By Randall Osborne
West Coast Editor
The enzyme replacement therapy that netted BioMarin Pharmaceutical Inc. a $30 million joint venture deal with Genzyme General Corp. in 1998 is entering a pivotal Phase III study, almost a year to the day after the companies said the FDA wanted more trial data.
"It's a fundamentally different trial," said Fredric Price, president and CEO of Novato, Calif.-based BioMarin, which early next month will begin testing Aldurazyme (recombinant alpha-L-iduronidase) in 42 patients with MPS-I, also known as Hurler, Hurler-Scheie and Scheie disease, at centers in the U.S. and Europe.
"This is a lot more complex process [than the first study]," Price said, referring to the length of time between trials. "It's not as easy as people think."
The first study enrolled 10 patients and was open-label, whereas the new trial is double-blinded and placebo-controlled. Most important, Price said, the endpoints are manifestations of clinical symptoms, rather than surrogate markers.
"We looked at organ size, specifically liver and spleen size [in the first study]," Price said. MPS-I, or muccopolysaccharidosis-1, is a lysosomal storage disease, characterized by an enzyme shortage, in which carbohydrates build up and swell the organs. Relief of the enlargement is "terrific, but it's a surrogate marker," Price told BioWorld Today. "If the patients aren't getting better, who cares?"
In the first study, "quality of life measurements were all good, but they weren't listed as primary endpoints," he said. "In the new trial, we've flipped the endpoints. We're continuing to look at surrogate markers, but they're secondary."
BioMarin entered the joint venture with Cambridge, Mass.-based Genzyme because of its expertise marketing two enzyme treatments for Gaucher's disease, another rare disorder: Cerezyme (recombinant glucocerebrosidase) and Ceredase, the natural version of the enzyme, derived from human placenta.
In the deal, Genzyme agreed to make an up-front $8 million equity investment in BioMarin, pay $12.1 million upon FDA approval of a product and purchase $10 million in stock when BioMarin completed its initial public offering, as the company did last July, raising $58.5 million. (See BioWorld Today, Sept. 16, 1998, and July 26, 1999.)
For Aldurazyme, analysts are estimating a worldwide market of about $500 million, Price said. "The patient population size is similar [to the population for Ceredase and Cerezyme], so it's not an illogical jump," he said.
Genzyme, however, is embroiled in a legal war with Transkaryotic Therapies Inc. (TKT), also of Cambridge, over patents related to products for yet another enzyme shortage condition called Fabry's disease.
This week, a patent in the U.S. was granted to the Women's and Children's Hospital, in Australia, and TKT has an exclusive worldwide license to the patent, which contains 11 claims covering alpha-L-iduronidase.
Price said, "Only three scenarios can exist. If the TKT patent is valid and covers our technology, then, after all parties take whatever legal remedies [they can], there has to be some accommodation made. It's a financial transaction."
The second possibility is that TKT's patent is valid, but doesn't cover the technology of BioMarin and Genzyme. "That has no relevance to any party," Price said, nor does the third possible scenario, in which TKT's patent is not valid.
"We don't know the answer; there's a lot more work done," Price said.
Elise Wang, analyst with PaineWebber, in New York, said the TKT patent related to BioMarin's product could become a bargaining chip in the Fabry's disease fight between Genzyme and TKT.
"I don't know if BioMarin will get stuck in the middle because I don't know [the details of] Genzyme's relationship with BioMarin," Wang said. "It could be they will be defending a potential patent situation together."
Price did not want to talk further about Genzyme's fight with TKT.
"Let me be very clear," he said. "We have a superb partner, and they are experts in the commercialization of enzyme replacement products. I have no comment at all."
In any case, Wang said, "there won't be any kind of legal action until [BioMarin and Genzyme] get closer to a product," probably at the filing of a biologics license application, which Price said will happen "most likely before the end of 2001."
The last patient probably will begin dosing in March, which would put the finish of the trial in September, he said.
BioMarin's stock (NASDAQ:BMRN) closed Wednesday at $8.875, down 62 cents. Genzyme's shares (NASDAQ:GENZ) ended the day at $77.75, up $1.75.