How a Little Serendipity Led Acceleron to a Crippling Blood Disease

7/17/14Follow @benthefidler

How maddening is drug development? Sometimes, all the scientific literature in the world leads you one way, and your own data take you another. That’s why even experienced drug hunters often need a little luck to succeed. Just ask longtime industry veteran John Knopf, who had no idea his Cambridge, MA-based Acceleron Pharma, would end up battling a gene therapy company to be first to market with an approved treatment for a devastating blood disorder called beta-thalassemia.

Indeed, Acceleron (NASDAQ: XLRN) started with a protein that theory suggested would be harmful to bone density. Surprisingly, the company found it did the opposite, and actually boosted blood levels to boot—so much so that it took awhile for Acceleron to figure out what disease to target with it. But the protein, called sotatercept, turned out to be just right for beta-thalassemia—a genetic disease that often leaves patients needing monthly transfusions and iron chelation therapy to survive the anemia they face. The drug is part of a big partnership with Summit, NJ-based Celgene (NASDAQ: CELG), was the centerpiece of a $96.7 million IPO Acceleron pulled off last year, and could head to the Phase 3 proving ground early next year with the chance to become the company’s first approved drug—if all goes well in clinical trials, of course.

“It’s just tremendous the way things have evolved, “ Knopf says. “We got lucky in a few spots.”

Significant hurdles are still on the horizon, among them a possible big commercial challenge from Cambridge-based Bluebird Bio (NASDAQ: BLUE)—which is developing a gene therapy for beta-thalassemia that produced some intriguing results in a very small study a month ago. But Acceleron will sign for that, given it wasn’t too long ago the company didn’t know what to do with sotatercept.

This tale of serendipity begins ten years ago, when Knopf was at the Genetics Institute—one of the early high-fliers in biotech. GI was bought out by American Home Products (later renamed Wyeth) for $1.25 billion in 1996, and Knopf, who started out there as a molecular biologist, left in 2003 when the two companies were later being merged together (“it really wasn’t something that I was cut out for,” he says).

Thinking of what to do next, Knopf brainstormed with GI founders Tom Maniatis and Mark Ptashne, and decided to form a company, Acceleron, around research into a group of proteins called the TGF-beta superfamily. These proteins help regulate the growth and differentiation of cells. Despite decades of research in the field, Knopf says there still were a lot of unknowns about the TGF-beta proteins. That meant there was plenty of room for Acceleron to snag some intellectual property and make something out of it.

The approach Knopf, one of many veterans of GI to lead new companies, took was broad. He brought in IP from a wide range of sources—from the Ludwig Institute for Cancer Research in New York, the Karolinska Institute in Sweden, and the University of South Florida, among other places—covering the receptors in this family of proteins and the antibodies directed at those receptors. Still, Knopf did so “without a clear idea precisely of what each of them would be used for,” he recalls.

Acceleron Pharma CEO John Knopf

Acceleron Pharma CEO John Knopf

“Our idea was this is a rich area with molecules that were known, at least from the developmental biology side, to have a dramatic effects on different tissues,” he says. “We felt that by gathering up all this IP and really understanding it better than anyone else, we’d be well positioned to capitalize on the low-hanging fruit.”

Investors agreed there was great potential. Acceleron became one of the more well-capitalized and larger privately-held biotechs in Boston over the past decade. It raised more than $140 million from industry partners and venture firms like Polaris Partners, OrbiMed Advisors, Flagship Ventures and others, and amassed a large, 150+ person workforce, bucking the trend towards virtual biotech companies.

Finding actual drugs in all that IP, however, proved to be a much tougher challenge. One of Acceleron’s earliest creations was a candidate now known as sotatercept. It’s is a genetically engineered protein that blocks a receptor on cells called activin receptor type IIa. The scientific literature, to that point, had indicated that in studies of isolated cells, activin appeared to help … Next Page »

Ben Fidler is Xconomy's Deputy Biotechnology Editor. You can e-mail him at Follow @benthefidler

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