Washington Editor

WASHINGTON - Anyone with an interest in lysosomal storage diseases is certain to focus this week on Bethesda, Md., where the FDA's Endocrinologic and Metabolic Drugs Advisory Committee will review applications from two companies that have a long history of competing with each another.

Genzyme General and Transkaryotic Therapies Inc. today and Tuesday, respectively, will finally get the opportunity to explain data supporting the cases for their competing biologics designed to treat a rare disorder called Fabry disease. In fact, the disease is so rare (only 5,000 people affected worldwide, according to TKT) that both companies looking to treat it will fight for the coveted orphan drug status, which guarantees seven-year market exclusivity.

Today, Genzyme General, a division of Genzyme Corp., is scheduled to present the panel with its biologics license application (BLA) for Fabrazyme (agalsidase beta), a recombinant enzyme replacement therapy made from Chinese hamster ovary cells.

Meanwhile, representatives of TKT, makers of the competing drug Replagal (agalsidase alfa), are sure to be on the edges of their seats waiting for a decision. On Tuesday, TKT will present its case for Replagal, an enzyme replacement therapy.

And in unrelated business Wednesday, Genzyme and partner BioMarin Pharmaceutical Inc., of Novato, Calif., will present the case to the same panel for another orphan product, Aldurazyme, for mucopolysaccharidosis 1 (MPS 1), a fatal genetic disease. (See BioWorld Today, Sept. 17, 2002.)

Outcomes Of All Panel Meetings In Doubt

Bill Tanner, managing director of Leerink Swann & Co. in Boston, told BioWorld Today that Aldurazyme has the best chance of getting a positive vote. (The panel makes recommendations to the FDA, which the agency often follows.)

"If you look at Aldurazyme, you don't have the political overhang," Tanner said. "You actually have clinical data that's probably a bit idiosyncratic, but you do have data where there is an interesting efficacy signal, and you could make the argument that there's a much more compelling unmet medical need [in MPS 1 than in Fabry's]," Tanner said.

According to TKT, Fabry is an inherited rare genetic disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. It affects both males and females and results in premature mortality in the third or fourth decade of life due to kidney disease, heart disease and stroke.

MPS 1 is caused by a deficiency of the enzyme alpha-L-iduronidase. The deficiency leads to the accumulation of complex carbohydrates in the lysosomes of cells, leading to the progressive dysfunction of cellular, tissue and organ systems, according to information provided by Genzyme. MPS-1 is historically known as Hurler, Hurler-Scheie and Scheie syndromes.

"Fabry patients might die in their 50s of kidney failure. But for something like Hurler-Scheie, which is what Aldurazyme treats, these babies could die at a very early age," Tanner said. "So you are going to have some emotional overtones probably that will be stronger for the Aldurazyme panel because presumably you will have parents there with children who are in dire need of a drug."

Others, though, believe Aldurazyme may face a few obstacles.

Research notes from Yaron Werber, vice president and biotech analyst with SG Cowen Securities Corp. in New York, said consultants are guardedly optimistic on the prospect of near-term approval of Aldurazyme because the FDA likely will request an additional trial. And whether the trial will be pre- or post-marketing may depend on the panel.

Still, Cowen's model assumes that Aldurazyme will be launched in the U.S. in the second half of 2004. Cowen estimates the U.S. market at $175 million.

Genzyme and BioMarin filed the final sections of the rolling BLA for Aldurazyme in July, and the FDA accepted the application in September. (See BioWorld Today, Sept. 17, 2002; July 30, 2002; June 25, 2002; and April 16, 2002.)

While Tanner believes Replagal and Fabrazyme are on equal footing, Werber's notes lean toward the latter.

In fact, Werber said Fabrazyme has "emerged as the leader" in the wake of TKT's recent shortfalls.

It started in early October when the FDA said some of TKT's pain data were "uninterpretable" and "not supportive" of approval. TKT's stock fell more than 60 percent in a day on that news, closing at $12.75. (See BioWorld Today, Oct. 4, 2002.)

Then in early December, the FDA said a preliminary review of six-month data from an 80-patient Phase III study of Replagal showed no statistically significant difference between the treatment and placebo in the primary endpoint of renal function. (See BioWorld Today, Dec. 2, 2002.)

But Tanner's view is a little different.

"The conversations that we have had with some of our physician consultants lead us to believe that the playing field is probably more level than perhaps most of the rest of market believes in terms of Replagal standing as good a chance as Fabrazyme of being approved," Tanner said.

Orphan Status Adds Additional Uncertainty

However, he cautioned that some consultants believe there is a chance neither product will win a positive recommendation. "The reasons aren't entirely clear, but it could include the fact that maybe the data that have been presented aren't that robust for either drug, or the FDA may be attempting to understand better what should be looked at and how these drugs should be tested and potentially, too, there could be a bit of a political overtone - when we have spoken to people at orphan drug [the FDA] they have indicated that only one will be approved."

Werber's notes agreed, stating, "Our conversations with FDA officials suggest that the orphan drug office is adamant that only one enzyme replacement therapy garner approval for Fabry disease."

Tanner added that there's no case to set a precedent for the situation like the one at hand.

"There's a precedent for multiple products on the market where there is orphan protection, but I don't believe there is any precedent for simultaneous granting of orphan status unless both drugs are found to be approvable and the companies agree to share it," he said. "I think the likelihood of that has to be practically zero."

Indeed, TKT and Genzyme, both located in Cambridge, Mass., are competitors that actually got entangled in a patent lawsuit over the Fabry drugs. Genzyme filed the lawsuit, claiming that TKT had infringed on its patent. A federal judge dismissed the case in December 2001.

The companies had submitted their respective BLAs within weeks of each other, TKT on June 16, 2000, and Genzyme on June 23, 2000. And to add to the similarities, the FDA subsequently asked both companies to submit additional data, ultimately creating a tie in the race to approval. (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 alleged that certain invited guests had clear-cut conflicts of interest. (See BioWorld Today, Oct. 4, 2002.)

Genzyme today will present data from a 58-patient Phase III trial, and on Tuesday, TKT will present data from two independent Phase II trials, one with 26 patients and the other with 15 patients. Both companies will present other data as well.

Fabrayzme's European sales for 2001 were $26 million, in line with Genzyme's guidance. Replagal sales in Europe for the first nine months were $22.8 million. For the year, TKT's guidance is $30 million to $35 million. Fourth-quarter results will be released in February.