Washington Editor

BETHESDA, Md. - Incomplete data and a failure to show statistically significant outcomes in clinical studies put Transkaryotic Therapies Inc. in the unenviable spot of trying to justify its application for Replagal to an FDA advisory panel Tuesday.

Members of the Endocrinologic and Metabolic Drugs Advisory Committee unanimously agreed (15-0) that TKT failed to provide substantial evidence of efficacy of Replagal (agalsidase alfa) in the treatment of Fabry disease.

"The enzyme could be effective and some of the material shows it does have some effect," Adam Jonas, a panel member and professor and chairman of pediatrics at Harbor-UCLA Medical Center in Torrance, Calif., said. "However, I must agree, the material presented is not persuasive. That may be because of the amount of time for the study or the dose, but I must agree there's not a compelling effect."

The same panel on Monday voted 14-1 in favor of Genzyme General's surrogate endpoint from its Phase III trial of Fabrazyme (agalsidase beta) in Fabry disease patients, saying it is likely to predict a clinically meaningful effect. (See BioWorld Today, Jan. 14, 2001).

TKT and Genzyme, both of Cambridge, Mass., are competing to win orphan designation for their respective products in Fabry disease, a rare, genetic disorder. Orphan status ensures seven-year market exclusivity, and according to research notes released by S.G. Cowen Securities in New York, the U.S. market is estimated at $350 million a year. FDA regulations prohibit more than one orphan drug per indication.

Unlike Genzyme General, a division of Genzyme Corp., TKT did not seek accelerated approval for its biologics license application. Still, the panel voted 8-7 that TKT did not have histological data "reasonably likely to predict" clinical benefit under accelerated approval provisions. Accelerated approval would allow Genzyme to win FDA clearance based on a surrogate endpoint while a verification (Phase IV) study is under way.

Regardless of how the trials ended for either company, one panel member said both Replagal and Fabrazyme should be cleared for marketing.

"I'm told whichever company gets approved first will get orphan status and the other company will have lost millions of dollars," Jerry Schneider, a panel member and dean for academic affairs, school of medicine at the University of California at San Diego, said. "After two days, I'm convinced that enzyme replacement therapy works in this disease, but this is a long-term disease. I think these companies have gone too fast. Personally, I think it is time to approve this drug and do long-term studies to get the answers we want. We have hundreds of patients who need this drug and it is obvious we are being too fanatical trying to demand things we want to see. I say we approve them both. But if I had to approve one, I would say the company yesterday [Genzyme] met the endpoint nicely, but that may have been because one company had better luck or better smarts."

Fabry disease is a lysosomal storage disorder caused by deficient activity of the enzyme, alpha-galactosidase A (a-gal). Without a-gal, the lipid ceramidetrihexoside (CTH), also referred to as globotriaosylceramide (Gb3), accumulates in lysosomes throughout the body and impairs the function of several major organs, including the kidney and heart.

The FDA makes the final decision on drug approvals and is not bound by the committee's recommendation. In the cases of Replagal and Fabrazyme, the panel was not asked to recommend approval or rejection.

Genzyme's action date (Prescription Drug User Fee Act date) is April 24.

As for TKT, Katherine Knowles, the consumer representative on the panel and executive director of Health Information Network in Seattle, said, "I would encourage the company to go back to the drawing board, review what the FDA has said, and let's hope it works."

Indeed, Ira Loss, an executive director with Washington Analysis, told BioWorld Today that TKT might consider reviewing its dosage since Fabrazyme is dosed at a level five times higher than Replagal. (See BioWorld Today, July 6, 2001.)

"I think Genzyme will get approval on its PDUFA date," Loss said. "That's the game, though. TKT will have to stay off the market for seven years. This is the risk you take in small biotech; there have been other companies that have had to stay off the market."

TKT submitted data from two Phase II trials conducted at the National Institutes of Health and the Royal Free Hospital in the UK.

Marc Walton, a reviewer with the FDA, told the panel that TKT's endpoint was "not interpretable," and that the studies had "methodological problems severely affecting our ability to review it."

The U.S. Phase II trial (TKT-003) was a 24-week, randomized, double-blind, placebo-controlled study of 26 Fabry disease patients. TKT-003 was designed with the primary objective of demonstrating a meaningful effect in the reduction of pain. According to the FDA, the pain outcomes of TKT-003 did not indicate a treatment-associated effect.

And the other Phase II, TKT-005, was a 24-week, randomized, double-blind, placebo-controlled study of 15 patients. The primary objective was demonstrating a biochemical effect on Gb3 content in heart biopsies. According to the FDA, the study results did not demonstrate treatment-associated effect on cardiac GB3.

However, the FDA said, while some renal function or renal histology outcomes suggested a treatment effect, they were secondary or exploratory endpoints in these studies, and were inconsistent or contradictory with multiple other endpoints.

Finally, the Phase III study, TKT-010, included 80 patients and was unblinded six weeks ago, and therefore not presented Tuesday. However, in early December the FDA said a preliminary review of the Phase III trial showed no statistically significant difference between the treatment and placebo in the primary endpoint of renal function. (See BioWorld Today, Dec. 2, 2002.)

Trading was held Tuesday on TKT's stock. Genzyme's shares (NASDAQ:GENZ), which were held Monday, gained $1.03 Tuesday to close at $32.61.

Genzyme today will again be featured at the panel meeting as it and partner BioMarin Pharmaceuticals Inc. present data from Aldurazyme, a potential product for MPS-1. FDA reviewers said Tuesday that the studies presented in the submission provide a "suggestion of efficacy" but the "data are limited in both statistical strength and in clinical significance." They said the drug failed to provide sufferers endurance to walk farther, but did appear to improve their lung function.