Washington Editor

SILVER SPRING, Md. - The FDA's Oncologic Drugs Advisory Committee split its vote regarding clofarabine, ILEX Oncology Inc.'s cancer product.

The 15-person panel voted 9-6 in favor of the drug's use in pediatric patients with acute lymphoblastic leukemia (ALL), but recommended 14-1 against its use in acute myelogenous leukemia (AML). Questions about the duration of responses dogged ILEX during the meeting, as committee members expressed concern over the number of patients who left the trials to receive bone marrow transplants, considered the best curative treatment option.

Pivotal data behind the new drug application stem from two Phase II studies. Those results, first reported at last summer's American Society of Clinical Oncology meeting, showed an overall response rate of 20 percent among 49 ALL patients and 3 percent of 35 AML patients. That latter figure proved problematic for committee members, who were charged with determining whether that magnitude of response among such patients was suitable for predicting a better long-term clinical response.

Patients' overall response rate was the studies' primary endpoint. But patients often turned to early transplant without the clofarabine response duration being determined by ILEX, sometimes without ILEX confirming the response with a second bone marrow exam and sometimes without the patients seeing a response to the drug at all.

While the FDA stressed the importance of sustained complete responses, the San Antonio-based company countered that partial responses produced by the drug sustained patients to the point that they could receive transplants. Partial responses totaled 31 percent for ALL patients and 26 percent for AML patients.

"These partial responses allowed patients to move to transplant," Steve Weitman, ILEX's chief medical officer, explained to the committee. He added that for AML patients, partial responses might be more meaningful than for ALL patients. Twelve of the 35 AML patients went to transplant.

The FDA has been evaluating the submission under priority review, and is considering it for approval in the separate pediatric ALL and AML indications. The clofarabine review process marks the first time the agency is considering accelerated approval for a pediatric indication.

Committee members acknowledged that the company had little control over the choice of physicians, patients and their families in seeking transplants.

"I don't think we can fault the company for the actions of the patients and the treating physicians," said Michael Perry, director of hematology and medical oncology at the University of Missouri.

The agency is not bound to follow its committee's recommendation, though it often does. Whether the product receives approval or not, the company will conduct a confirmatory study under guidelines established by the accelerated approval process, though the FDA said a protocol for a confirmatory study has yet to be discussed.

"We are very concerned," Richard Pazdur, director of the agency's division of oncology products, told the committee. "It is quite bothersome that we're at this point talking the approval of the drug and not gotten to talk to the sponsor [about a confirmatory study]."

The NDA's safety data are based on integrated findings from the two Phase II trials, as well as a Phase I study. Among the heavily pretreated patients, many of the adverse events were consistent with leukemia, and the events were not unexpected for a cytotoxic agent such as clofarabine.

ILEX earlier this year completed its new drug application for the product to treat refractory or relapsed ALL and AML in heavily pretreated children. It submitted the first part of the rolling NDA a little more than a year ago. (See BioWorld Today, Oct. 23, 2003.)

The FDA has named clofarabine an orphan drug for adult and pediatric ALL and AML. The next-generation purine nucleoside analogue is being investigated for use in both adult acute leukemias, as well as in advanced solid tumors. It also has fast-track status.

Clofarabine has been developed in the U.S. by ILEX, which has proposed Clolar as its trade name. The company licensed exclusive North America development, marketing and manufacturing rights for the product more than three years ago. The drug is being developed outside North America by Bioenvision Inc., of New York. (See BioWorld Today, March 16, 2001.)

ILEX is the subject of a $1 billion buyout by Cambridge, Mass.-based Genzyme Corp., which entered the deal largely because of ILEX's cancer drug portfolio. In addition to clofarabine, ILEX earns revenue from sales of Campath (alemtuzumab for injection) for B-cell chronic lymphocytic leukemia. (See BioWorld Today, March 1, 2004.)

Wednesday, ILEX's stock (NASDAQ:ILXO) rose 10 cents to close at $24.96. Genzyme's shares (NASDAQ:GENZ) lost 60 cents to close at $55.41. Bioenvision's shares (NASDAQ:BIVN) fell $1.92, or 18.6 percent, to close at $8.38.

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