Washington Editor

Two weeks after a positive FDA advisory panel hearing, Genzyme General and partner BioMarin Pharmaceutical Inc. said Wednesday the agency issued a complete response letter for Aldurazyme without requesting additional clinical data for final approval.

Aldurazyme, an orphan product, is an enzyme replacement therapy for the treatment of mucopolysacchariodosis-1 (MPS-1), a degenerative, genetic disease. The FDA's Endocrinologic and Metabolic Drugs Advisory Committee Jan. 15 voted unanimously (12-0) that trial data supported a meaningful treatment effect on lung function, and that the data showed a meaningful benefit in endurance (also in a 12-0 vote). (See BioWorld Today, Jan. 16, 2003.)

And in accordance with the Prescription Drug User Fee Act (PDUFA) action date of Jan. 28, the agency issued a complete response letter late Tuesday asking the companies to provide additional information on post-marketing commitments, final product labeling and completion of the manufacturing inspections process.

"It is clear to us, from what the FDA has told us, that they recognize the extraordinary need for this product," Fredric Price, chairman and CEO of Novato, Calif.-based BioMarin, told BioWorld Today. "There's an enormous amount of information that they have had to digest and then on top of that, they have had to review everything the panel had just gone over, so it is absolutely not unusual that they would need more than 13 days to do all of the work that has to get done.

"We believe [the approval process] is going to be fairly rapid, but we just don't know when it will happen," he said. "But it is very clear, from what they have told us and from what our discussions are, that this is going to move diligently and promptly with great care and great speed."

MPS-1 is caused by a deficiency of the enzyme alpha-L-iduronidase, which leads to the accumulation of complex carbohydrates in the lysosomes of cells. Resulting symptoms can include impaired cardiac and pulmonary function, delayed physical development, skeletal and joint deformities, reduced endurance and in some cases delayed mental function. There's nothing on the market to treat this rare disease that affects an estimated 3,000 to 4,000 people worldwide.

The Aldurazyme biologics license application (BLA) was based on a six-month, randomized, placebo-controlled Phase III study (also called ADIL-003) of 45 patients. The application, filed as a rolling BLA, was granted fast-track, priority-review status by the FDA. (See BioWorld Today, Sept. 17, 2002; July 30, 2002; June 25, 2002; and April 16, 2002.)

Neither company would discuss details related to information the FDA seeks. However, Dan Quinn, a spokesman for Genzyme General, a division of Genzyme Corp., of Cambridge, Mass., told BioWorld Today that postmarketing commitments generally involve tracking patients for safety. "These are the kinds of routine questions you would think would be outstanding, but there's nothing unusual about these things," he said.

Bill Tanner, managing director of Leerink Swann & Co. in Boston, characterized the letter as positive for both companies. "It doesn't completely give them the green light, but you have to believe that it certainly gets them much further down the road in that direction. It sounds like what they are asking for would be the typical information that they would ask from many companies developing drugs."

Tanner said it's possible that the companies could launch the drug late this year.

BioMarin and Genzyme in 1998 signed a partnership to develop Aldurazyme. The companies will split sales revenues 50-50, and approval of the BLA would trigger a $12.1 million milestone for BioMarin. Price said the $12.1 million payment is the only milestone in the deal. (See BioWorld Today, Sept. 16, 1998.)

As per the agreement, Genzyme will be responsible for worldwide commercialization. Already, the company employs a sales force for Cerezyme, an enzyme replacement therapy for Gaucher's disease, and it is gearing up for anticipated approval of Fabrazyme, also an enzyme replacement therapy, for Fabry disease. (See BioWorld Today, Jan. 14, 2003, and Jan. 15, 2003.)

While neither company would comment on the cost of Aldurazyme, Cerezyme costs about $150,000 to $175,000 per year per patient, and Fabrazyme is sold in Europe for about $160,000 to $165,000 per patient per year.

Research notes released by S.G. Cowen Securities Corp. in New York estimate the U.S. market for Aldurazyme at $175 million (based on a cost of $175,000 per patient per year). The worldwide estimate is $525 million annually.

Quinn said the companies expect a response for European approval in the first quarter.

Meanwhile, Genzyme is waiting on final word on Fabrazyme. The same panel that supported Aldurazyme also voted in favor of Fabrazyme (14-1), when asked if the study showing "near-normalization" of renal capillary endothelium was reasonably likely to predict a clinically meaningful effect. The company is seeking approval based on a surrogate endpoint under accelerated approval.

Genzyme's PDUFA action date for Fabrazyme is April 24.

BioMarin's stock (NASDAQ:BMRN) Wednesday closed at $10.50, up $1.45, or 16 percent, while Genzyme's stock (NASDAQ:GENZ) closed at $33.30, up 33 cents.