Standing on a Ledge Once Again, Amicus Holds Breath for Latest Study

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dumping the program, especially after GSK—which had been covering 75 percent of the drug’s development costs—decided to take a more “passive” role in rare disease drug development. GSK was burned by Amicus’ December 2012 failure, and then by a high-profile Phase 3 flop of a Duchenne Muscular Dystrophy drug it was developing with Prosensa (NASDAQ: RNA) in September.

“That was really the tipping point for GSK to say we’re really better situated to make passive investments in the rare disease field,” Crowley says.

The mood at Amicus was grim. Crowley admits to losing some good employees “almost every week because of the uncertainty.” Instead of shutting down the migalastat effort, though, Crowley recommended at a board meeting in the fall of 2013 to “double down” on the drug.

“GSK was a great partner and we learned a lot through that partnership—in a couple of years, they made the program better,” Crowley says. “But I think now to take [migalastat] over the finish line, it takes a more entrepreneurial culture, and a more nimble environment.”

Crowley embarked on a series of deals to provide the company with enough cash to make it work without GSK. Crowley recalls three different teams of lawyers working in different conference rooms simultaneously on three separate deals. In one of the deals, Amicus restructured its arrangement with GSK, taking back worldwide rights to migalastat and a “next-generation” preclinical ERT for Fabry, and inheriting all of the risk and development costs that come with them. (GSK bought 1.5 million more shares of Amicus at $2 apiece as part of the deal, and still holds a roughly 20 percent stake). In the other deals, Amicus raised equity and debt financing, chopped 14 percent of its workforce, and even acquired a small, privately-held company called Callidus Biopharma with a preclinical ERT for Pompe—if nothing else, giving Amicus some more options to fall back on in case of continued disaster.

Amicus also dug deep into the data from the failed trial to figure out what had gone wrong. It found that some patients, those with certain specific genetic mutations, were responding better than those that didn’t have those particular mutations. So Amicus went to the FDA in 2013 to plead that it be allowed to change the clinical goals. Instead of having to prove that all the treated patients in the trial had significant reductions in GL-3, it only had to show that those with “amenable mutations” (about 30 to 50 percent of the Fabry population) got a benefit.

It wasn’t an easy case to make. Such changes always get sideways looks from investors and come across as post-failure data-mining. But Crowley swears his company “wasn’t cherry-picking,” that Amicus’s understanding of Fabry has “evolved” over the course of the trial, and the study’s revision was a reflection of that.

“It wasn’t as if we went back, found the one endpoint that looked good, and said well we’re going to hit this one again and declare victory,” he says.

The FDA was only partly convinced. While the agency ruled that the discouraging 6-month results couldn’t be adjusted, it allowed Amicus to change the goal for the rest of the U.S. trial. Still, it said that both the U.S. trial and the European trial were now part of the data package Amicus would have to submit—something it hadn’t required before. That meant that Amicus has to be right about how it measures the results, and must put up aces in two separate trials.

So far the gamble is paying off. After a long wait, Amicus finally got some good news on April 29. Using the new clinical goals, patients who had been on placebo for the first six months and then were switched to migalastat for the next 6 months had a statistically significant reduction in GL-3. Moreover, those who had been on the drug for 12 months had a “durable reduction” in the fatty substance. More important, these patients “generally maintained their kidney function” after 18 and 24 months of treatment, Crowley says. Shares jumped over 25 percent on the news.

But whether or not this long journey will end in triumph or another setback will depend on the results from the European study. It was more complicated to set up than the U.S. study. Amicus had to convince doctors to take patients already on an approved drug off of their treatment, and switch to an experimental drug. Nonetheless, that’s what happened. 36 people switched to, and are being compared to 24 staying on ERT. The goal is to show that migalastat is at least as effective as the enzyme replacement therapy, as measured by its ability to slow the decline of patients’ kidney function.

“Fingers crossed on the results, but this will really be where the proof is in the pudding,” Crowley says.

After a decade of work and a roller coaster of ups and downs, Amicus will soon know if the sweat, and its gamble to move on without the help of GSK, were worth it.

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