RA: Tofacitinib/MTX Improved Pain, Function in Major RCT

Janis C. Kelly

August 20, 2013

The novel Janus-associated kinase (JAK) inhibitor tofacitinib (Xeljanz, Pfizer) helped bring rheumatoid arthritis (RA) under control in patients for whom methotrexate (MTX) alone was inadequate or not tolerable, researchers report in an article published online August 19 in the Annals of Internal Medicine.

The Pfizer-funded study was previously presented as a late-breaking abstract at the European League Against Rheumatism (EULAR) Congress 2011. In November 2012, the US Food and Drug Administration (FDA) approved tofacitinib 5-mg twice a day for the treatment of moderately to severely active RA in patients who had an inadequate response to or did not tolerate MTX, but so far, the European Medicines Agency (EMA) remains unconvinced of the drug's safety.

Joel Kremer, MD, from the Albany Medical College, The Center for Rheumatology, New York, and colleagues enrolled 792 patients with RA in the randomized, 1-year, double-blind, placebo-controlled clinical trial. All had inadequately controlled RA despite treatment with nonbiologic disease-modifying antirheumatic drugs (DMARDs), most commonly MTX (82.5% - 87.6% of patients; mean MTX dose, 13.6 - 14.6 mg/week).

Patients continued treatment with 1 or more background biologic DMARDs (77.2% - 80.0% of patients used MTX) and were also randomly assigned to 1 of 4 twice-daily regimens: 5 mg tofacitinib, 10 mg tofacitinib, placebo advanced to 5 mg tofacitinib, or placebo advanced to 10 mg tofacitinib. In the placebo groups, patients were advanced to tofacitinib after 3 months if they did not achieve at least a 20% reduction from baseline in swollen and tender joint counts.

Primary endpoints were assessed at month 6. These included 20% improvement in American College of Rheumatology (ACR20) criteria and rates of remission, defined by a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate of less than 2.6. Health Assessment Questionnaire Disability Index (HAQ-DI) scores were assessed at month 3.

The researchers report that at month 6, ACR20 response rates were 30.8% with placebo, 52.1% with 5 mg tofacitinib twice daily, and 56.6% with 10 mg tofacitinib twice daily.

Month 6 remission rates were 2.6% with placebo, 8.5% with 5 mg tofacitinib twice daily, and 12.5% with 10 mg tofacitinib twice daily.

Month 3 HAQ-DI improvement was −0.16 with placebo, −0.44 with 5 mg tofacitinib twice daily, and −0.53 with 10 mg twice daily tofacitinib. (Minimum clinically important difference in HAQ-DI is −0.22.)

"The clinical responses are roughly equivalent to [other] biologic agents," Dr. Kremer told Medscape Medical News.

Safety Issues Still Under Discussion

Dr. Kremer added, "We studied the 5- and 10-mg doses in this study, and the FDA has only approved the 5-mg dose. The 10-mg dose appears to be a bit more efficacious. It is possible that we might see approval of the 10-mg dose at some time in the future if the FDA determines that the overall safety of that dose is acceptable. It appeared to be in this trial."

Tofacitinib has been approved in the United States, Argentina, Kuwait, the United Arab Emirates, Russia, Japan, and Switzerland, however, the EMA denied marketing approval for the second time on July 15, denied. The EMA decision was based on "major concerns about the overall safety profile of Xeljanz" that included serious infections, cancers, gastrointestinal perforations, liver damage, and hyperlipidemia. "It was not clear that these risks could be managed successfully in medical practice," the EMA statement said.

In Dr. Kremer's study, serious adverse event rates were 10.9/100 patient years of exposure in the placebo groups, 6.9 in the 5-mg tofacitinib group, and 7.3 in the 10-mg tofacitinib group. "Of the 4 deaths, 1 (reported as respiratory failure by the investigator and as an infection by the Cardiovascular Safety Endpoint Adjudication Committee), was attributed to the study drug by the investigator. In all 4 deaths, the patients were receiving (or had received) tofacitinib. Four opportunistic infections were reported (all considered by the investigator to be related to the study drug): pulmonary tuberculosis (in 2 patients), disseminated (multidermatomal) herpes zoster, and cryptococcal pneumonia. The 2 patients with pulmonary tuberculosis lived in Thailand and China, countries classified by the World Health Organization as having a high burden of tuberculosis." Changes from baseline in neutrophil counts, hemoglobin levels, and lipid levels stabilized soon after 3 months.

Conclusions on Tofacitinib May Await Long-Term Safety, Efficacy Data

"Although in general the acceptance of injectable drugs is quite high among patients with RA, given an effective alternative, many patients would prefer an oral drug to an injectable," said Eric L. Matteson, MD. Dr. Matteson, who was not involved in the study, is chair of the Department of Rheumatology at the Mayo Clinic in Rochester, Minnesota.

He added, "I think we need to know about the impact [of tofacitinib] on joint erosions, and about long term safety and efficacy."

"Tofacitinib is efficacious in patients with active RA who have had an inadequate response to MTX, other nonbiologic DMARDs, and biologic DMARDs. It is an alternative to other biologic DMARDs. Some patients may prefer an oral agent to an injectable agent. This provides an option for them," Marc C. Hochberg, MD, MPH, told Medscape Medical News. Dr. Hochberg, who was not involved in the study, is professor of medicine and epidemiology and public health, and head, Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore.

The study was funded by Pfizer. Several authors are employees of Pfizer and hold stock in the company. Several other authors report receiving grants or fees for consulting for the company. The remaining coauthors and Dr. Matteson have disclosed no relevant financial relationships. Dr. Hochberg has received funding from Abbott Laboratories, Astra Zeneca, Bioiberica S.A., Eli Lilly Inc, Genentech/Roche, Merck Inc, Novartis Pharma A.G., Pfizer Inc, Stryker LLC, and Xoma.

Ann Intern Med. Published online August 19, 2013. Abstract

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