By Lisa Seachrist

Washington Editor

BETHESDA, Md. — An FDA advisory panel unanimously recommended that Genetics Institute's platelet growth factor be approved for the prevention of recurrent chemotherapy-induced thrombocytopenia — or platelet deficiency.

In an 18-0 vote recommending approval of Neumega, members of the Biological Response Modifiers Advisory Committee, however, denied the company a wider indication for use in cancer patients who hadn't yet suffered a depletion of platelets but were scheduled to begin a high-dose chemotherapy regimen.

"We are very pleased," said John Petricianni, vice president at Genetics Institute, in Cambridge, Mass. "To me, this entire process from start to finish was absolutely excellent. It serves as a prototype for how the FDA should manage its review process."

Neumega is a recombinant version of human interleukin 11 (rhIL-11) that stimulates platelet production and modulates immune response agents like tumor necrosis factor. Patients undergoing high-dose chemotherapy regimens are at high risk for platelet depletion as a result of those regimens. Without an adequate number of platelets, a patient may suffer serious bleeding complications.

Currently, physicians either give patients a platelet transfusion or reduce or delay cancer therapy until platelet count increases. While transfusions often rescue patients whose platelet levels have dropped too low, it exposes them to the risk of viral and bacterial infections. In addition, once patients have suffered from thrombocytopenia, they are at risk of depleting their platelets with each round of chemotherapy. Multiple platelet transfusions encourage immune responses to blood components, which may make subsequent attempts at platelet transfusion less successful.

Neumega, should it gain marketing clearance, would offer physicians an opportunity to continue chemotherapy uninterrupted without subjecting patients to the risk of platelet transfusions.

"Approving Neumega would be a major advance in the treatment of chemotherapy-induced thrombocytopenia," James Kaye, director of clinical research/hematology at Genetics Institute, told BioWorld Today. "Currently, physicians have no choice but to reduce chemotherapy or transfuse platelets."

Genetics Institute, which is a wholly owned subsidiary of American Home Products, presented data from two small pivotal trials testing Neumega in patients who had already suffered thrombocytopenia and in patients who were undergoing chemotherapy for the first time.

Pivotal trial 9308 tested two doses of Neumega, 25 micrograms per kilogram and 50 micrograms per kilogram vs. placebo in 93 patients. Patients were given either one of the doses of Neumega or placebo as a subcutaneous injection every day for 14 days to 21 days after they had received three days of chemotherapy. The company defined a failure as needing a platelet transfusion.

Thirty percent of the patients in the high dose Neumega arm avoided transfusion while only 4 percent of the placebo group didn't need platelets.

"There is a sufficiently strong indication that Neumega is effective in these patients," said panel chair Julie Vose, assistant professor at the University of Nebraska Medical Center, in Omaha.

The panel didn't view the study of patients who had never suffered thrombocytopenia with the same enthusiasm, however. That study, 9416, looked at Neumega's ability to prevent thrombocytopenia in 77 breast cancer patients receiving cyclophosphamide and doxorubicin.

Because these patients were on their first rounds of chemotherapy, they were at little risk of needing a platelet transfusion, and there wasn't a large difference between placebo and drug. In addition, eight patients dropped out of the study before receiving the drug.

Kaye told the panel that "the efficacy of Neumega was diluted by patients with little risk for thrombocytopenia."

Many on the panel felt that losing 10 percent of the trial participants made it particularly difficult to determine if Neumega was effective.

"It is a concern that the data doesn't support its effectiveness as a primary prophylaxis for thrombocytopenia," Vose said. "I think there is a hint that it may be effective, but we need more data."

The panel voted 14-3 with one abstention against recommending Neumega for use in patients who haven't yet suffered a bout with platelet deficiency.

In deciding that Neumega's benefits outweighed its risks, the panel focused on the fact that Neumega causes fluid retention. Sixty percent of patients suffered from peripheral edema, and 50 percent had difficulty breathing. In addition, approximately 25 percent of patients suffered an increased heart rate and palpitations. Some patients also suffered from atrial arrhythmias.

Two patients on Neumega died as a result of low potassium levels, which led Ellin Berman, associate professor at Memorial Sloan-Kettering Cancer Center, in New York, to suggest that the label include a warning that patient suffering from fluid retention need to have their potassium levels monitored.

The panel also suggested that the company follow up with post-marketing studies to pinpoint the patients who are most likely to benefit from rhIL-11 therapy.

The agency usually follows the advice of its advisory panels but is under no obligation to do so.

Kaye told BioWorld Today the company also is exploring Neumega as a treatment for Crohn's disease and chemotherapy-induced mucositosis — inflammation and breakdown of the lining of the mouth and gastrointestinal tract. *