BETHESDA, Md. - An FDA panel supported data submitted by Genzyme General and partner BioMarin Pharmaceutical Inc. for Aldurazyme, an enzyme replacement therapy for the treatment of a rare degenerative disease, mucopolysaccharidosis-1 (MPS-1).
In a unanimous vote (12-0), the Endocrinologic and Metabolic Drugs Advisory Committee said the data supported a meaningful treatment effect on lung function. And in a second unanimous vote, the panel agreed that the data indicated a meaningful treatment benefit in walking distance (endurance).
The FDA has granted the Aldurazyme biologics license application (BLA) six-month priority review status and orphan drug designation. The Prescription Drug User Fee Act action date is Jan. 28, meaning the FDA has to take some action on the BLA by then.
"The panel's unanimous support of Aldurazyme's clinical benefit is a very encouraging step forward for patients with MPS-1, and an acknowledgement of the significant achievements by the members of the companies' development teams," Emil Kakkis, BioMarin's senior vice president, business operations, said in a prepared statement following the meeting. "We look forward to working with Genzyme and the FDA to bring Aldurazyme to MPS-1 patients as quickly as possible."
There's nothing on the market to treat this rare disease that affects an estimated 3,000 to 4,000 people worldwide. Research notes released by Yaron Werber, vice president and biotechnology analyst at S.G. Cowen Securities Corp. in New York, estimate the U.S. market at $175 million, based on a cost of $175,000 per year per patient. The worldwide estimate is $525 million annually.
As part of a joint agreement signed in 1998, Genzyme, of Cambridge, Mass., and BioMarin, of Novato, Calif., will split Aldurazyme sales revenues 50-50. FDA approval of the BLA would trigger a $12 million milestone for BioMarin. (See BioWorld Today, Sept. 16, 1998.)
During the public information period, Abbey Meyers, president of the Washington-based National Organization for Rare Disorders Inc., said the FDA hasn't caught up with science. Enzyme replacement therapy works, she said, pleading with the panel to approve a drug that could help so many desperate families.
However, regarding the trials, she said, "I know the company and the FDA sit down and negotiate endpoints, but it boggles my mind that anyone would choose a six-minute walk as an endpoint because if you give this [Aldurazyme] to children, their joints aren't going to be cleared in six months," she said.
Children as young as 6 could participate in the pivotal Phase III trial that had included co-primary endpoints of pulmonary function and distance covered in a six-minute walk test.
MPS-1 is a genetic disease 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.
When asked what type - if any - confirmatory clinical trials should be conducted, David Schade, a panel member and professor of medicine and chief, division of endocrinology at the University of New Mexico School of Medicine in Albuquerque, offered his support of the application, saying, "We need to get these drugs to patients who need them and not continue to delay."
The BLA was based on a six-month, randomized, placebo-controlled Phase III study (also called ADIL-003) of 45 patients.
The first co-primary endpoint was pulmonary function as measured by percent predicted in forced vital capacity (FVC). According to the FDA, the overall treatment-associated difference in percent-predicted FVC was a mean of 6 percentage points. The "p" value was 0.02 for that difference.
In the walk test, according to the FDA, there was a 38-meter difference between groups in the distance walked over six minutes, from a baseline of more than 300 meters in each group. The "p" value for this difference was 0.07 (the difference in the six-minute walk between groups at baseline was 319 meters vs. 367 meters in treatment and placebo groups, respectively). However, the net result was that by the end of the randomized, controlled portion of the study, the difference between groups at baseline was largely absent, meaning it may not actually have met statistical significance.
In a twist to the story, according to Cowen's notes, Genzyme rival Transkaryotic Therapies Inc., also of Cambridge, owns a U.S. patent related to the use of a purified alpha-L-iduronidase made from cells transfected with DNA encoding the protein (related to Aldurazyme). It's possible that TKT could be in line for a royalty off Aldurazyme.
TKT and Genzyme have been neck and neck in a race for years to capture the market for Fabry disease, another rare, genetic disorder.
Earlier this week in a 14-1 vote, the panel said Genzyme's surrogate endpoint for the biologic Fabrazyme likely would predict a clinically meaningful outcome. The following day, the panel unanimously agreed that TKT had failed to provide substantial evidence of efficacy in Replagal, its proposed treatment for Fabry disease. (See BioWorld Today, Jan. 14, 2003, and Jan. 15, 2003.)
BioMarin's stock (NASDAQ:BMRN) gained $2.13 Wednesday, or 30.3 percent, to close at $9.15. Genzyme's stock (NASDAQ:GENZ) gained $2.50 to close at $35.11. TKT's shares (NASDAQ:TKTX), trading for the first time since Friday, fell $2.25, or 25.7 percent, to close at $6.49.