FDA panel recommends approval for rheumatoid arthritis drug

The FDA Arthritis Advisory Committee voted 8-2 today in favor of approval of Janus kinase 3-inhibitor tofacitinib as a treatment for patients with rheumatoid arthritis.

The drug, sponsored by Pfizer, was proposed with a starting dose of 5 mg twice daily for patients with moderately to severely active rheumatoid arthritis (RA) who have had inadequate response to at least one disease-modifying anti-rheumatic drug (DMARD). The proposed dosage could increase to 10 mg based on clinical response.

The sponsor presented data from several studies indicating statistically significant improvements to ACR response and Disease Activity Score 28 and Health Assessment Questionnaire-DI scores from both 5-mg and 10-mg dosages among RA patients relative to placebo, as well as a comparative analysis of tofacitinib and adalimumab. A single study also provided data on radiographic outcomes suggesting a possible but uncertain influence on radiographic scores as a result of both dosages.

When asked if the radiographic data provided substantial evidence of efficacy, two members voted yes and eight voted no. However, several indicated that a beneficial effect was likely to exist based on the presented data and that, while the overall quality was insufficient to definitively suggest efficacy, it was unlikely that better data would be obtained. Some members recommended further study, and temporary member James Ware, PhD, Frederick Mosteller professor of biostatistics at Harvard School of Public Health, said an additional study with equally encouraging results would dramatically improve the committee’s confidence.

The committee voted unanimously that the evidence supported the efficacy of tofacitinib for the proposed indication, citing consistent results across five studies, active comparison of clinical outcome measures with adalimumab and results comparable or better to those from other biologic agents.

Most members also agreed that the presented safety profile adequately supported approval for the indication (7-2 vote, one abstaining), but many also expressed reservations about the level of risk associated with the drug, particularly at the 10-mg dose level. Data suggested that a higher rate of infection, including serious and opportunistic infections, among treated patients could be related to dosage levels and treatment duration, along with a higher number of solid and hematologic malignancies relative to patients receiving placebos or adalimumab.

The committee voiced concerns that the drug, used in combination with other immunomodulatory agents, could lead to over-immunosuppression and increase the risk for infection and malignancy, particularly at higher dosages. Members suggested that additional research yielding long-term safety data taken from a larger population was warranted.

Safety concerns were echoed in the final 8-2 vote. Members were asked to clarify after voting if they supported one, both or neither of the 5-mg and 10-mg dosage options, and most indicated support only for the 5-mg dosage, with some adding that lower dose options also would be favorable.

“I would really like to have this drug available for patients with RA, since we know one-third of them won’t respond to available therapies,” Maria Suarez-Almazor, MD, PhD, professor and section chief of rheumatology at the Department of General Internal Medicine at The University of Texas MD Anderson Cancer Center, said during the meeting. “I’m very uncomfortable with the indication as stated, however ... I’m also uncomfortable with using this drug before trying an anti-TNF agent.”

Several committee members called for vigorous post-marketing surveillance of the agent should it be approved.

“There are concerns about some of the safety signals presented today, but I think the sponsor ... did as much as a sponsor can do at this phase of the process to assess the risk,” David Blumenthal, MD, committee member and assistant professor of medicine at Case Western Reserve University Cleveland Veterans Affairs Medical Center in Cleveland, said. “ ... With immunomodulating agents for RA, there will always be [safety] concerns, and sometimes additional data on that risk is obtained during the post-marketing phase rather than at this phase.”

The FDA, which is not required to follow the recommendations of the advisory committee, but generally does, is expected to make a decision on approving tofacitinib in August.