Washington Editor

BETHESDA, Md. - The FDA's Oncologic Drugs Advisory Committee voted 10-5 in favor of approving Celgene Corp.'s Revlimid (lenalidomide) for myelodysplastic syndromes (MDS) in transfusion-dependent patients with a 5q-deletion chromosomal abnormality.

"To my knowledge, there has not been an agent that gives that type of complete transfusion independence, clinical response associated with both a cytogenic remission and bone marrow normalization, and hemoglobin normalization," Sol Barer, Celgene's president and chief operating officer, told BioWorld Today. "We really do think that this is going to be one of the largest oncology products in history."

The Summit, N.J.-based company based its rolling new drug application largely on a 148-patient Phase II study, expressing confidence in the data underlying the submission but also acknowledging the strategy's risk. The decision to file was based on findings showing that the drug led to red blood cell transfusion independence in two-thirds of patients, the study's primary endpoint. Notably, that benefit has proved durable, with 83 of 99 patients who achieved transfusion independence maintaining that response for at least six months, and 52 of them for more than a year. (See BioWorld Today, April 11, 2005.)

"I think that the efficacy is unquestionable," said Susan O'Brien, a panel member from the University of Texas. The company decided to target MDS patients with the 5q deletion based on evidence from a previous pilot study. In the U.S., between 35,000 and 55,000 people have primary MDS, a group of hematologic malignancies.

As Barer noted, in addition to resolving anemia among the 5q-deleted patients, use of the drug also led to a significant rise in hemoglobin, cytogenetic responses and remissions, as well as marrow normalization and improvements. Those benefits, said Graham Burton, Celgene's senior vice president of regulatory affairs, are "evidence that Revlimid is having a disease-modifying effect."

The FDA, which typically follows the advice of its advisory committees, must issue its final decision by Oct. 7. And Barer noted that importantly, the panel voted for full approval, "a high hurdle."

But in presenting some skepticism, the agency raised a number of issues related to the drug's potential toxicities, as it is an analogue of Thalomid (thalidomide, also from Celgene). FDA investigators said such toxicities are difficult to characterize because the company filed for approval on data from a single-arm trial.

Richard Pazdur, the director of its oncology products division, noted that the agency had recommended Celgene conduct a randomized study that "gives more information than single-arm trials." His concerns were taken a step further by Maitreyee Hazarika, a medical officer in the cancer division, who said, "The absence of a control arm makes attribution of adverse events and deaths difficult." She also charged that the company's tests in rat and rabbit models were inadequate in establishing Revlimid's safety with regard to fetal development and limb deformities. "The structural similarities of lenalidomide and thalidomide suggest a human development risk," Hazarika said.

Neutropenia and thrombopenia were the primary adverse events in the Phase II study, in which 80 percent of patients had their 10-mg dose cut in half at some point during the testing. The company stressed that the cytopenia side effects could be controlled, but many of the panel members worried over the prevalent dose reductions, and the committee voted 13-2 that the data did not provide a basis for a recommended dose or adequately describe the product's safety profile.

"I think the dose is an unsafe dose," said Bruce Cheson, a panel member from Georgetown University. Earlier, though, he said he was "reasonably comfortable that there is a treatment effect with this agent."

Barer spoke to the dosing issues, saying 10 mg "is acceptable, from the risk-benefit perspective, especially in oncology, given the fact that many, many oncology drugs are started at one level and the dose is reduced to specific patient requirements. Physicians are used to doing that."

As to the adequacy of the trial, the panel voted 11-4 that its design showed Revlimid's treatment effect in that 5q-deletion patient population.

In the end, the efficacy won out, as the company maintained. Its speakers all stressed that the Phase II findings were too compelling to wait on a Phase III. Nevertheless, Celgene has begun accrual in a randomized Phase III trial in Europe that allows for placebo patients to cross into a 5-mg or 10-mg drug arm after four months. The company also has proposed a risk-management program for patient education to ensure product safety.

"We're looking at other doses," Barer said, "in an effort to optimize it."

He added that Celgene is in the process of talking to European regulatory authorities about a submission overseas, where the company would consider partnering rights in a deal with commercial and financial components that would allow Celgene to grow into a global drug firm.

If approved, Revlimid would compete in an MDS market that last year added another new treatment, Vidaza (azacitidine, from Pharmion Corp.). That drug acts as a pyrimidine nucleoside analogue.

Looking down the road, Celgene also is preparing to file for Revlimid's approval in multiple myeloma, with a submission planned for next quarter. A pair of Phase III trials in that indication exceeded pre-specified efficacy endpoints and hit their primary endpoint, time to disease progression. But the company continued them to further examine survival. (See BioWorld Today, March 8, 2005.)

On Wednesday, Celgene's shares (NASDAQ:CELG) rose $1.86 to close at $54.77.

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