National Editor

As Transkaryotic Therapies Inc. revealed a weak hand regarding Replagal (agalsidase alfa), all eyes turned to competitor Genzyme General, which has been playing its cards close to the vest.

TKT said the preliminary review of six-month data from an 80-patient Phase III study of the enzyme replacement therapy for Fabry's disease showed no statistically significant difference between the treatment and placebo in the primary endpoint of renal function.

The Cambridge, Mass.-based company's stock (NASDAQ:TKTX) closed Wednesday at $9.60, down $4.66, or 32.7 percent.

TKT's rival, Genzyme, a division of Genzyme Corp., also of Cambridge, is awaiting FDA approval on its Fabry's disease biologic, Fabrazyme (agalsidase beta). Both are already marketed in Europe, and both seek approval with orphan drug status to provide seven-year exclusivity.

Genzyme's shares (NASDAQ:GENZ) ended Wednesday at $33.78, up $3.64, or 12.1 percent.

"I don't think it's a plus for Genzyme," said Thomas Shrader, a biotech analyst with Gerard Klauer Mattison & Co. in New York, who said he regards the drugs as "the same, pound for pound. I would hope Genzyme has a trial like [TKT's] started. If it was a six-month trial, they've just extended it."

Genzyme has claimed "TKT patients are under-dosed, and I find that argument plausible," he said. "Based on Genzyme's dosing, TKT is at the bottom of the effective range," which could mean better news from Genzyme (using the bigger dose), when the company decides to disclose it.

"If they have it they could say so now," Shrader said. "They couldn't before without tipping their hand." Neither company could be reached Wednesday.

The latest TKT development follows an even harder hit for the company last month, when the FDA characterized some pain data in TKT's biologics license application as "uninterpretable" and "not supportive of approval" of the BLA. The company's shares fell more than 60 percent that day, closing at $12.75. (See BioWorld Today, October 4, 2002.)

"Pain is an acceptable endpoint, but it's notoriously difficult," Shrader noted.

TKT said it also got a complete response letter from the FDA, formally reinforcing what the agency had already said. That letter also provided guidance on how TKT should proceed in order to improve its case for an accelerated approval based on a histopathological surrogate endpoint. Since the company believes it can show renal pathology correlates with renal function, TKT said the former may work as a surrogate marker.

Genzyme, for its part, "has been down this road before," Shrader said. "I would expect them to do what they need to do."

He pointed to the company's approved enzyme-replacement product Cerezyme (imiglucerase) for Gaucher's disease, calling it a "miracle drug like almost no other."

The "Cerezyme landscape" has changed, he said, when "you could have one 10-person trial, and the FDA says, Fine.' Since then, the FDA has realized these are small drugs in terms of market size but not in market value, so maybe you can hold [drug developers] to a higher burden of proof."

With Fabrazyme, Genzyme had "always planned on molecular endpoints, and they were probably very careful," Shrader told BioWorld Today. "They'll tell you the FDA signed off on those endpoints, but that doesn't mean much to me, since the person who signed off may not even work at the FDA anymore. TKT's endpoints made sense and I found them reassuring, but now they've gone up in smoke."

TKT's news of the unfavorable preliminary data also puts more chips on the table when the Endocrinologic & Metabolic Drugs Advisory Committee meets Jan. 14. Both companies were scheduled to present their BLAs to the panel Sept. 26 and 27, but the meeting was postponed following a complaint by TKT.

Although TKT has been told its data won't hold up, Genzyme has not revealed what will be in the company's package for review in January.

It's been two years since the firms first disclosed what they intended as pivotal data at a meeting of the American Society of Human Genetics in Philadelphia. For even longer, both firms have been in talks with the FDA (which wanted more information from each), in a contest that has included lawsuits by both sides.

"Orphan drug has been the enemy of both of these companies," Shrader said. "They've been rushing against each other, and it's really hurt the whole process."

Although orphan drug status is a good idea in principle, he added, the situation between TKT and Genzyme represents a "bizarre perversion" of it, with competitively imposed pressure on both companies.

"It wasn't supposed to put a gun to their heads," he said.

Even if both companies' drugs work and make it to market, Shrader said, "Genzyme will get more than their fair share" because of its size and respect gained through Cerezyme and expertise in enzyme replacement therapies.

In September, Genzyme and partner BioMarin Pharmaceutical Inc., of Novato, Calif., submitted their biologics license application for Aldurazyme (laronidase), an enzyme replacement therapy for mucopolysaccharidosis 1.

The next Genzyme drug of Cerezyme's caliber, though, will be a Tay-Sachs disease therapy, Shrader predicted.

"You can take infants who would have died at 2 and died horribly, and they are going to be normal people," he said. "But that's probably three years away."