John Maraganore: From “Prototypical Geek” To Canny Alnylam Chief

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some musical chairs going on among the faculty. Heinrikson, Maraganore’s thesis advisor, was moving to the Upjohn Company, opening up a lab the school’s thesis committee wanted to use—but couldn’t until Maraganore and another grad student were finished with their experiments. As a result, the committee was “incredibly motivated” to approve Maraganore’s thesis, he says. He was just 24 years old.

His rapid path to a PhD didn’t make his father happy, though. “He was very disappointed about it, like, ‘what are you going to do with your life? What do you do with a PhD? How will you ever make a living? How will you have a family? He was, like, ‘you’re going to become a taxi driver,’” he says.

Maraganore never had to drive a cab. While finishing his thesis, he started doing some postdoc work for Heinrikson at Upjohn in Kalamazoo, MI. Biotechnology was just beginning to emerge. Upjohn, like many other pharmas, was dabbling, and brought in Heinrikson and a bunch of others to do some research. Maraganore tagged along as a postdoc in 1986 and was awed. In academia, he’d become an expert in one specific, tiny area of research, and the goal was to publish papers. In the emerging biotechnology industry, there were a slew of broader and new approaches—and he could make a real impact on people’s lives.

The old Seattle City Light Steam Plant, the headquarters of ZymoGenetics

The old Seattle City Light Steam Plant, the headquarters of ZymoGenetics

Maraganore began working his way up through industry, hopping cross-country in the process. After applying to places like Schering-Plough and Biogen, he landed a senior scientist gig at ZymoGenetics in Seattle, then a pioneer in recombinant DNA work. Maraganore stayed for only nine or 10 months, however, before heading to the Boston area to Biogen (Maraganore says his then-wife, whom he had met in college, hated living out west).

Biogen, which merged with San Diego-based Idec Pharmaceuticals in 2003, is Big Biotech these days, with an $81 billion market cap. But back then, it was just another high-risk biotech startup. The company was losing $24 million a year—typical for a biotech now, but “unheard of” a few decades ago, according to Maraganore. He remembers asking Bruce Carter—who would eventually become ZymoGenetics’ CEO years later—whether he should move. Carter was skeptical Biogen would even survive.

“Bruce is like. ‘John, you’d be crazy to go there,’” he recalls. “Good luck to you, but it’s a huge mistake.”

It wasn’t. Maraganore started at Biogen in Kendall Square on April Fools day in 1987, and spent a decade there, working under what became a who’s who of biotech names—like the late Biogen CEO James Vincent, Nobel laureate Phil Sharp, and then Biogen research head Vicki Sato. He also forged key relationships, like one with Starr, then an up and comer who was doing financial planning and analysis for Biogen, and began undergoing a personal and career transformation.

“John was the prototypical geeky scientist at the bench,” Starr says. “He communicated that way, he looked the part, he was very studious, not entirely comfortable in crowds. He would wear those tan khaki pants or jeans and he’d have cowboy boots on and the hem of the pants was probably four or five inches from the top of his instep—pulled up way high—and he would have his shirt tucked in with his belt probably around midway up his chest. He was not the smooth John that you would picture today. He was literally focused on everything he was doing in the lab.”

It was heady days for biotech. Interferon, human growth hormone, and insulin were getting approved by the FDA, and the possibilities for recombinant DNA and engineered antibodies seemed huge. Searching for its first viable product, Biogen was working on things like recombinant GM-CSF, a product now used to boost low white blood cell counts; and a protein called lipocortin, which, Maraganore says, “turned out to be nothing.” Maraganore and about 200 other scientists worked on these projects. But he made a bigger name for himself with the work he did on the side.

Biogen encouraged its scientists to use 20 percent of their time to “do something innovative,” outside of their assigned projects. Maraganore went overboard, spending hours after work and on the weekends in the lab kicking around ideas. The extra effort “probably didn’t help so much” with his personal life, Maraganore concedes. He was divorced from his first wife in 1991.

Still, that work paid off for Maraganore significantly career-wise. One of his ideas was trying to make a smaller version of hirudin, a protein found in the saliva of leeches, so that it was less likely to provoke a response from the immune system. Such a molecule had the potential to be a potent anticoagulant drug like the market leaders, heparin and warfarin. He and his colleagues spent hours designing peptide fragments of hirudin, synthesizing them, evaluating them, and then measuring how they’d impact thrombin, an enzyme that helps clot the blood. They ultimately came up with a 20 amino acid peptide called bivalirudin that looked like an incredibly potent inhibitor of thrombin. “It was just like, ‘wow, we did it,’” Maraganore says. “It was an incredibly exciting moment in my life.”

Maraganore presented his findings to Biogen’s scientific advisory board and received a standing ovation. A patent was filed in 1989, and Biogen got the drug into the clinic in 18 months. The molecule did what it was designed to, inhibiting clotting in humans.

Maraganore’s drug became the star prospect in Biogen’s portfolio—ahead of a recombinant beta interferon drug called Avonex. An immune system modulator, Avonex was initially seen as a risky drug that might help a fraction of patients with hepatitis C.

“Literally everybody within the company was convinced that Avonex would not work, and that [bivalirudin] would be Biogen’s savior, and be the first drug that Biogen ultimately commercialized,” Maraganore says.

They were wrong on both counts. Avonex began showing early clinical promise—inklings, Starr says, that it might be useful in treating multiple sclerosis. Meanwhile, Maraganore was leading a major double-blind trial comparing the anticlotting ability of bivalirudin to that of heparin in 4,675 patients who had gotten angioplasties.

In the fall of 1994, Maraganore was given the fateful news with the results of the study. It was an “incredibly tense” moment for Maraganore, but he was eager to find out. Once he scanned the data, though, he was crushed. He took a long walk around Kendall Square to digest it, he says.

The data showed that bivalirudin was a little safer than heparin—it cut patients’ propensity to bleed excessively during surgery. But it wasn’t more effective than heparin—the primary endpoint of the trial—and that was a big problem because Biogen had been hoping to price it much higher than heparin, a generic drug.

Bivalirudin wasn’t done as a drug, Biogen concluded. But getting enough data needed to win approval could require another big and costly cardiovascular trial, and even then the outcome might be uncertain. The company couldn’t afford to continue on with both Avonex and bivalirudin. Company executives decided that Avonex was more promising—and decided to try to license bivalirudin to someone else.

It was a good choice. Avonex would go on to fuel Biogen’s rise to prominence. Today the company brings in around $7 billion annually, largely from its multiple sclerosis drugs.

But the decision to leave bivalirudin behind “was pretty devastating,” Maraganore recalls. “It’s like your child, and like saying we’re going to stop working on your child. In hindsight, I wish we’d held onto it. I should’ve fought harder to keep it as an active program. But I thought it was the right business decision. [And] Jim Vincent was pretty resolute on stopping it, so it probably would’ve been a career-ending move at Biogen if I pushed it.”

The decision was also the turning point in Maraganore’s career. After it was made, Vincent called Maraganore into his office with … Next Page »

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One response to “John Maraganore: From “Prototypical Geek” To Canny Alnylam Chief”

  1. Bill Massey says:

    John is the real deal. A humble, bright visionary. Proud to know him.