Tofacitinib, an experimental oral JAK inhibitor, reduced signs and symptoms of rheumatoid arthritis even after traditional disease-modifying medications failed to produce a response, researchers said here.
In a phase III trial, both the 5 mg twice daily dose of tofacitinib and the 10 mg twice daily dose of tofacitinib (formerly tasocitinib) were superior to placebo in the three primary endpoints, reported Joel Kremer, MD, chief of medicine at Albany Medical College in N.Y., at the meeting of the European League Against Rheumatism (EULAR).
The researchers determined that after six months of therapy, 52.7% of the 315 patients on the lower dose of Pfizer’s experimental drug achieved an ACR20, which is the American College of Rheumatology criteria for clinical improvement of symptoms. Also, 58.3% of the 318 patients on the 10 mg dose of tofacitinib achieved an ACR20. The researchers found that 31.2% of the 159 patients who began therapy on placebo achieved an ACR20 (P<0.0001).
Kremer and colleagues also reported that more patients on tofacitinib were able to reach clinical remission of disease as reflected by a score of less than 2.6 on the Disease Activity Score, using the erythrocyte sedimentation rate (DAS28-4 [ESR]). Remission was achieved by 11% of the patients on 5 mg twice a day of tofacitinib (P=0.001) and by 14.8% of patients on the higher dose of the experimental drug (P<0.0001) compared with 2.7% of patients on placebo.
The study’s third primary endpoint was the change at baseline after three months in the HAQ-DI (Health Assessment Questionnaire Disability Index). Patients taking tofacitinib showed a 0.46 decline in scores if they were on low-dose tofacitinib and a 0.56 decline in scores if they had been assigned to the high-dose tofacitinib treatment. Placebo patients showed a 0.21 decline in scores (P<0.0001).
“Tofacitinib appears to reduce the signs and symptoms of rheumatoid arthritis very quickly,” Kremer said in a EULAR news briefing on the late-breaking abstract. “We hope that after carefully considering the benefit/risk equation, this compound will provide an additional valuable treatment option for patients who have experienced in adequate response to prior treatments.”
Paul Emery, MD, from the University of Leeds, in Leeds, England, and president of EULAR, commented that if tofacitinib gains regulatory approval, its use would depend on the treatment environment and how the drug is priced.
“This information is the most important phase III data we have seen. The data are quite impressive,” Emery said. “The biggest factor will be the cost of the drug. However, I have learned never to underestimate the power of marketing.”
Kremer also reported several secondary and safety findings. In April, Pfizer, tofacitinib’s developer, experienced a shake-up in its stock prices when the company announced that four patients had died in this final-phase study of tofacitinib. Safety concerns for tofacitinib were first raised when results of a phase II trial were presented at the 2009 EULAR meeting.
In the 12-month safety analysis, Kremer said that four patients died in the trial including one serious cardiovascular event. However, an adjudication committee absolved the drug from any cardiovascular cause of death. The investigators theorized that one of the deaths may have been related to treatment-related infections, but the patient’s family refused an autopsy, making it difficult to determine the true cause of death.
Kremer said that four opportunistic infections were considered drug related: Two cases of tuberculosis, one case of pneumonia, and one case of herpes. All of these patients responded to treatment.
In terms of secondary findings, the researchers used the ACR50, a tougher hurdle that requires about a 50% improvement in symptoms, and found that 33.8% of patients on 5 mg twice daily tofacitinib, and 36.6% of those on the 10 mg tofacitinib treatment, reached that level of recovery compared with 12.7% of placebo patients.
In the ACR70, about 13% of patients on the low dose and 16% of patients on the high dose of the drug achieved that improvement, a 70% or greater reduction in signs and symptoms of the disease compared with 3.2% of placebo patients (P<0.0001).
In this 12-month study, rheumatoid arthritis patients who were treated with background, nonbiologic disease-modifying anti-rheumatic agents, such as methotrexate, were randomized to tofacitinib 5 mg twice a day or 10 mg twice a day or placebo for zero to six months. At three months, nonresponding placebo patients were reassigned to either 5 mg tofacitinib or 10 mg tofacitinib. After six months, the remaining placebo patients were put on one of the two doses of tofacitinib.
Kremer said that once all the patients were on tofacitinib, the placebo patients achieved similar treatment responses as the tofacitinib patients, and then all the patients were able to maintain those improvements through 12 months.
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