Washington Editor

SILVER SPRING Md. - An FDA advisory panel Tuesday said more data were needed to validate the efficacy and safety of drugs from Genzyme Corp. and Vion Pharmaceuticals Inc. to treat elderly patients with acute myeloid leukemia (AML), stating that the firms' single-arm Phase II studies were insufficient on which to base approval.

Shares of Genzyme (NASDAQ:GENZ) closed at $55.39, down 32 cents, while shares of Vion (OTC BB:VION) plunged 23 percent, or 77 cents, to close at $2.60.

In a 9-to-3 vote, the FDA Oncologic Drugs Advisory Committee (ODAC) said Genzyme should be required to conduct a randomized controlled trial before regulators consider approving Clolar (clofarabine) as a first-line treatment for adults 60 years or older with AML with at least one unfavorable baseline prognostic factor.

A larger ODAC panel in the afternoon voted 13 to 0 that Vion also be required to conduct a randomized trial of Onrigin (laromustine) to establish the safety and efficacy of the drug as a single agent for remission induction in patients 60 years or older with de novo, poor-risk AML.

AML, the most common type of acute leukemia, affects elderly adults very differently than younger patients with the disease. Elderly patients have higher risk factors and have lower response rates, with shorter overall survival.

Genzyme and Vion argued that their drugs would fill an unmet need for elderly patients, a population for which two-thirds typically go untreated because of the poorer outcomes.

In Genzyme's CLO243 study, 51 of 112 patients, or 45.5 percent, achieved overall remission, defined as either complete remission or complete remission with incomplete platelet recovery. Of the 51 responders, 38, or 74.5 percent, achieved OR after one cycle of Clolar and 13, or 25.5 percent, achieved OR after two cycles.

In Vion's single-arm CLI-043 study, 27 of 85 patients, or 31.8 percent, achieved OR. In the company's CLI-033 supportive single-arm study, 38.2 percent of patients achieved OR. Across all 140 elderly de novo poor-risk AML patients in both studies, 34.3 percent achieved OR.

Although the ODAC panelists agreed that the remission rates were impressive, they were unconvinced that the Genzyme's and Vion's single-arm studies were sufficient to show that the drugs' benefits outweighed the risks or that it was clear that the medications were any better than chemotherapy.

Richard Pazdur, director of the FDA's Office of Oncology Drug Products, noted that the agency had urged both companies to conduct randomized controlled trials before submitting their applications - advice that went unheeded by Genzyme and Vion.

Clolar already is marketed in the U.S. The FDA in 2004 granted accelerated approval for the drug as treatment for pediatric patients with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. The company has a commitment to complete a Phase III study of the drug in pediatric patients to gain full approval in that population.

Pazdur, however, appeared to lob a warning shot across the bow by calling out the fact that the company has yet to start that trial six years after the approval.

Genzyme officials said the company is nearing completion of its Phase I/II development program of Clolar in combination with chemotherapy and plans to start the Phase III randomized controlled trial in newly diagnosed children in 2010.

But panelist Thomas Fleming, a professor of biostatistics at the University of Washington in Seattle, scolded Genzyme, asserting that the "congressional intent" of accelerated approval was for a "fairly timely" completion of follow-up studies.

Michael Vasconcelles, group vice president and global therapeutic area head of transplant and oncology at Genzyme, said the early combination safety studies, which will serve as the basis of the randomized Phase III pediatric trial, were initiated "immediately after" the accelerated approval was granted and have been ongoing for the past four years.

Mark Enyedy, head of oncology and multiple sclerosis at Genzyme, told reporters after the meeting that the company has had a "strong track record" of fulfilling postapproval commitments. "Genzyme is one of the companies in the industry that has completed those postapproval commitments," he contended.

Genzyme submitted its supplemental application for AML in elderly patients to the FDA in November 2008 based on its single-arm Phase II CLO243 trial of Clolar in older adult patients with previously untreated AML who were deemed unfit for conventional treatment with seven days of continuous infusion cytarabine plus three days of an anthracycline or anthracenedione, known as 7+3 induction chemotherapy.

The company also submitted data from a supportive multicenter, single-arm study, known as BIOV-121, in a similar population.

Mark Hayes, group vice president of regulatory affairs at Genzyme, said the company had proposed a randomized controlled trial and submitted a special protocol assessment to the FDA for study CLO342 in March 2006 of Clolar in combination with low-dose cytarabine vs. low-dose cytarabine alone in previously untreated older adults with AML.

But, he said, a panel of outside AML experts who reviewed the study protocol for Genzyme could not agree on an appropriate comparator arm for the proposed study population and recommended a single-arm, single-agent clinical study instead.

But Pazdur noted that the FDA has heard similar arguments before from drugmakers.

"This is a common, common comment," he said. Pazdur argued that companies have several options for comparator arms, including using investigational drugs.

Genzyme currently has an ongoing Phase III randomized, double-blind, placebo-controlled study comparing Clolar plus intermediate-dose cytarabine vs. intermediate-dose cytarabine alone in adult patients 55 years or older with relapsed or refractory AML after receiving up to two prior induction regimens.

But panelists noted that the population in that trial is very different in age and disease type as the population Genzyme is seeking approval for in its supplemental application.

Vion's application primarily relies on the findings of a single-arm study and a post-hoc subset of patients from a second single-arm study. The company also submitted data from a randomized controlled trial, which was placed on clinical hold due to excess death in the Onrigin arm.