Washington Editor

BETHESDA, Md. - An FDA panel on Monday said Genzyme General's surrogate endpoint from its Phase III trial of Fabrazyme in Fabry disease patients is likely to predict a clinically meaningful effect.

While the Endocrinologic and Metabolic Drugs Advisory Committee didn't take a formal vote to recommend or reject the application for Fabrazyme (agalsidase beta), the panel voted 14 to 1 in favor when asked if Genzyme's study showing "near-normalization" of renal capillary endothelium was reasonably likely to predict a clinically meaningful effect.

Genzyme General, a division of Genzyme Corp., of Cambridge, Mass., is seeking accelerated approval for Fabrazyme under regulations requiring the surrogate to be "reasonably likely, based on epidemiologic, therapeutic, pathophysiologic or other evidence, to predict clinical benefit." The FDA said the Phase III trial demonstrated reduced substrate deposition in other cell types, including cardiac and skin biopsies. Clinical efficacy was not observed in this trial.

Under these accelerated approval provisions, Genzyme will conduct a verification Phase IV trial, a trial for which 76 patients already have been accrued. Panel members discussed whether the company should conduct that trial before approval is decided on. (If approval came first and the Phase IV study failed to show benefit, the FDA could withdraw Fabrazyme.)

A few panel members, including Thomas Fleming, professor and chair of the Department of Biostatistics at the University of Washington in Seattle, questioned the surrogate endpoint, saying there wasn't enough clinical data to support the accelerated application, but others disagreed.

"I think we should focus on the Phase IV trial to give us the information we need," said a consumer representative on the panel and executive director of the Health Information Network in Seattle.

Fabrazyme (agalsidase beta) is a recombinant enzyme replacement therapy made from Chinese hamster ovary cells. It is designed to treat the underlying pathology of Fabry disease by significantly clearing globotriaosylceramide (GL-3) to normal or near normal levels from the vascular endothelium of the kidney, heart and skin, Genzyme said.

Fabry disease is a rare, genetic disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A.

While there are no treatments for Fabry, Genzyme's rival, Transkaryotic Therapeutics Inc., also of Cambridge, has developed its own enzyme replacement therapy, Replagal, (agalsidase alfa). The panel will hear the BLA for that product today. FDA staff on Monday issued a briefing document suggesting Replagal studies did not demonstrate the product reduced pain or improved heart and kidney function.

Both companies are seeking orphan designation, which guarantees seven-year market exclusivity. Approximately 5,000 people worldwide suffer from Fabry disease. During the public information period, several attendees, including Abbey Meyers, a representative of the National Organization of Rare Disorders Inc., asked the panel to consider both biologics, citing the possibility of patients developing immunities to one product or the other.

But Elliott Hillback, Genzyme's senior vice president of corporate affairs, told BioWorld Today that immunities are not likely issues with Fabrazyme.

In its presentation, the company discussed its Phase III trial (AGAL-002), a double-blind, multicenter study of 58 patients.

According to the FDA, AGAL-002 was designed with the primary objective of demonstrating a treatment-associated effect on a histologic endpoint of "near-normalization" of substrate deposition in renal capillary endothelium on light microscopic examination. A "robust" effect was observed in reducing the deposition of substrate in the capillary endothelium (surrogate).

Among the secondary outcomes of AGAL-002 were the effects of the enzyme on pain and renal function. There were no changes in either group in renal function during the controlled study period and there was no treatment-related difference in pain assessment. But, the trial was not specifically designed or powered to show an effect on the secondary outcomes, the FDA said.

Meanwhile, there's the issue with the Phase IV trial, scheduled for completion in 18 months. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled study of patients with mild to moderate renal disease. It will assess the effectiveness of Fabrazyme vs. placebo in prolonging the time to clinically significant deterioration in renal function, cardiac function or death.

But the company wants to modify it to a blinded, two-control-group study to compare renal event rates of Fabrazyme-treated patients with appropriate untreated controls. Genzyme is concerned about the ethics and feasibility of the current design of the Phase IV because it is a long-term, placebo-controlled trial with an endpoint of irreversible organ damage.

Genzyme also proposed a method for analyzing the historical data to provide a historical disease progression rate, but panel members balked at that idea as well the idea of modifying the Phase IV.

Fleming and others said more can be learned from randomized trials, and that the historical data can be helpful as secondary measures.

Fabrazyme and Replagal have already made it to market in Europe.

Fabrazyme's European sales for 2001 were $26 million, in line with Genzyme's guidance. Replagal sales in Europe for the first nine months of 2002 were $22.8 million. For the year, TKT's guidance is $30 million to $35 million.

The companies had submitted their respective BLAs within weeks of each other, TKT on June 16, 2000, and Genzyme on June 23, 2000. Some months later, the FDA asked each company to submit additional data. All the while, the companies were entangled in a patent lawsuit filed by Genzyme. A federal judge dismissed the case in December 2001. (See BioWorld Today, June 19, 2000; June 26, 2000; Oct 6, 2000; and Dec. 28, 2000.)

And each company faced another setback when the FDA postponed their Sept. 26 and 27 panel meetings after TKT raised concerns over conflicts of interest among certain attendees. (See BioWorld Today, Oct. 4, 2002.)

Trading was held for the shares of both Genzyme and TKT Monday. Genzyme's shares gained 9 percent Friday in advance of the meeting.