West Coast Editor

As expected, Genzyme Corp.'s clofarabine - the first new leukemia treatment for children in more than 10 years - won FDA approval, and the company plans to make the next-generation purine nucleoside analogue brand-named Clolar available as quickly as possible in January.

"There certainly are established combination regimens that, in some patients, allow them to proceed to bone-marrow transplant, and that's the intent of Clolar, too," said Michael Vasconcelles, vice president of clinical research for Cambridge, Mass.-based Genzyme. "But this is the only approved option available."

Worth pointing out, he added, is that "children treated in studies to date had already been treated with all of, or the bulk of, those other agents."

Genzyme's stock (NASDAQ:GENZ) closed Wednesday at $58.16, up 63 cents. Shares of New York-based Bioenvision Inc. (NASDAQ:BIVN), which is developing the drug outside North America, ended the day at $9.14, up 67 cents.

Clolar was cleared for marketing against pediatric refractory or relapsed acute lymphoblastic leukemia (ALL). The FDA designated the compound an orphan drug, which provides seven years of market exclusivity, and recently added six months under the Best Pharmaceuticals for Children Act.

Earlier this month, the FDA's 15-member Oncologic Drugs Advisory Committee split its vote regarding clofarabine, coming out 9-6 in favor of use in pediatric patients with ALL, but 14-1 against its use in acute myelogenous leukemia (AML). Data from a pair of Phase II studies showed an overall response rate of 20 percent among 49 ALL patients and 3 percent of 35 AML patients. (See BioWorld Today, Dec. 2, 2004.)

Granted accelerated approval, Clolar has not been proved to increase survival or other clinical benefit in randomized trials specifically geared that way.

"We're working that out with the FDA," Vasconcelles told BioWorld Today. "It will be part of the post-approval commitment."

Use of the drug is based on the induction of complete responses. Genzyme also has submitted a pediatric development plan that includes further tests of Clolar in combination with existing therapies.

Next year, about 3,400 new cases of pediatric acute leukemia are expected, with ALL the most common form. Children who do not respond to initial therapy, or who relapse, have a very poor survival prognosis. Clofarabine has been developed in the U.S. by ILEX Oncology Inc., which was bought by Genzyme in a $1 billion stock deal that closed earlier this month. ILEX licensed exclusive rights in North America from Bioenvision more than three years ago. Phase I trials started in 1999. (See BioWorld Today, March 16, 2001.)

Pricing will be disclosed when the drug is launched. Clolar's label calls for intravenous infusion for two hours on five consecutive days, with the cycle potentially to be repeated every two weeks to six weeks when the patient returns to baseline organ function. What the average number of cycles might be is hard to predict, as is how much might be used per patient, since the label indicates Clolar for patients from 1 year to 21 years old.

The median age of patients with acute leukemia is 10 to 11 years old, Vasconcelles said.

"We do have a growing experience with duration of therapy," he said. "The median number of cycles across the studies was just over two, but the range was quite broad and we have patients who have continued for more than five cycles."

One concern with such agents is cumulative toxicity, he noted, but "with clofarabine that has so far not been the case, except for myelosuppression," which was expected.

"If the length of time of recovery [from that] becomes too protracted, it may be prudent to discontinue therapy," he said. "We don't yet fully know."

Although Clolar is "a distinct agent with a distinct mechanism of action and clinical population that derives benefit, it is [also] in a broader class of agents that we generally have experience with," Vasconcelles added. "In that class, the mechanism is such that one would not necessarily expect a biomarker that would indicate a patient would respond better or not. It's something we're continuing to look at."