Panel Recommends Tofacitinib Approval for Refractory RA

SILVER SPRING, MD. – There soon may be a new oral disease-modifying antirheumatic drug in town, the first in more than 10 years to be approved for the treatment of rheumatoid arthritis.

The drug is tofacitinib, and it is the first in a new class of agents for RA patients.

On May 9 the Food and Drug Administration’s Arthritis Advisory Committee voted 8 to 2 in favor of approving tofacitinib for RA patients who have had inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

A small-molecule inhibitor of the Janus kinase (JAK) pathways, Pfizer’s tofacitinib blocks inflammatory cytokines that play a role in the pathogenesis of RA. If approved, tofacitinib would be the first JAK inhibitor for RA. Another JAK inhibitor, ruxolitinib (Incyte’s Jakafi) was approved to treat myelofibrosis in November.

Pfizer’s application was based on five randomized controlled phase III efficacy trials involving a total 3,315 patients. The application also included safety data for a total of 4,816 patients from the phase II and III studies, of whom 4,053 were treated for at least 6 months and 567 for more than 3 years, up to 42 months. Among the trials was one that compared tofacitinib with placebo in patients with moderate to severe RA who had incomplete responses to tumor necrosis factor (TNF) inhibitors, and four studies of patients who had inadequate responses to other DMARDs. One study included an arm with adalimumab as an active comparator, and one evaluated radiographic response. In three studies, the participants were taking background methotrexate, and in one study, tofacitinib was used as monotherapy. The studies were conducted in a total of 44 countries.

All five of the phase III studies were designed to show the superiority of 5-mg and 10-mg twice-daily doses of tofacitinib to placebo for the primary end points: a 20% or better increase in the American College of Rheumatology’s definition of improvement in the signs and symptoms of RA (ACR20), improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and a Disease Activity Score-28 (DAS28) of less than 2.6. In most of the assessments conducted at 6 and 12 months, both doses exhibited statistical superiority over placebo, with the 10-mg dose showing greater improvement than the 5-mg dose.

However, the fact that only one study evaluated radiographic evidence, which the FDA reviewers deemed inconclusive, was cause for concern for the FDA reviewers and committee members. According to the FDA’s Dr. Yongman Kim, 18% of the 278 patients on 5 mg of tofacitinib, 16% of the 290 with 10 mg of tofacitinib, and 14% of the 140 placebo patients showed an "improved" modified total sharp score (mTSS) of less than 0, suggesting it inhibited joint damage.

The FDA was also concerned about dose- and time-dependent elevations in malignancies, and particularly lymphomas, with a standardized incidence ratio of 2.35 at a median 9 months duration of exposure. Of the seven total patients who developed lymphoma, three were on 5 mg of tofacitinib, three were on 10 mg, and one was in a still-blinded arm of the trial. Overall malignancy rates increased with time, from 0.79 per 100 patient-years at 0-6 months to 1.06 at 12-18 months to 1.43 beyond 24 months.

Several of the committee members who voted in favor of tofacitinib said that they did so because they wanted a new oral option for RA patients and that they don’t anticipate any better data from clinical trials. They strongly urged postmarketing studies of both radiologic efficacy and safety. Pfizer has proposed a Risk Evaluation and Mitigation Strategy that will include, alongside labeling provisions, a Medication Guide, a "Dear Health Care Professional" letter, and routine pharmacovigilance. Additional clinical studies that are ongoing or planned include long-term extension studies to assess cardiovascular safety, serious and opportunistic infections, malignancies, and gastrointestinal perforations; studies to monitor any unidentified risks; a cholesterol kinetic study; and studies to evaluate the effect of tofacitinib on the immune response to pneumococcal and influenza vaccines as well as to further delineate the effects of tofacitinib on lymphocyte subsets.

The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Martin Bermin-Gorvine of "The Pink Sheet" contributed to this story. This news service and "The Pink Sheet" are both owned by Elsevier.

SILVER SPRING, MD. – There soon may be a new oral disease-modifying antirheumatic drug in town, the first in more than 10 years to be approved for the treatment of rheumatoid arthritis.

The drug is tofacitinib, and it is the first in a new class of agents for RA patients.

On May 9 the Food and Drug Administration’s Arthritis Advisory Committee voted 8 to 2 in favor of approving tofacitinib for RA patients who have had inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

A small-molecule inhibitor of the Janus kinase (JAK) pathways, Pfizer’s tofacitinib blocks inflammatory cytokines that play a role in the pathogenesis of RA. If approved, tofacitinib would be the first JAK inhibitor for RA. Another JAK inhibitor, ruxolitinib (Incyte’s Jakafi) was approved to treat myelofibrosis in November.

Pfizer’s application was based on five randomized controlled phase III efficacy trials involving a total 3,315 patients. The application also included safety data for a total of 4,816 patients from the phase II and III studies, of whom 4,053 were treated for at least 6 months and 567 for more than 3 years, up to 42 months. Among the trials was one that compared tofacitinib with placebo in patients with moderate to severe RA who had incomplete responses to tumor necrosis factor (TNF) inhibitors, and four studies of patients who had inadequate responses to other DMARDs. One study included an arm with adalimumab as an active comparator, and one evaluated radiographic response. In three studies, the participants were taking background methotrexate, and in one study, tofacitinib was used as monotherapy. The studies were conducted in a total of 44 countries.

All five of the phase III studies were designed to show the superiority of 5-mg and 10-mg twice-daily doses of tofacitinib to placebo for the primary end points: a 20% or better increase in the American College of Rheumatology’s definition of improvement in the signs and symptoms of RA (ACR20), improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and a Disease Activity Score-28 (DAS28) of less than 2.6. In most of the assessments conducted at 6 and 12 months, both doses exhibited statistical superiority over placebo, with the 10-mg dose showing greater improvement than the 5-mg dose.

However, the fact that only one study evaluated radiographic evidence, which the FDA reviewers deemed inconclusive, was cause for concern for the FDA reviewers and committee members. According to the FDA’s Dr. Yongman Kim, 18% of the 278 patients on 5 mg of tofacitinib, 16% of the 290 with 10 mg of tofacitinib, and 14% of the 140 placebo patients showed an "improved" modified total sharp score (mTSS) of less than 0, suggesting it inhibited joint damage.

The FDA was also concerned about dose- and time-dependent elevations in malignancies, and particularly lymphomas, with a standardized incidence ratio of 2.35 at a median 9 months duration of exposure. Of the seven total patients who developed lymphoma, three were on 5 mg of tofacitinib, three were on 10 mg, and one was in a still-blinded arm of the trial. Overall malignancy rates increased with time, from 0.79 per 100 patient-years at 0-6 months to 1.06 at 12-18 months to 1.43 beyond 24 months.

Several of the committee members who voted in favor of tofacitinib said that they did so because they wanted a new oral option for RA patients and that they don’t anticipate any better data from clinical trials. They strongly urged postmarketing studies of both radiologic efficacy and safety. Pfizer has proposed a Risk Evaluation and Mitigation Strategy that will include, alongside labeling provisions, a Medication Guide, a "Dear Health Care Professional" letter, and routine pharmacovigilance. Additional clinical studies that are ongoing or planned include long-term extension studies to assess cardiovascular safety, serious and opportunistic infections, malignancies, and gastrointestinal perforations; studies to monitor any unidentified risks; a cholesterol kinetic study; and studies to evaluate the effect of tofacitinib on the immune response to pneumococcal and influenza vaccines as well as to further delineate the effects of tofacitinib on lymphocyte subsets.

The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Martin Bermin-Gorvine of "The Pink Sheet" contributed to this story. This news service and "The Pink Sheet" are both owned by Elsevier.

SILVER SPRING, MD. – There soon may be a new oral disease-modifying antirheumatic drug in town, the first in more than 10 years to be approved for the treatment of rheumatoid arthritis.

The drug is tofacitinib, and it is the first in a new class of agents for RA patients.

On May 9 the Food and Drug Administration’s Arthritis Advisory Committee voted 8 to 2 in favor of approving tofacitinib for RA patients who have had inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

A small-molecule inhibitor of the Janus kinase (JAK) pathways, Pfizer’s tofacitinib blocks inflammatory cytokines that play a role in the pathogenesis of RA. If approved, tofacitinib would be the first JAK inhibitor for RA. Another JAK inhibitor, ruxolitinib (Incyte’s Jakafi) was approved to treat myelofibrosis in November.

Pfizer’s application was based on five randomized controlled phase III efficacy trials involving a total 3,315 patients. The application also included safety data for a total of 4,816 patients from the phase II and III studies, of whom 4,053 were treated for at least 6 months and 567 for more than 3 years, up to 42 months. Among the trials was one that compared tofacitinib with placebo in patients with moderate to severe RA who had incomplete responses to tumor necrosis factor (TNF) inhibitors, and four studies of patients who had inadequate responses to other DMARDs. One study included an arm with adalimumab as an active comparator, and one evaluated radiographic response. In three studies, the participants were taking background methotrexate, and in one study, tofacitinib was used as monotherapy. The studies were conducted in a total of 44 countries.

All five of the phase III studies were designed to show the superiority of 5-mg and 10-mg twice-daily doses of tofacitinib to placebo for the primary end points: a 20% or better increase in the American College of Rheumatology’s definition of improvement in the signs and symptoms of RA (ACR20), improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and a Disease Activity Score-28 (DAS28) of less than 2.6. In most of the assessments conducted at 6 and 12 months, both doses exhibited statistical superiority over placebo, with the 10-mg dose showing greater improvement than the 5-mg dose.

However, the fact that only one study evaluated radiographic evidence, which the FDA reviewers deemed inconclusive, was cause for concern for the FDA reviewers and committee members. According to the FDA’s Dr. Yongman Kim, 18% of the 278 patients on 5 mg of tofacitinib, 16% of the 290 with 10 mg of tofacitinib, and 14% of the 140 placebo patients showed an "improved" modified total sharp score (mTSS) of less than 0, suggesting it inhibited joint damage.

The FDA was also concerned about dose- and time-dependent elevations in malignancies, and particularly lymphomas, with a standardized incidence ratio of 2.35 at a median 9 months duration of exposure. Of the seven total patients who developed lymphoma, three were on 5 mg of tofacitinib, three were on 10 mg, and one was in a still-blinded arm of the trial. Overall malignancy rates increased with time, from 0.79 per 100 patient-years at 0-6 months to 1.06 at 12-18 months to 1.43 beyond 24 months.

Several of the committee members who voted in favor of tofacitinib said that they did so because they wanted a new oral option for RA patients and that they don’t anticipate any better data from clinical trials. They strongly urged postmarketing studies of both radiologic efficacy and safety. Pfizer has proposed a Risk Evaluation and Mitigation Strategy that will include, alongside labeling provisions, a Medication Guide, a "Dear Health Care Professional" letter, and routine pharmacovigilance. Additional clinical studies that are ongoing or planned include long-term extension studies to assess cardiovascular safety, serious and opportunistic infections, malignancies, and gastrointestinal perforations; studies to monitor any unidentified risks; a cholesterol kinetic study; and studies to evaluate the effect of tofacitinib on the immune response to pneumococcal and influenza vaccines as well as to further delineate the effects of tofacitinib on lymphocyte subsets.

The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Martin Bermin-Gorvine of "The Pink Sheet" contributed to this story. This news service and "The Pink Sheet" are both owned by Elsevier.