A Phase III trial by Amicus Therapeutics Inc., of Cranbury, N.J., and GlaxoSmithKline plc, of London, testing a drug candidate for Fabry disease missed its primary and secondary endpoints.

The study, designated Study 011, was designed to identify the number of patients who showed a 50 percent or greater reduction in kidney interstitial capillary GL-3 after six months of treatment with migalastat HC1 (Amigal) compared to placebo.

At the six-month point, 13 of 32 patients, or 41 percent, had a 50 percent or greater response, compared to only 28 percent in the placebo group. But the difference (p = 0.3) did not achieve statistical significance.

Shares of Amicus (NASDAQ:FOLD) tumbled $2.71, or 47 percent, to close at $3.06 Thursday.

"The confounding factor was that the placebo response was higher than expected," John Crowley, Amicus CEO, told BioWorld Today.

Study 011 randomized 67 patients to receive oral migalastat HCL 150 mg or placebo every other day for a six-month period. Researchers analyzed kidney biopsies from patients at six months, and compared them to baseline using a histological scoring method, the Barisoni Lipid Inclusion Scoring System with Virtual Microscopy.

The secondary analysis of absolute percent change in kidney interstitial capillary GL-3 from baseline showed a median reduction of 41 percent in the migalastat group, compared to 6 percent in the placebo group, but again those data missed statistical significance (p = 0.093).

No drug-related serious adverse events occurred. The rate of treatment-emergent adverse events was 10 percent, with the most common being headache, fatigue, nausea, nasopharyngitis and parasthesia.

Crowley said secondary endpoints from 011 are being analyzed further, and those results will be presented at the Lysosomal Disease Network WORLD Symposium in Orlando, Fla., in February. Those endpoints include urine GL-3 and renal function.

Those data, Crowley said, "capture the very strong signal and direction we're seeing from migalastat, rather than the binary pure responder analysis."

Future events in the trial could shift the outcome in migalastat's favor, as well. After the next six-month point, patients have the option to continue therapy, and placebo patients taking that option will be crossed over to migalastat. "Those will be very important data," Crowley said. "We hope to show trends toward improvement."

Crowley said 57 of 59 patients who had completed a year of treatment volunteered to go on to the open-label extension study. "It speaks at least to patient compliance and tolerability of the medicine," Crowley said.

Fabry disease is an inherited lysosomal storage disorder caused by mutations of alpha-Gal A. That gene codes for alpha-galactosidase A, an enzyme that breaks down lipids within lysosomes, including globotriaosylceramide (GL-3).

When levels of alpha-galactosidase are low, GL-3 accumulates in kidney, heart, central nervous system and skin tissue, leading to effects such as pain, kidney failure and increased risk of heart attack and stroke.

About 5,000 to 10,000 people worldwide suffer from Fabry disease.

Genzyme Corp. markets an enzyme replacement therapy (ERT) for Fabry, Fabrazyme (agalsidase beta). However, Genzyme has struggled with disruptions in production of Fabrazyme. (See BioWorld Today, Oct. 22, 2009.)

Amicus partnered with GSK to develop and commercialize migalastat HC1 in 2010 for a potential $230 million ($60 million up front), and the firms extended their alliance in July. (See BioWorld Today, Nov. 1, 2010, and July 19, 2012.)

As part of the extension of that deal, GSK increased its ownership stake in Amicus to 19.9 percent, investing an additional $18.6 million to purchase 2.95 million shares of common stock at $6.30 per share.

Migalastat is designed to bind to and stabilize, or chaperone, alpha-galactosidase A. In addition to studies of migalastat as a monotherapy, Amicus also is investigating the drug in combination with ERTs in the Phase II trial, Study 013, and a co-formulation of migalastat with JCR Pharmaceutical Co. Ltd.'s ERT, JR-051, is at the preclinical stage.

According to Leerink Swann analyst Joseph Schwartz, the high placebo signal coming out of Study 011 could be due to the high percentage of women in the study. About 60 percent of study participants were women, and women have two copies of the alpha-Gal A gene, one normal and one mutated.

"Random inactivation of one of the two copies in different tissues of the body leads to highly variable disease expression in female patients, even in the same patient depending on the location within the kidney," Schwartz wrote.

Another possible contributor to the unexpected placebo response could be that some patients had low levels of kidney GL-3, which can drop by 50 percent very easily.

Schwartz noted that Amicus has "two more shots on goal for Amigal monotherapy," with 12-month data due for Study 011 in the first half of 2013, and Study 012 data due in 2014.

"We also see other sources of value for the chaperone technology such as combination therapy with enzyme replacement therapy (ERT)," Schwartz wrote.