Amicus Therapeutics Inc. reported promising Phase II data that bode well for both its Fabry's disease drug and the remainder of its pharmacological chaperone platform, yet concerns that the company's Amigal might falter next to leading enzyme replacement Fabrazyme sent shares tumbling 37 percent.

The firm's stock (NASDAQ:FOLD) lost $5.59 Thursday to close at $9.54. Shares of Fabrazyme maker Genzyme Corp. (NASDAQ:GENZ), however, gained $2.50 to close at $75.08.

As reported late Wednesday afternoon, results from the recently completed Phase II trials in patients with Fabry's disease, a genetic disorder that results in deficient activity of the alpha-galactosidase A (á-GAL) enzyme and leads to symptoms such as pain and kidney failure, showed that Amigal (migalastat hydrochloride) produced an increase in á-GAL in 24 of 26 patients, as measured in white blood cells, kidney and skin.

Meanwhile, levels of the substrate globotriaosylceramide (GL-3), which accumulates in Fabry's patients, decreased in those who demonstrated greater increases in á-GAL levels.

More importantly, the benefit was seen in patients with a range of mutations and in both early- and late-onset Fabry's.

"There was a time when it was thought that only a very small number of patients" might benefit from Amigal, a small-molecule drug designed to bind to and stabilize á-GAL, said John Crowley, president and CEO of Cranbury, N.J.-based Amicus.

Some of those early estimates were as low as 5 percent of the Fabry's population - overall there are about 5,000 to 10,000 Fabry's patients in the developed world - but Amicus' Phase II data indicated that the drug appears to be efficacious in patients with missense genetic mutations, which accounts for about 60 percent of the Fabry's population, Crowley said. And, of those, "about two-thirds of them would qualify for Amigal treatment."

Also, he added, recently published reports suggested that there might be even more patients out there, namely undiagnosed late-onset patients. That late-onset group could be "very amenable" to Amigal treatment, he said.

Wall Street, however, remained unconvinced. Analyst Christopher Raymond, of Chicago-based Robert W. Baird & Co., called the Phase II results "less-than-robust data," and several analysts worried that Amicus relied more heavily on a urine test to measure patients' GL-3 levels rather than kidney biopsies.

"We understand from [Genzyme's] clinical experience that the FDA may not believe that this measure correlates with disease," Raymond wrote in a research note.

Cambridge, Mass.-based Genzyme gained approval for Fabrazyme (agalsidase beta), a recombinant enzyme replacement therapy, in 2003, following pivotal trials showing its ability to lower GL-3 levels, as determined by kidney biopsies.

Amicus' biopsy data from the Phase II Amigal trial was less clear.

Of the 18 biopsies done, only three of four men who responded to treatment had favorable biopsy results. Crowley attributed those findings to the fact that half of those 18 patients were women, for whom kidney biopsies tend to be inconclusive, and to the difficulty in obtaining adequate samples.

GL-3 levels can be measured in urine samples more readily and much less invasively, he added.

And Crowley said Amigal shouldn't be compared to Fabrazyme given that its molecule is designed to boost a patient's enzymes by correcting protein function rather than simply replacing enzymes with recombinant versions.

"I think where the message has gotten lost is when people have started trying to compare a Phase II study for an entirely different approach to enzyme replacement therapy to a study done for registrational purposes eight years ago," he told BioWorld Today. "It's apples to oranges."

That means Amigal might travel a slightly different regulatory pathway.

"We're looking at all the data, and there are a number of endpoints to choose from," Crowley said. The firm anticipates meeting with the FDA "as soon as we can," to determine protocol for a pivotal study.

Analyst Matthew Osborne, of New York-based Lazard Capital Markets, who maintained a "buy" rating on Amicus, wrote in a research note that the "task ahead for management" may be "to persuade the FDA to adopt urinary GL-3 level reduction as a surrogate endpoint" in the Phase III trials.

A plus for Amicus is that the Phase II study confirmed that the company can use pharmacogenetic screening to determine which Fabry's patients have the missense mutations that respond to Amigal, which increases the likelihood of success.

Moreover, the Amigal results offer "clinical validation of our platform technology," Crowley said.

The pharmacological chaperone technology aims to create small-molecule compounds for treating genetic diseases caused by mutations that lead to less stable, or misfolded, proteins. The compounds are designed to bind to those proteins to help them fold correctly and restore function.

Immediately beyond Amigal, the company has Plicera (isofagomine tartrate), for Gaucher's disease, which is expected to report Phase II data early in 2008. In Phase I development, Amicus has AT2220 (deoxynojirimycin), a small molecule for Pompe disease.

The firm also has plans to test Amigal in combination with Fabrazyme, which could be used to treat patients who can't tolerate Amigal monotherapy, or could be used to make Fabrazyme more stable, Crowley said. "We're going to explore that preclinically in 2008."

All three of those products are partnered with Shire Human Genetic Therapies, of Basingstoke, UK. The companies entered that partnership last month for ex-U.S. development and commercialization.

Terms of the deal included a $50 million up-front payment to Amicus, plus the chance to earn up to $390 million in clinical, regulatory and sales milestones. (See BioWorld Today, Nov. 9, 2007.)

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