By Mary Welch

The filing of a biologics license application for Aldurazyme, an enzyme replacement therapy for muccopolysaccharidosis-1 (MPS-1), will be pushed back a year as BioMarin Pharmaceutical Inc. and Genzyme General Corp. will conduct a confirmatory Phase III trial.

"The FDA was very encouraged by the data we had collected but felt that, because this was essentially a Phase I, II and III trial, that more data was needed," said Bo Piela, Genzyme's spokesman. "It was not unexpected. We always intended on doing a confirmatory trial but we had planned on doing a post-approval Phase IV trial because of the compelling need for treating these patients. The FDA is working with us and wanted us to further validate and expand the findings."

When the trial was started, BioMarin called it a "pivotal Phase I" and said the FDA previously had never condoned going from strong animal data into one trial upon which a BLA could be filed. (See BioWorld Today, Sept. 16, 1998, p. 1.)

"This was a total shock to us because we had a commitment from the agency [FDA] and all of our activities were based on that prior commitment," said John Klock, BioMarin's president. "Why did it happen? We don't know. We can only read between the lines. We will conduct a confirmatory trial so efficacy is not at issue. It may be because of policy shifts taking place within the agency. We've heard that the FDA may require two confirmatory trials even if a product has orphan drug status. This could be related. They didn't tell us anything."

The two companies now expect to file the BLA by the end of next year in the U.S., with market introduction in 2001. Regulatory filings in Europe would follow the U.S. filing.

The protocol for the confirmatory trial is still being written but should involve more than 10 patients, which was the number in the first trial. The trial will encompass patients representing the full spectrum of MPS-1 severity, including Hurler, Hurler-Scheie and Scheie syndromes.

"It will have an international arm to it and, while it will be more than 10 people, it will not be huge and will have quick endpoints," Klock said. "The other trial involved 10 patients done in six months. This one will be a little larger but the same duration."

Following discussions with the FDA, the two companies agreed to design a protocol for another trial that treats the most severely ill MPS-1 patients.

Getting the drug to market later than planned is the only adverse effect on BioMarin, Klock said. "It just puts the actual product out on the market at a later date. We know it works and we can show its effectiveness in scientific presentations. What we can't control is the internal workings of the FDA."

The completed trial involved 10 patients with intermediate MPS-1 severity who ranged in age from 5 to 22 years. Aldurazyme was given weekly. The endpoints were a normalization of liver size and a decrease in the excretion of urinary glycosaminoglycans, the carbohydrate substance that accumulates in patients with MPS-1.

Results from the trial showed there was a rapid 20 percent or more reduction in liver size after six to 12 weekly doses in almost all patients, and that liver size returned to normal in the majority of patients by 26 weeks. In addition, patients reported improvements in physical abilities and quality of life. (See BioWorld Today, Nov. 2, 1998, p. 1.)

Two years after starting the trial, patients are still receiving treatment.

BioMarin, of Novato, Calif., and Cambridge, Mass.-based Genzyme started their collaboration in 1998, in a 50-50 deal worth about $30 million to BioMarin. Genzyme agreed to make an up-front $8 million equity investment in BioMarin, pay $12.1 million upon FDA approval and purchase $10 million in stock when BioMarin completed an initial public offering, which it did this July. However, BioMarin predicted the downstream revenues would be between $300 million and $400 million. (See BioWorld Today, Sept. 16, 1998, p. 1; and July 26, 1999, p. 1.)

BioMarin's stock (NASDAQ:BMRN) closed Thursday at $12.187, down 68.75 cents. Genzyme's stock (NASDAQ: GENZ) closed Thursday at $37, down $1.875.