotrexate-IR while upadacitinib has been shown to be superior to adalimumab. All (TNFi, IL6i and JAKi) suppress radiographic inhibition and improve patient reported outcomes."
Are TNF and IL inhibitors limited in their effectiveness? In other words, do JAK inhibitors fill an unmet need?
"TNF and IL-6 inhibitors have been very welcome additions to our armamentarium and have been effective in many patients who have not completely responded to methotrexate or cannot tolerate methotrexate. In spite of this, there are still patients with active disease despite these therapies. JAKi are also quite effective and have been shown to be effective in patients who have failed a TNF inhibitors (adalimumab). As they are oral and can be used as monotherapy in a majority of patients, they help fill the unmet need of patients who cannot or will not take methotrexate, are adverse to injections or who prefer an oral medication. Considering that they are effective prior to a TNFi, they are a very reasonable option as first line post methotrexate or later in the paradigm."
How will doctors know when to select a TNF for treatment? Or, an IL inhibitor? Or, one of the three JAK inhibitors?
"There are no means for a physician to know, at this time, whether a patient will respond preferentially to a JAK, TNF inhibitor or IL-6 inhibitor or tolerate one better than the other. This is the hope of the future to have a biomarker which can show who will respond well to one medication and who will not. At this time, it is physician preference, patient preference and, most importantly, payor preference."
In terms of safety, how do JAK inhibitors compare to TNF and IL treatments?
"All these medications have the same side effects but their incidence varies between classes. There is more tuberculosis with TNF inhibitors but tuberculosis does occur with the others. There is more cholesterol elevation with JAK inhibitors and IL-6 but it occurs with TNF inhibitors. There are more HZ with JAKs but it does occur with TNF inhibitors and IL-6 inhibitors. VTE occur will all three mode of actions. So, the side effects are the same, the incidence varies and the physician and the patient should be on the lookout for all."
Is there a high risk for infections, cancer or other adverse effects with JAK inhibitors?
"Infections, cancers and other adverse effects occur with JAKs but also with the other mode of actions.. The incidence of infections and cancer is probably similar amongst the classes―the risk is relatively low, but the physician and patient need to be aware that they can occur."