Washington Editor

The race between Transkaryotic Therapies Inc. and Genzyme General to win regulatory approval plus orphan drug designation for their respective Fabry's disease biologics evolved late Wednesday when Transkaryotic said the FDA expressed concerns about some of its data.

Indeed, Transkaryotic (TKT), of Cambridge, Mass., watched its stock tumble Thursday on news that the FDA found certain data in the Replagal biologics license application "uninterpretable" and "not supportive of approval." TKT's stock (NASDAQ:TKTX) fell $20.50 Thursday, or about 61.7 percent, to close at $12.75.

TKT's rival, Genzyme, a division of Genzyme Corp., also of Cambridge, Mass., is awaiting FDA approval on its Fabry's disease biologic, Fabrazyme (agalsidase beta). Both drugs are on the market in Europe, a scenario not likely in the U.S. since each company is seeking orphan status, a designation that guarantees a product seven-year exclusivity. Genzyme's stock (NASDAQ:GENZ) moved up $1.36 Thursday to close at $22.36.

Referencing TKT's release that said the FDA thinks the Replagal pain data is uninterpretable, Bill Tanner, managing director of Leerink Swann & Co. in Boston, told BioWorld Today: "I think things have changed significantly. What we believe would have been a potential competitive advantage on the regulatory front has pretty much evaporated."

Just weeks ago, Tanner was among the analysts who believed Replagal likely would win approval before Fabrazyme because it had a better efficacy and safety profile.

"Before, we thought TKT had a better data package - that they showed clinical efficacy vs. what Genzyme was showing [which was] improvement in a surrogate endpoint," Tanner said. "Basically, what TKT said last night was that they did not have a clinical endpoint that it looked like the FDA would accept and that they would have to go with a surrogate endpoint. So in our minds, their data package really got significantly weaker."

In a conference call, Richard Selden, TKT's president and CEO, said he expects Replagal to win FDA approval in the first half of 2003 on the renal and cardiac clinical endpoint data, and by using the kidney pathology data as a surrogate endpoint for possible accelerated approval.

Selden said the FDA has "expressed concerns" regarding TKT's clinical data and is particularly critical of the company's pain data related to Replagal.

"Given the complexity of the trial design and the small number of patients in the studies, the FDA felt that our pain data were not interpretable and that data supporting our pain primary endpoint would not support marketing approval," he said. "While we do not agree with much of the FDA's interpretation of the pain data and we believe patients are benefiting in terms of pain from Replagal therapy, we decided the best approach to obtain prompt approval was to agree to disagree with the FDA and to focus on our other data and not to use the pain data as part of the basis for seeking approval at this time."

Replagal is an enzyme replacement therapy for the treatment of Fabry's disease, an inherited rare genetic disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. It affects both sexes and results in premature mortality in the third or fourth decade of life due to kidney disease, heart disease and stroke, according to information released by TKT.

While few patients worldwide are affected by Fabry's disease, TKT and Genzyme have been in a long battle to win the market in the U.S. Eric Schmidt, a biotechnology analyst with SG Cowen in New York, said in a research note that both companies are essentially in the same position - both have to "convince the agency to grant accelerated approval based on surrogate markers data."

But Tanner said, "We've had physician consultants comment that if the FDA was to look at safety as being the primary criteria by which the drugs were approved, then Replagal would be approved because it is perceived to be a safer drug than Fabrazyme."

When asked which drug he believes will win approval, Tanner said, "it's difficult to handicap at this point."

The companies were scheduled to present their respective BLAs to the FDA's Endocrinologic and Metabolic Drugs Advisory Committee Sept. 26 and 27. However, the meeting was postponed one week in advance following a complaint by TKT.

The problem, Selden told conference call listeners, was that certain invited guests had clear-cut conflicts of interest. "We brought this to the attention of the FDA. We felt the potential conflicts were egregious and posed a risk to the conduct of the fair and unbiased meeting," he said. "However, at no time did we suggest that the meeting should be postponed. At the time of the postponement, we were unaware of any conflicts involving voting members of the committee, and any issues related to those members were not raised by TKT."

Bo Piela, a spokesman for Genzyme, on Thursday told BioWorld Today that Genzyme was "extremely disappointed and surprised that the meeting was canceled."

Like TKT, Genzyme has been in constant contact with the FDA since the cancellation. Both companies have suggested that the advisory panel hear their applications at the next regularly scheduled meetings Dec. 5 and 6.

Tanner doesn't expect TKT to get a panel hearing until early 2003. "Part of the problem was they had a difficult time fielding a panel, so when they try to field another panel, they'll have another problem," he said.

On the financial side of things, Selden said TKT was lowering its 2002 guidance for Replagal in Europe from the previously stated $35 million to $42 million, down to the $30 million to $35 million range. First-quarter sales were $6.1 million and second-quarter sales were $8.8 million. Third-quarter sales totals will be released Oct. 30, Selden said, and noting that the summer months were unexpectedly slow in Europe. He expects a rebound in the fourth quarter.

By comparison, first-quarter Fabrazyme European sales were $4 million and second-quarter sales were $6 million. Third-quarter results will be announced Oct. 16.