By Brady Huggett

As Genzyme General and Transkaryotic Therapies Inc. bump and jostle each other on their way to the finish line with Fabry disease treatments ¿ Fabrazyme (agalsidase beta) and Replagal (agalsidase alfa), respectively ¿ it remains unclear which, if either, will get sole U.S. orphan drug status.

In June, TKT published results from a pivotal Phase II trial in the Journal of the American Medical Association. Yesterday, Genzyme said it had results from a Phase III trial published in the current New England Journal of Medicine. The companies, entangled in a patent infringement lawsuit, submitted their biologics license applications to the FDA within weeks of each other in June 2000. Both were asked to submit further data after the FDA reviewed the applications. They are even located in the same city, Cambridge, Mass. (See BioWorld Today, Oct. 6, 2000; Dec. 28, 2000; and Jan. 5, 2001.)

But one marked difference between the drugs is their dosing. Fabrazyme is dosed at 1 mg per kg; Replagal at one fifth of that, 0.2 mg per kg. The published Fabrazyme data highlight that difference, said Mark Goldberg, senior vice president for clinical research at Genzyme.

¿People need to look at the data,¿ Goldberg said. ¿Is there a substantive difference between the two drugs? I haven¿t seen any data that point to a significant difference between [them]. I think that is something the FDA and the orphan drug group would need to decide for themselves. But if there isn¿t a substantive difference, then what is the right dose? I think we have an excellent product, when you give the appropriate dose.¿

Thomas Schuetz, vice president, clinical affairs at TKT, said the products are far from identical.

¿I think my first comment is that they are different molecules,¿ Schuetz said. ¿They are certainly different proteins. We know for sure they are quite different. The differences we see in the molecules are reflected in the dosing.¿

The 58-patient trial of Fabrazyme had an endpoint of clearance of globotriasylceramide (GL-3) from the microvascular endothelial cells in the kidney. After 20 weeks of treatment, 20 of 29 patients who received Fabrazyme achieved complete, or almost complete clearance, compared to none in the placebo group. It is that endpoint, and the fact that the trial was conducted at several centers, that might give Genzyme an edge, said Elise Wang, analyst for Salomon Smith Barney in New York.

¿Our comfort level has been higher with Genzyme,¿ she said. ¿The FDA has favored studies that were done in multiple sites. And the FDA did endorse the endpoints that Genzyme had in their study.¿ Wang said both of TKT¿s pivotal Phase II trials were conducted at a single site.

Because of the fivefold dosing difference, the infusion time for Fabrazyme is substantially longer than Replagal¿s. Replagal takes 40 minutes to infuse; Fabrazyme can take as long as four and a half hours, said TKT¿s Schuetz. Dennis Harp, analyst for Deutsche Banc Alex. Brown Inc., of New York, said dosing and the related infusion times for the products also could influence the FDA.

¿There are clearly differences in the way the products have been dosed,¿ he said. ¿So that accounts for the longer infusion time [for Fabrazyme]. If the infusion time results in a difference in safety, then that could be a factor with the FDA.¿

Wang, however, doubts the dosing will carry much weight with regulatory authorities.

¿I don¿t think that matters as much as what you have done with efficacy,¿ she said.

Both drugs were recommended for approval from the Committee for Proprietary Medicinal Products of the European Agency, and it is likely that both will get marketing approval in Europe. What will happen in the U.S. is not clear, mainly because this scenario is a new one.

¿There is a possibility [that both get approval],¿ Wang said. ¿There is no precedent that one can look to, but it is still possible.¿

Harp not only finds it possible, he thinks it will happen.

¿I have modeled that both companies will get approval in the U.S.,¿ he said. ¿I¿ve assumed, for modeling purposes, a 50-50 share in the U.S.¿ In Europe, where he feels both will be approved as well, Harp assumes Replagal will take ¿the dominant market share¿ because of the fragmented European market and the shorter infusion time.

With estimates of worldwide Fabry patients numbering anywhere from 2,000 to 5,000, and these drugs yet unpriced, it is difficult to tabulate what either product could do in sales. Genzyme is not interested in splitting the market.

¿What are the outcomes [of the trials]?¿ Goldberg asked. ¿Where can you compare which does a better job of clearing? We welcome a comparison of Replagal and Fabrazyme.¿

Genzyme¿s stock (NASDAQ:GENZ) fell $1.54 Thursday, to close at $57.46. TKT¿s stock (NASDAQ:TKTX) rose 49 cents, closing at $29.06.

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