By Lisa Seachrist
GAITHERSBURG, Md. — An FDA advisory panel unanimously recommended that the agency approve Immunex Corp.'s rheumatoid arthritis (RA) therapy, Enbrel, for patients who have failed other therapies.
The Arthritis Advisory Committee, however, unanimously voted not to recommend Enbrel as therapy without regard for disease severity. The Seattle-based company's anti-cytokine therapy garnered a 12-to-5 endorsement for use in combination with the standard RA drug methotrexate.
"We are delighted to have the first biologic product recommended for use in RA," said Peggy Phillips, senior vice president of pharmacological development for Immunex. "[The indication] is for the population that we studied. More important is the indication for use in combination with methotrexate, because we believe this is the way that these drugs will be used."
Enbrel is two molecules of recombinant human tumor necrosis factor (TNF) receptor, bound together by the constant region of the human IgG1. Enbrel regulates inflammation by blocking the interaction of the inflammation-inducing cytokine TNF with the cells that respond to its signal.
In effect, the drug reduces levels of biologically active TNF in the bloodstream without destroying cells that have bound TNF, which is a major mediator of joint destruction in RA.
The company presented data showing that Enbrel significantly decreases disease activity, increases functional ability, and improves quality of life. In addition, Immunex showed that Enbrel was effective alone or in combination with the RA standard methotrexate. RA affects approximately 2.5 million Americans, mostly women.
Results Submitted From Three Trials
Immunex provided results from three clinical trials: a Phase II dosing trial; a Phase III pivotal trial testing a 25 milligram dose for six months; and a trial testing Enbrel's efficacy in combination with methotrexate.
In judging Enbrel's benefit to RA patients the company used the American College of Rheumatology (ACR) assessment called the ACR response rate, which includes measures of tender and swollen joints, pain, morning stiffness, a physician's assessment and a patient's assessment of disease activity. In addition, the company included common laboratory measures and a health assessment questionnaire.
The pivotal trial included 234 patients who had failed at least one and up to four disease-modifying therapies, such as methotrexate. Patients were allowed to take low-dose steroids and non-steroidal anti-inflammatory drugs. Participants were treated with either 25-milligram subcutaneous injections twice a week for six months, a 10-milligram dose or a placebo.
At the six-month mark, 15 percent of the patients treated with the 25-milligram dose had a 70 percent decrease in their ACR score, compared to 1 percent of the placebo group.
Forty percent of the patients treated with the higher-dose Enbrel achieved a 50 percent reduction in ACR scores, while 24 percent of patients given the low-dose Enbrel and 5 percent of the placebo group enjoyed the same response. Fifty-nine percent of the patients treated with high-dose Enbrel, 51 percent of those receiving the lower dose and 11 percent of the placebo group had a 20 percent reduction in their ACR scores.
In the combination therapy trial, 59 patients were treated with the 25-milligram dose twice weekly in combination with methotrexate, while 30 patients received methotrexate and placebo. At six months, 15 percent of the Enbrel treated patients had a 70 percent reduction in their ACR scores, while none of the placebo group achieved that relief.
Thirty-nine percent of the Enbrel treated patients had a 50 percent reduction in their ACR score while 3 percent of the placebo group had a similar response. Seventy-one percent of the Enbrel-treated patients and 27 percent of the placebo-treated patients achieved a 20 percent reduction in their ACR scores.
Immunex presented results indicating treatment with Enbrel provided a sustained benefit over long-term use of the drug, as demonstrated by an open-label extension of the Phase III study. Patients have been followed for up to two years in that study.
Side effects of the drug included injection site reactions, such as redness and itching. Immunex determined that Enbrel didn't cause generalized immunosuppression and therefore didn't increase the incidence of infection or malignancy.
The agency, however, determined that there was an increase in infections among the Enbrel-treated group. Because patients on placebo were crossed over to the active treatment group and lost to follow-up after the trial, the panel decided it did not have enough data to determine whether there were more infections among patients taking Enbrel than placebo.
"I think we need to see a Phase IV study of patients on Enbrel coupled with an appropriate comparison group," said panel member David Felson, a rheumatologist at Boston University School of Medicine. "You can enumerate the infection risk that way."
Phase IV Study Advised To Look At Long-Term Safety
The panel recommended a Phase IV study to establish long-term safety data for the drug and describe the drug's utility as first-line therapy. Immunex is currently collecting long term-data on patients who have taken Enbrel.
In addition, the company is conducting a placebo-controlled trial of Enbrel in children, as well as a study that pits Enbrel against methotrexate in patients in the early stages of RA.
The drug's marketing partner is Wyeth-Ayerst Laboratories, a division of American Home Product Corp., of Madison, N.J., which owns 54 percent of Immunex.
Last month, the FDA approved another TNF blocking drug: Remicade from Centocor Inc., of Malvern, Pa., for the treatment of Crohn's disease. Centocor will present Phase III results for Remicade in RA at a scientific meeting later this year.
The agency is not bound by the recommendations of its advisory committees, but often follows their advice. *