By Karen Pihl-Carey

Staff Writer

Biotechnology companies focus on enzyme replacement therapies to treat rare diseases, such as Fabry disease and Gaucher disease, for various reasons.

For one, they may hope to ease discomfort and pain, to prolong life, in those people who suffer from a disease usually ignored by drug makers because of its rarity. Also, they may hope to gain seven years of market exclusivity for finding an effective therapy for an orphan indication.

Whatever the reason, the therapies have been crucial in altering people's lives for the better. The marketing exclusivity also has allowed companies to charge high prices to make their research in such a small patient population worthwhile.

But, according to analysts, that may change. Patients may soon have more than one option for orphan indications if the FDA sets a precedent by granting co-marketing exclusivity to Genzyme General's Fabrazyme (agalsidase beta) and Transkaryotic Therapies Inc.'s Replagal (alpha-galactosidase), the companies' Fabry disease products.

"As you read orphan drug law, there is no precedent for two drugs that have been developed simultaneously, so this has been a very new thing for both FDA and securities analysts to see," said Christopher Raymond, a senior analyst with Prudential Vector Healthcare. "But when the data first came out in October of last year, the drugs appeared different enough that many folks, including ourselves, felt that there was good reason to provide co-exclusivity."

Decisions granting marketing approval to both, one or neither of the drugs are expected in October. Some analysts have speculated that the approval of both drugs could start a lawsuit from the companies against the FDA.

"It's hard to say," Raymond told BioWorld Financial Watch. "There's a possibility of that. Although, the FDA is in a tight spot because there is also a possibility for litigation if only one is approved. They're basically looking at two drugs that have shown in clinical trials to be efficacious."

Some analysts believe that the FDA purposely set up the data for each product in such a way that they couldn't be compared, leaving it on solid ground for approving both because they appear so different. While the drugs themselves are different ­ Replagal is manufactured in a human cell line, whereas Fabrazyme is manufactured in a CHO cell line – so are the data. Fabrazyme was tested at 1.0mg/kg, with surrogate efficacy endpoints, and Replagal was tested at 0.2mg/kg with more "clinically relevant but less convincingly met endpoints," according to a Prudential research note.

There was no overlap in the dose ranges used and "no comparability in the pivotal trial patient populations, or in the clinical endpoints studied."

The note put out earlier this month by Raymond, and colleagues Peter Drake and Warren Durbin, stated: "We find it odd that FDA would have suggested such diametrically different trial designs, making direct comparisons virtually impossible – unless, of course, such a lack of comparability was, in fact, the desired outcome."

Typically, a drug granted approval for an orphan indication has seven years of market exclusivity, encouraging drug makers to seek treatments for indications with smaller markets. There is an advantage to companies that develop such treatments. The fact that they are marketing the only drug available for a rare disease enables the company to charge high prices, showing that a small market does not necessarily mean small revenues.

Genzyme's Gaucher disease product, Cerezyme, for example, is expected to bring in revenues of $565 million to $575 million this year, said Bo Piela, spokesman for the Cambridge, Mass.-based company. Transkaryotic Therapies also is based in Cambridge. Its officials could not be reached for comment.

"The annual cost of therapy for Cerezyme can be as much as $170,000 per patient per year," Raymond said.

His firm's research note said Fabrazyme likely would be almost as costly as Cerezyme, with worldwide revenues of $13.6 million in 2001, $35 million in 2002, and $45 million in 2003. Those figures also assume the approval of Replagal.

Fabry disease is caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, which leads to accumulations in the body of ceramidetrihexoside, resulting in extreme pain, serious renal and cardiovascular disease, and stroke. As many as 2,000 patients in the U.S. are afflicted with the disease.

Piela added that Genzyme's interest in orphan drugs has continued because it already has the global infrastructure, with regulatory, reimbursement, commercial and manufacturing capabilities.

"And we made a conscious decision to build on that infrastructure and expertise by introducing other therapies for similar diseases," he told BioWorld Financial Watch.

Genzyme's Cerezyme, which replaced its earlier drug Ceredase as a treatment for Gaucher disease, came off of its marketing exclusivity in the spring, opening the door for Oxford GlycoSciences Inc.'s Vevesca. Oxford, based in Oxford, UK, filed a new drug application in August for Vevesca.

But Raymond remains skeptical about Vevesca.

"That drug is not without controversy. The latest data that we've seen has shown a sizable population of people who take the drug develop severe diarrhea," he said.

Other analysts have given it only a 50 percent chance of reaching the market, adding that it does have an advantage being an oral drug. It also is estimated to cost at the most about $50,000 per year per patient, compared to Cerezyme's $170,000 cost.

Said Raymond: "In our view, if it is approved, we don't believe it will be a replacement by any means of Cerezyme therapy. At the very most, it would be complementary."

Gaucher disease is a glycolipid storage disorder in which an enzyme deficiency leads to the accumulation of unmetabolized lipids.

If both Fabrazyme and Replagal are approved, it may seem to contradict the whole concept of market exclusivity, but it does increase the likelihood that a patient with a rare disease finds an effective therapy.

"I don't think we can really speculate on what the FDA will do," Piela said. "I think this is virtually an unprecedented situation, which makes it difficult to determine how the FDA will respond."

Piela declined to comment on whether a lawsuit against the FDA could occur following the decision, but did point out that Genzyme still has a lawsuit against Transkaryotic Therapies (TKT) for patent infringement. Genzyme filed the suit in July 2000. Two months later, TKT filed against Genzyme for a judgment of patent non-infringement and invalidity. That trial is expected to begin in March 2002.

The European Union granted approval last month to both Genzyme's Fabrazyme and TKT's Replagal.