Amicus Therapeutics Inc.'s decision last week to move into a pair of Phase II trials with its Gaucher's disease compound Plicera might have cast anxiety into some shareholders of Genzyme Corp., which "has a lot at risk," Christopher Raymond, analyst with Robert Baird & Co., pointed out last week.

"If [Plicera] works, it's a big problem," he said.

Gaucher's disease, caused by a lack of activity of the enzyme glucocerebrosidase, results in an enlarged liver and spleen, low levels of red blood cells and platelets, and bone pain. Plicera (isofagomine tartrate), also known as AT2101, yielded positive data from Phase I trials in healthy volunteers, along with good preclinical results in a mouse model. The drug boosted enzyme activity by three and a half times in healthy humans and as much as five times in mice.

Phase II trials include a four-week study testing safety in 32 patients previously treated with enzyme replacement therapy such as Genzyme's injected Cerezyme (imiglucerase), the standard of care for Type 1 Gaucher's.

Overall, Gaucher's is caused by a defect in the GBA gene. Type 1 is by far the most common form of the condition, which afflicts children and adults. Type 2 symptoms begin to show during infancy, and the children die by about their second year. Type 3 resembles Type 2, but milder.

In general, one in 50,000 to 100,000 people gets Gaucher's disease, but Type 1 is much more common among Jewish people from eastern and central Europe - Ashkenazi Jews - and strikes one in 500 to 1,000 people in that segment.

Therapy includes blood transfusions for anemia, removal of the spleen and joint replacement. Bone marrow transplants have worked in some patients. Cerezyme, which puts the missing enzyme back, sold $1 billion in 2006, and is expected to bring in as much as $1.075 billion for Genzyme this year. In January, a study published in the Journal of Bone and Mineral Research showed long-term use of Cerezyme significantly improved bone mineral density in Type 1 Gaucher's patients in a dose-dependent manner.

The second, six-month trial with Plicera, an oral therapy that acts as a pharmacological chaperone binding to glucocerebrosidase, will test the compound in 16 treatment-na ve Gaucher's patients.

Also this month, Amicus completed enrollment in all ongoing Phase II studies with Amigal (migalastat), also known as AT1001, in another of Genzyme's specialty areas: Fabry's disease. The four studies are using various dose levels and frequencies of Amigal to test safety and tolerability, with a secondary aim to evaluate pharmacodynamic measures of treatment, including effects on alpha-galactosidase A and globotriaosylceramide levels in various cells and tissues of disease.

Results from Amigal trials are expected by the end of the year. The Fabry's situation is more distinct than the scenario that might be shaping up with Gaucher's, Raymond noted, and is "very different in the genetic determinants." Amicus' drug for Gaucher's therapy gets more press, and caused some trouble for Genzyme's stock last year.

"The shares suffered last summer - at the time, I thought, unnecessarily," he said, and more recent weakness in the stock "could be concern about Amicus, but it's recovering a little here."

For Plicera, the dilemma could involve dosing, Raymond told BioWorld Financial Watch.

"What we know is that it looks like there's a pharmacological effect in healthy patients, but if you have low circulating enzyme to begin with, the key question is will this drug be able to help people - will you be able to dose patients high enough without [gastrointestinal] toxicity?" he said. "That's the question of the day."

GI toxicity has been a problem with Zavesca (miglustat), from Actelion Ltd., cleared in the European Union, the U.S., Canada, Israel and Switzerland for the treatment of adult patients with mild to moderate Type 1 Gaucher's, where enzyme replacement therapy is not suitable or an option.

For a small indication, Gaucher's has been rather much in the news lately. At the start of the year, the public shell firm Orthodontix Inc. finished merging with Protalix Ltd., changing the company's name to Protalix BioTherapeutics Inc., and hopes were high for the firm's Phase III-stage recombinant glucocerebrosidase, produced in plant-cell cultures.

Raymond believes that, even if Plicera succeeds in Phase II, it might not be able to grab a significant share of the market. "We have seen data that appear positive, but in populations or models that have significant residual enzyme activity, i.e., those patients with generally milder forms of these diseases," he wrote in a research report.

Amicus maintains a "substantial majority" of Gaucher's patients could benefit, but Raymond questioned the entire class of molecules, including the company's drugs for Fabry's and Pompe disease. (Amicus plans to file a new drug application for the Pompe drug, AT2220, by the end of the year.) The chaperone approach deployed by Amicus is intended to stabilize the bound protein and fold it correctly to improve function.

Genzyme's therapy for Pompe disease is the firm's most recently launched product, Myozyme (alglucosidase alfa), which began selling in the second quarter of last year. Sales in 2006 reached $59 million and are expected to increase to at least $155 million and maybe as much as $180 million this year, when Genzyme plans to launch Myozyme in Japan, Brazil and a number of other markets. The company also has its own Phase II, small-molecule program for Gaucher's. Data from the study with GENZ-112638 are expected in the second half of next year.

Meanwhile, watch for data from Amicus' first trial with Plicera - the trial in patients treated with Cerezyme - about the fourth quarter of this year, if recruitment goes well (never a sure thing in rare conditions such as Gaucher's). The other study likely will report late in 2008.

Raymond maintained an "outperform" rating on Genzyme, and downplayed the potential threat from Amicus. "While we will continue to monitor developments in this space, we do not yet see anything that would affect our investment thesis," he wrote.