Amicus Counts on “Chaperone” Tech to Enhance Rare Disease Treatments

Xconomy New York — 

On Thursday, Amicus Therapeutics CEO John Crowley will join the long procession of biotech executives making presentations at one of the industry’s most important gatherings, the JP Morgan Healthcare Conference in San Francisco. But Crowley does have one claim to fame that makes him stand out from the crowd: He’s the only biotech CEO whose early career was portrayed in a glitzy Hollywood movie. And that film, Extraordinary Measures starring Harrison Ford, focused on one of the illnesses Amicus is tackling—Pompe disease, an enzyme-related muscle disorder that two of Crowley’s three children have. “That’s what got me into the biotech field,” Crowley (pictured at right) told Xconomy a few weeks before the JP Morgan event.

Like the others speaking at the event, Crowley will have a short 25 minutes to make his pitch to investors, Wall Street analysts, and fellow executives. His goal, in brief, is to build confidence in the company’s pipeline, which includes a drug that Amicus is testing in combination with alglucosidase alfa (Myozyme)—the Genzyme treatment for Pompe that Crowley famously helped develop and that his own children take.

Amicus’ investors will surely be looking for signs of hope. Shares of Amicus (NASDAQ: FOLD), which is based in Cranbury, NJ, dropped 43 percent to $3.44 in the nine months ended December 30. That was a time filled with “some measure of instability,” Crowley says, primarily because it took longer than expected for Amicus to enroll patients in a key clinical trial of a drug it’s developing for a second rare disease, called Fabry.

Before we delve into Amicus, though, let’s briefly review the Hollywood-worthy events leading up to Crowley’s tenure there. In 2000, Crowley, a Harvard-trained MBA, left a management position at New York-based Bristol-Myers Squibb to help start Novazyme, an Oklahoma City-based company founded by a scientist working on a Pompe treatment. They sold Novazyme to Cambridge, MA-based Genzyme in 2001 for $137.5 million and Crowley became chief of Genzyme’s Pompe program. (If you’re not impressed yet, consider that Crowley is also a graduate of Notre Dame law school and a commissioned officer in the U.S. Navy Reserve.)

Genzyme won approval for alglucosidase alfa in 2006. Crowley’s children, Meghan and Patrick, who were put on the drug in 2003 as part of a clinical trial, are still on it and doing well in the 9th and 8th grades, respectively, Crowley says. His family’s experience inspired a Wall Street Journal story, and later, a book called The Cure. Then Harrison Ford optioned the rights to the story, which led to the movie, starring Brendan Fraser as Crowley and Ford as a prickly (and fictional) scientist who worked on an enzyme treatment for Pompe.

What attracted Crowley to Amicus was the opportunity to make Genzyme’s treatment for Pompe—and drugs for related disorders—even more effective. Pompe and Fabry are among about 50 inherited, often fatal disorders that occur when the enzyme-making machinery in the body’s cells malfunction, causing them to make too little of a particular enzyme, or to make a “misfolded,” or unstable, version of it. Genzyme’s treatment is one of a number of enzyme replacement therapies designed to fix those deficiencies.

Amicus was founded in 2002 on a technology developed at Mount Sinai Medical School in New York. The technology yields small molecules that attach themselves to the defective enzymes, stabilize them, then transport them to the part of the cell where they need to go in order tobreak down the harmful substances that cause symptoms of Pompe and related diseases. “Our drugs promote stability and enable the patients’ own enzyme to fold in the right configuration,” Crowley explains.

Crowley—who left Genzyme in 2002 and went to work with the Princeton, NJ-based venture group Domain Associates—was recruited as CEO, and employee No. 6 of Amicus in January 2005. The company had been founded by Stamford, CT-based venture capital firm CHL Medical Partners, and it was housed in a science incubator in northern New Jersey. Amicus raised $170 million in venture capital and went public in May 2007.

Amicus’ lead compound, AT1001, is in late-stage trials to treat Fabry disease, an enzyme disorder that results in an abnormal build-up of fatty substances in cells. Amicus is testing it alone and in combination with agalsidase (Fabrazyme), another Genzyme treatment. On January 6, the company announced that the combination performed well in a Phase 2 study, with patients showing as much as four times more active enzyme as patients who took enzyme-replacement alone.

Testing the combination is important, Crowley says, because a large subset of patients don’t make any of their own enzyme, and therefore there is nothing for Amicus’ drug to chaperone. In those cases, AT1001 should bind to Genzyme’s enzyme-replacement product, making it more potent, potentially at a lower dose than what patients would normally get, Crowley says. “We know in animals at reduced doses we can significantly enhance enzyme activity,” he says. More details about the clinical trial will be discussed at the Lysosomal Disease Network World Symposium in February.

In October 2010, GlaxoSmithKline licensed AT1001, giving Amicus a $30 million up-front payment and the potential to earn $170 million in milestone payments. GSK also took a nearly 20 percent ownership stake in Amicus for $31 million. Crowley says GSK was one of three pharma companies vying for the molecule, all of whom offered almost identical financial terms. But GSK was the right cultural match, he says. “GSK’s vision is to become one of the leading companies in rare diseases,” he says. “And they did the deepest diligence. They came in here for weeks on end with about 20 people, tearing through our patents and our manufacturing processes. They came back with a lot of ideas about how to make the program better.”

Amicus’ second drug is its Pompe product, AT2220. Initially, Amicus was studying the drug as a monotherapy, but there was a problem: It had to be given in such high doses that patients experienced side effects like fatigue. In March 2009, the FDA put a “clinical hold” on AT2220, essentially killing the program. So Amicus’ scientists began looking at the drug in combination with Genzyme’s Pompe treatment. In early 2011, Amicus presented data to the FDA, along with a plan to develop a combination treatment. The agency removed the clinical hold in March of 2011. Amicus started a Phase 2 study late last year and plans to report preliminary results in the first half of this year.

That’s just one of the milestones Crowley expects to reach this year. “What I hope for 2012 is to be able to deliver data in multiple different programs,” he says. Amicus is also testing a drug for Gaucher disease, another enzyme disorder. At JP Morgan, Crowley plans to discuss that program, as well as Amicus’ early-stage molecule for Parkinson’s disease, which addresses a subset of patients who also carry the Gaucher gene. The link between the two diseases has only recently been discovered, Crowley says, and is still not fully understood. “We think we’re a couple of years ahead of everyone else at developing a toolset to intervene there,” he says.

Leerink Swann analyst Joseph Schwartz believes Amicus’ recent progress bodes well for its technology platform. Schwarz discussed the Fabry data with a doctor specializing in rare diseases, who surmised that Amicus’ chaperone molecule may increase the efficacy of enzyme replacement, lessen the risks, and allow clinicians to give it in lower doses to patients with Fabry. “He believes the benefit may be of even greater value in Pompe,” Schwartz wrote in a Jan. 9 report. Schwartz has a $9 target on the share price, which has risen a bit since the start of the year to $3.72.

Crowley hopes Amicus’ technology can be applied across a range of rare diseases, but he’s not shy about admitting that combating Pompe remains one of his biggest goals. Crowley’s office in Amicus’ suburban New Jersey headquarters is filled with reminders of his family’s moment in the show-biz spotlight. There are photos of Meghan and Patrick with the kids who played them in the movie, and photos of Ford visiting Amicus’ office, so he could observe what real scientists do, Crowley says. Even though Crowley’s children are doing well, it’s conceivable they could benefit from AT2220 if it makes it to market, he says. “There are a lot of things enzyme replacement can do, but there are a lot of limitations,” he says. “I’m hopeful these drugs will make a difference.”

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