By Kim Coghill

Washington Editor

BETHESDA, Md. - In a 14-to-1 vote Thursday, an FDA advisory committee recommended that the agency grant accelerated approval for Campath, an orphan drug for the treatment of chronic lymphocytic leukemia (CLL).

With dissention from Richard Simon, chief of the Biometric Research Branch of the National Cancer Institute in Bethesda, the Oncologic Drugs Advisory Committee recommended approval of Campath for patients with CLL who have been treated with alkylating agents and who have failed fludarabine therapy.

The compound is a monoclonal antibody developed in a 50-50 joint venture between San Antonio-based Ilex Oncology Inc. and Cambridge, Mass.-based Millennium Pharmaceuticals Inc. (Millennium acquired its rights to Campath through its December 1999 acquisition of LeukoSite Inc., also of Cambridge.) Richmond, Calif. based-Berlex Laboratories, a division of Berlin-based Schering AG, will distribute and market the product. Schering already markets fludarabine. (See BioWorld Today, Aug. 25, 1999; and Dec. 27, 1999.)

Both companies are looking forward to launching Campath during the first half of 2001. Analysts from CIBC World Markets Corp., of New York, expect Campath to generate about $37.5 million in 2001 and $71 million in 2002.

"Needless to say, we're just as pleased as punch about this," Richard Love, Ilex president and CEO, said in a press conference following the advisory committee hearing. "Accelerated approval was our original objective. This set about our strategy aimed at getting accelerated approval and that was fulfilled as far as the ODAC recommendation today. The ODAC decision represents a milestone in a partnership that has evolved and combines the best resources from each company involved in getting Campath closer to market."

Matthew Geller, managing director of equity research at CIBC World Markets, said the ODAC decision is an indicator that "both of these companies are extremely competent in developing products and choosing products that are going to work and in dealing with the FDA. I think they did a brilliant job of working with the FDA. This was a crisp and clear presentation and I think the vote reflected that, and it reflects the professionalism of these companies."

Millennium's stock (NASDAQ:MLNM) closed Thursday at $60.125, up $4.50, or 8 percent. Ilex's stock (NASDAQ:ILXO) closed at $28.75, up $2.25, or 8.5 percent.

CLL, the most prevalent form of adult leukemia, is characterized by an accumulation of malignant lymphocytes, a subclass of white blood cells, in the bone marrow and other tissues. It causes bone marrow dysfunction and enlargement of the lymph nodes, liver and spleen. With no current cure, most patients eventually become refractory.

In the next step toward approval, Ilex and Millennium will meet with the FDA to discuss a Phase IV trial, Love said. "We've agreed to another trial."

His comments are the result of a lengthy discussion by ODAC members who were concerned about the toxicity of Campath and who viewed another trial as being a move in the right direction.

"I hate to see accelerated approval used as a way of making it more difficult to do a clinical trial that really should have been done," Simon said. "I can see the rationale for accelerated approval." He cautioned, however, that trials should not be compromised in the interest of speeding up the process.

Among the types of Phase IV trials discussed were the FDA's recommended multicenter, randomized study of fludarabine vs. Campath in patients with CLL who have not yet received fludarabine. Another recommended study is a multicenter, randomized study of Campath vs. supportive care (no additional therapy) in patients who have failed fludarabine.

In the primary efficacy study conducted in 93 patients with fludarabine-refractory CLL, an overall response rate of 33 percent was observed. The median duration of response was 6.9 months, with seven of the 93 patients (8 percent) experiencing a response lasting greater than one year. The overall response rates in two small studies conducted in a similar, though less heavily pretreated, population were 29 percent and 21 percent and the median duration of response in these studies also was similar.

Due to the lack of a control group, one cannot determine whether specific patient benefits occurred, according to the FDA.

The FDA stated in guidance that for refractory malignancies, reduction in tumor volume may serve as a surrogate for clinical benefit. The association of this surrogate (reduction in tumor) with patient benefits is stronger when the tumor is reduced to undetectable amounts (complete response) and when the reduction in tumor is durable and extends beyond the period when toxic agents are being administered.

In the primary efficacy study, 90 percent of patients experienced infusional toxicity, 47 percent required an interruption of therapy, 32 percent required an interruption of therapy for one week or greater, 24 percent of patients discontinued treatment for adverse events, an additional 4 percent refused to continue, 67 percent experienced serious adverse events characterized as infusional, infectious or hematological toxicity, and the latter two were often interrelated, according to the FDA. Fifteen percent of the patients died, possibly or probably from toxicities related to Campath, the FDA said. In the absence of a well-controlled trial, the impact of Campath on overall survival cannot be determined, according to the FDA.

ODAC members said although Campath is not a perfect drug, it does appear to offer hope where there currently is none.

"There's no question that this is potentially a toxic regimen. However, in the hands of responsible oncologists - hopefully that's all who are practicing - and provided that the risks are well delineated and the packaging shows this, I think this is acceptable," said Ellin Berman, associate professor of Leukemia Service at the Division of Hematologic Oncology of Memorial Sloan-Kettering Cancer Center in New York.

According to Millennium and Ilex, the most common adverse events from use of the compound are acute infusion-related events. Severe infections were seen in 28 percent of patients including those due to opportunistic pathogens. Hematologic toxicity, which can be severe, emerges on treatment in some patients.