the treatment altogether, lost a partnership deal with Shire, and cut 20 percent of its workforce to save cash.
Crowley and Amicus’ scientists still thought the general approach was sound, however. To this day, Crowley contends, for instance, that the company had the right drug, just the wrong dose—and given the rough financing environment at the time, Amicus didn’t have the bandwidth to run more dosing studies and try to fix the problem. So the company dumped afegostat tartrate and turned its attention, and hopes, to migalastat, its candidate for Fabry, which afflicts about 1 in every 117,000 people and has very few treatment options.
First tested in human beings in 2005, the drug got Amicus encouraged because a Phase 1 study in healthy volunteers didn’t just demonstrate safety—it also spiked their levels of the alpha-galactosidase enzyme, the one that Fabry patients lack. That meant the drug appeared to be hitting its target in humans, not just animals, Crowley says.
Before the company could get to pivotal trials in Fabry patients, though, it had to answer two vital questions: Scientists had learned chaperone drugs like migalastat and afegostat tartrate could actually make the disease worse at the wrong dose. So what was the right dose? And with about 800 different known Fabry-triggering genetic mutations, which patients had the best chances of responding to the drug?
It took four years of hard work and several Phase 2 studies to find the right dose (150 mg every other day) and to develop an assay to identify the potential responders.
“It was a long journey to even get to Phase 3,” Crowley says.
At the time, the journey seemed especially promising. With the dosing work done, migalastat seemed a safer bet than the ill-fated Gaucher drug. And the mid-stage results showed some indications that migalastat was being well tolerated while helping patients maintain kidney function—good enough for GlaxoSmithKline to license the drug and take a 19.9 percent stake in Amicus. It was the second time a pharmaceutical company had taken a shot on migalastat, which was part of Amicus’s 2007 deal with Shire. Still, Wall Street was skeptical. Shares only traded around $4 apiece at the time, and the new partnership didn’t really move the needle. More proof was needed.
Unfortunately, neither company knew then just how hard that evidence would be to obtain.
Regulators in the U.S. and Europe gave Amicus two different regulatory approval paths. One of the two existing Fabry ERTs, Shire’s Replagal, wasn’t approved for sale in the U.S. The other, Fabrazyme, was only conditionally approved in the U.S. So the FDA advised Amicus that it didn’t have to compare migalastat to those biologic drugs in a Phase 3 study in the U.S. A placebo-controlled trial was sufficient instead.
Europe was a different story, however, because both drugs had been prescribed to Fabry patients there for more than a decade. Amicus’ European trial needed to compare the two approaches.
So Amicus launched two different Phase 3 trials, one in the U.S. in 2009 with 67 patients, and one in Europe two years later with 60, each planned to continue for one to two years.
News from the U.S. study came first, in December 2012, and it wasn’t good. The clinical goal over the first 6 months was to reduce by 50 percent the amount of the fatty substance (GL-3) that builds up in the kidney cells of Fabry patients.
Just under half (41 percent) of the patients getting migalastat for six months hit the target reduction. Not great, but not bad either. The really bad news was that 28 percent of patients who only got the placebo saw their GL-3 levels plummet too. As a result, the difference between the two treatment and control groups wasn’t statistically significant.
The results were a nasty shock. “There’s absolutely no way that taking a dummy placebo pill is going to have a positive biochemical effect on GL-3 levels in the kidney,” Crowley says. “It didn’t jive with the Phase 2 results, and it didn’t make sense in terms of our understanding of the disease or these endpoints.” But the bottom line, as Amicus was forced to acknowledge in its press release, was that the trial had failed to prove a benefit for the drug.
“Of course the stock gets hammered and everyone says ‘oh my god I told you so, the drug isn’t working,’” Crowley says.
Amicus shares plummeted 55 percent. The company continued both trials, hoping for better results, but investors were dubious. Amicus hasn’t closed higher than $5 per share since December 2012, and for much of that time hasn’t been worth a whole lot more than its own cash. Crowley admits Amicus thought long and hard about
