Editor

Amicus Therapeutics Inc.'s Phase III trials that started last week with Amigal (migalastat) for Fabry disease include three arms, but none comparing the drug's clinical benefit with that of the approved (and strong-selling) Fabrazyme, from Genzyme Corp.

That's partly because clinical benefit has not been established for Fabrazyme (agalsidase beta) itself. The enzyme-replacement therapy was cleared by the FDA more than nine years ago based on data from trials that used a surrogate endpoint. "That plays into the FDA's perspective on our drug," said Matthew R. Patterson, chief operating officer for Cranbury, N.J.-based Amicus. (See BioWorld Today, June 26, 2000.)

Trying to show benefit, Genzyme later conducted a Phase IV trial that missed statistical significance in a composite endpoint that included renal function as well as cardiac and neurological events.

When Fabrazyme won accelerated approval in 2003, Genzyme already had started the Phase IV trial, which enrolled 90 patients given drug vs. placebo on a 2-1 basis, said Edward Kaye, group vice president of clinical research.

"One of the things that did appear to be significant was an effect on kidney function," Kaye told BioWorld Insight. "We didn't really have enough strokes or cardiac symptoms to be able to say anything [about those]. It really came down to a statistical question in regards to stratification" of the kidney findings, he said.

Proteinuria is known to be a particularly bad prognostic indicator in treating Fabrazyme, but Cambridge, Mass.-based Genzyme did not include the condition as a pre-specified outcome measure. "Frankly, it was a mistake on our part," Kaye said, calling the left-out piece an oversight. The FDA refused to accept the Phase IV study as a verifier for full approval, though information from the trial was allowed on Fabrazyme's label.

Even without statistical significance, the proteinuria findings taught researchers more about how Fabrazyme works. "The patients without significant proteinuria had a better response - we learned that [those] with not as severe disease responded better," Kaye said.

A 20-year registry study is ongoing. "We make that commitment for all of our products," Kaye said. "You can't learn everything that's required in a Phase III or Phase IV trial." Fabry, he pointed out, is a "chronic disease that begins in the womb and carries on for the lifetime of a patient. It takes a long time to demonstrate obvious clinical benefit."

Some may be surprised to know that Fabrazyme, which sold $494 million last year (up 14 percent from 2007), has yet to gain its stripes, just as some were probably surprised to see the FDA not insist on multi-year trials for Amigal, Amicus' pharmacologic-chaperone therapy, which will start a 60-patient, six-month trial later this year.

A few probably were surprised that Amigal - shooting for the same surrogate endpoint as Fabrazyme - made it to Phase III at all, said John F. Crowley, president and CEO of Amicus. The latest news "substantially mitigates the regulatory risk that people have put out there," Crowley said, especially so since the FDA has given its blessing to the design.

Amigal, dosed orally, will be given at 150 mg every other day, and the 30-site trial's primary endpoint will be the change in the amount of interstitial capillary G globotriaosylceramide (GL-3, the substrate that accumulates in Fabry patients' kidneys) measured in biopsies.

In lysosomal storage disorders, chaperones are intended to improve on what's available not only by being oral, but also by lower cost of goods sold and efficacy in the central nervous system, where large-molecule proteins are not appropriate.

Chaperones provide folding templates for proteins that may have been skewed by coding mutations, and refolding along the template's lines could restore enzyme function, thus clearing the substrate in cells that cause disease.

Outside the U.S., Fabrazyme goes up against Replagal (agalsidase alfa) from Shire plc, of Basingstoke, UK - Amicus' licensor for Amigal and other candidates for LSDs. (See BioWorld Today, Nov. 9, 2007.)

To get approval for Amigal in Europe, Amicus will test the drug against Fabrazyme (which has full approval there), Crowley told BioWorld Insight. Meanwhile, 23 of 26 patients who took part in the Phase II study in the U.S. have chosen to continue an extension study, where all of them remained in late June. Amigal has been given for 50 patient-years without a serious adverse event, Crowley said.

Laura Barisoni, assistant professor in pathology and medicine at the New York University School of Medicine, called "very encouraging" the analysis of Prochymal's Phase II data using the same, more refined histology that the Phase III trial will deploy. Crowley cited a "big advancement over the last 10 years in [measuring] renal pathology." Barisoni was among the experts on the advisory panel that evaluated Fabrazyme.

"I think we're going to be in a very good spot," Crowley said.