Washington Editor

Genzyme General received FDA approval of the orphan drug Fabrazyme, an enzyme replacement therapy for a rare, genetic disorder called Fabry's disease.

Word came in mid-afternoon Thursday, leaving enough time for the company's stock (NASDAQ:GENZ) to gain $3, or 8.3 percent, to close at $39.38.

Orphan status gives Genzyme General, a division of Genzyme Corp., of Cambridge, Mass., seven-year market exclusivity in the patient population of about 5,000 worldwide.

Genzyme officials expect the cost in the U.S. to be similar to the amount Europeans are charged - on average, $180,000 per year per patient. The company expects to launch within weeks.

It's been a long road to the winner's circle, and on Thursday, the joy of the news was palpable, particularly since the company received a broad label, basically covering anyone with Fabry's disease, Alison Lawton, Genzyme's senior vice president for regulatory affairs, said during an "ad hoc" conference call held within hours of releasing the news.

"This is really fantastic news and we feel really good about this moment," Henri Termeer, Genzyme's chairman and CEO, said in the conference call. "This is very good for the patients who will have access to Fabrazyme."

Fabry disease is caused by deficient activity in the lysosomal enzyme alpha-galactosidase A.

Indeed, there's nothing on the market for this small population, but there certainly was a race to develop a drug. Genzyme's chief competition came from its neighbor in Cambridge, Transkaryotic Therapies Inc. (TKT), which was studying its own enzyme replacement therapy called Replagal (agalsidase alfa). The FDA's Endocrinologic and Metabolic Drugs Advisory Committee in January unanimously agreed (15-0) that Replagal failed to show clinical efficacy in two Phase II trials. (See BioWorld Today, Jan. 15, 2003.)

A day before TKT was shot down, the same panel voted 14-1 in favor of Genzyme's application when asked if its Phase III trial showing "near-normalization" of renal capillary endothelium was reasonably likely to predict a clinically meaningful effect. (See BioWorld Today, Jan. 14, 2003.)

While Genzyme and TKT raced for the coveted orphan designation, the companies found themselves in a patent lawsuit over the Fabry's biologics. Genzyme filed a lawsuit claiming TKT had infringed on its patent, but a federal judge ended up dismissing the case in December 2001. And the companies were supposed to have back-to-back FDA panel meetings in September, but at the last minute the meetings were postponed when TKT alleged that certain invited guests had clear-cut conflicts of interest. Industry watchers were interested in what the FDA would have done had both products made it through the process without stumbling, and some speculated the agency might even have given both orphan status.

Back on the approval news, even FDA Commissioner Mark McClellan issued a statement on Fabrazyme's approval.

"This priority approval of an orphan drug illustrates FDA's commitment to approving innovative new therapies for patients with serious and life-threatening diseases quickly, based on response to treatment of biological markers likely to predict long-term clinical benefit," McClellan said. "The orphan drugs program provides crucial incentives for innovators to develop new treatments for rare diseases. By approving this new biotechnology therapy under the accelerated approval process, we are making this product available more quickly to patients who need it."

Fabrazyme (agalsidase beta) was approved based on a surrogate endpoint believed to predict benefit in patients. In this case, the Phase III trial demonstrated reduced substrate deposition in other cell types, including cardiac and skin biopsies. Clinical efficacy was not measured in the trial. The Phase III (AGAL-002) was a 58-patient, double-blind, multicenter study.

Fabrazyme is a recombinant enzyme replacement therapy made from Chinese hamster ovary cells. It is designed to treat the underlying pathology of the disease by significantly clearing globotriaosylceramide (GL-3) to normal or near-normal levels from the vascular endothelium of the kidney, heart and skin, the company said.

A key part of the accelerated approval process is to conduct confirmatory studies, and Mark Goldberg, Genzyme's senior vice president of clinical research, told conference call listeners that Genzyme will take the Phase IV seriously.

In January 2001, Genzyme initiated its Phase IV, multinational, multicenter, randomized, double-blind, placebo-controlled study of 70 patients (the trial is over-enrolled and now includes 82 patients). The trial is evaluating the effectiveness of Fabrazyme in the time to clinically significant deterioration in any of the following: renal function, cardiac function, central nervous system disease or death.

Goldberg said the trial should be complete in January 2004.

When asked to describe his best hopes for the Phase IV, Goldberg said, "We are confident that we will be able to complete it and we hope to find a significant treatment effect with respect not only to impact on renal disease, but also cardiac and central nervous system disease."

Also, he said the company would like to look at individual patients as their own control group in order to observe the rate of progression.

And if the study shows no impact on patients, "First of all, we think that is unlikely, but with accelerated approval, as clearly stated in the regulations, if confirmatory studies fail to verify clinical benefit, further discussions could lead to removal of the product."

Additionally, Genzyme has agreed to regularly evaluate creatinine levels in the Phase IV patients through an open-label extension study, and it has agreed to obtain long-term data through a Fabry registry.

Lawton said the registry data are expected to provide important information in the event the Phase IV fails to perform.