Tofacitinib, an oral Janus kinase inhibitor that blocks signaling for several cytokines that are integral to lymphocyte function, was found to be effective as either a monotherapy or an adjunctive therapy in two industry-sponsored phase III studies of adults with refractory rheumatoid arthritis, which were reported separately online Aug. 9 in the New England Journal of Medicine.
Compared with placebo, two doses of tofacitinib induced clinically meaningful and statistically significant reductions in the signs and symptoms of RA, and improved physical function. However, the drug was no better than placebo at inducing remission.
In the first study, 611 patients who previously had an inadequate response or excess toxicity to at least one nonbiologic or biologic disease-modifying agent were treated for 6 months at 94 medical centers worldwide, said Dr. Roy Fleischmann of the Metroplex Clinical Research Center, Dallas, and his associates in the Oral Rheumatoid Arthritis–Solo (ORAL-Solo) trial.
The study subjects were randomly assigned to receive 5-mg tofacitinib twice daily for 6 months, 10-mg tofacitinib twice daily for 6 months, or placebo twice daily for 3 months followed by 5-mg or 10-mg tofacitinib for 3 months. They were permitted to continue on stable doses of antimalarials and to use NSAIDs and glucocorticoids if needed.
The mean patient age was approximately 50 years, and the mean duration of RA was approximately 8 years. In all, 67% of the subjects were white and 87% were women.
The first efficacy end point was the percentage of patients who met the criteria for an ACR 20 (American College of Rheumatology 20) response, defined as at least a 20% reduction in the number of tender and swollen joints and at least a 20% improvement in three of the following measures: pain, disability, C-reactive protein level, patient’s global assessment of disease, and physician’s global assessment of disease.
At 3 months, 59.8% of patients receiving 5-mg tofacitinib and 65.7% of those receiving 10-mg tofacitinib achieved this end point, a significantly higher percentage than the 26.7% receiving placebo, the investigators said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1109071]).
The second efficacy end point was the percentage of patients who showed improvement in physical function as measured by the HAQ-DI (Health Assessment Questionnaire–Disability Index). Again, significantly more patients in both tofacitinib groups showed significant improvement by week 2 and continued to improve throughout the study, compared with patients in the placebo group. At 3 months, the proportions were 52.9% with 5-mg tofacitinib and 55.7% with 10-mg tofacitinib, compared with 31.7% with placebo.
The third efficacy end point was the percentage of patients who showed significant improvement on the DAS28-4(ESR), a measure of disease activity that includes a 28-joint count and the erythrocyte sedimentation rate. Tofacitinib was not superior to placebo in this outcome measure. At 3 months, the percentage of patients with a DAS28-4(ESR) score less than 2.6, which indicates remission, was 5.6% with 5-mg tofacitinib, 8.7% with 10-mg tofacitinb, and 4.4% with placebo.
Serious adverse events were more common with both doses of tofacitinib than with placebo. Six patients developed seven serious infections, including cellulitis, liver abscess, bronchitis, pyelonephritis, one case of tuberculous pleural effusion in a patient from India, and one case of nondisseminated herpes zoster. Other serious adverse events included heart failure in two patients.
Nonserious adverse events occurred in approximately half of the study subjects, with similar frequencies across the treatment subgroups. In all, 12 patients (2%) discontinued the study drug because of adverse events during the first 3 months, and another 6 (1%) discontinued during the final 3 months of the study.
Neutropenia developed more frequently with the active treatment than with placebo. In addition, tofacitinib raised LDL cholesterol levels, liver aminotransferase levels, and serum creatinine levels.
In the second phase-III study, oral tofacitinib was compared against subcutaneous injections of adalimumab and placebo in 717 patients who were also taking stable doses of methotrexate. These subjects were treated at 115 medical centers worldwide for 1 year, said Dr. Ronald F. van Vollenhoven of the Karolinska Institute, Stockholm, and his associates in the Oral Rheumatoid Arthritis–Standard (ORAL-Standard) trial.
In this study, the patient population also was predominantly female (approximately 80%) and white (approximately 70%), and the mean duration of RA was approximately 8 years.
The study subjects were randomly assigned to receive 5-mg oral tofacitinib twice daily, 10-mg oral tofacitinib twice daily, subcutaneous adalimumab every 2 weeks, or placebo for either 3 months or 6 months. At 3 months, patients in the placebo group who showed an inadequate response were blindly switched to either 5-mg or 10-mg tofacitinib. At 6 months, all patients in the placebo group were blindly switched to 5-mg or 10-mg tofacitinib.