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

Xconomy Boston — 

John Maraganore opened up an envelope in 1994 that changed his life. Inside were the results of the pivotal study of an anticoagulant drug Maraganore had created in the lab. It was the star prospect for Maraganore’s employer, Biogen. If the drug, bivalirudin, worked, Biogen might have its first product—and Maraganore, the glory of designing it.

The news, however, was bad. Bivalirudin failed the study. Biogen jettisoned the drug altogether, and moved on to become the world’s leader in multiple sclerosis treatments.

And Maraganore, the classic geek scientist obsessed with basic research, would never work at the lab bench again. Instead, Biogen leadership forced him down a new path, one that would transform him into a successful biotech business executive. He would authorize strategic decisions, weigh multi-billion dollar deals, handle the fates of hundreds of employees—and even find a way to bring bivalirudin to market. And ultimately, he would become one of the driving forces behind a new, high-risk, and high-reward, field of science—RNA interference (RNAi)—that aims to “silence” disease-causing genes.

Indeed, 20 years later, Maraganore now is synonymous with RNAi. He’s the CEO of Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY), which has grown from fledgling startup to the biggest RNAi operation in the world.

And soon, another crucial envelope is coming for Maraganore. After burning through more than $600 million of invested dollars and enduring a series of highs and lows, Alnylam is running its first Phase 3 trial, with a drug called patisiran. The drug treats a rare condition that causes proteins to clump up in the body and stifle organs. Successful results will turn Alnylam from an expensive 13-year-long science project into a real revenue-generating pharmaceutical company with many more opportunities—and help validate the whole field of RNAi.

If patisiran fails? The chorus of those who doubt RNAi will grow louder.

“That’s fine,” Maraganore says. “That’s just the price of leading an effort.”

Indeed, Maraganore has never played it safe. He could have followed the path of his father and brother, and become a doctor with a stable income. He chose high-risk research instead. He could’ve stayed at Biogen, or later, Millennium Pharmaceuticals—established, stable drugmakers. Instead, he chose to lead a tiny startup pursuing a new field of science. He could have kept quiet when Novartis backed out of RNAi research earlier this year. Instead, he publicly blasted Big Pharma and criticized its ability to innovate.

Kevin Starr

Kevin Starr

“John is very much not risk-averse. That’s always been his MO as a scientist—he was a very bold scientist,” says Third Rock Ventures partner Kevin Starr, a longtime friend of Maraganore, a colleague at Biogen and Millennium, and a fellow Alnylam boardmember. “Alnylam has survived because he’s looked at it as one of his children and he’s put all that passion in there.”

Still, Maraganore is unfailingly self-effacing. He’s quick to point out his failures (there’s been “tons,” like deals he decided against that burned him down the road) or weaknesses (like running the day-to-day operations of a company). He’ll often point out others who are more qualified than he is to do a job—even if, in potential merger discussions, that may cost him his own. He’ll promote people past him. Starr, for instance, started out as his employee, but became his boss after a promotion Maraganore endorsed. He loves travel and good food, a glass of wine and a cigar, and a game of pool.

“John’s a fun guy,” Starr says, ”[and] he’s been successful by being a giver.”

And by pursuing his passions despite the risks. Maraganore (pronounced mare-a-ga-NOR-ee) was born in 1962 in Chicago, the son of two Greek immigrants and the second of three children. The family started out in a 2-bedroom townhouse in Rogers Park, on the far north side. When Maraganore’s father’s career as a pathologist took off, they were able to move to the upscale suburb of Skokie when Maraganore was about eight years old.

Much was expected of Maraganore and his older brother and younger sister. “We were driven to do important things,” he recalls. If he got an A at school, his parents wanted to know why wasn’t it an A+. Get a B? God forbid. It was tough on Maraganore, because school didn’t come easy to him, as it does for some of those kids that can slack off and ace a test.

“They held you to high standards, and they were hard drivers. It was all around, ‘you need to do better, you need to work harder,’” he says of his parents. “I had to work like a dog. But it did create a real work ethic in me that I have to this day.”

While he sheepishly acknowledges a “Dungeons & Dragons” phase, Maraganore took on all sorts of additional extra-curricular tasks, like the chemistry club, chess club, and yearbook editor. He finished high school near the top of his class.

Maraganore’s father believed that being a doctor meant stability and a good life, and pushed his children towards medicine. The unspoken expectation, according to Maraganore, was that father and sons would open and run a clinic together. His father would bring things home from his lab for his kids, like a microscope that a young Maraganore became obsessed with. “Propaganda,” Maraganore jokes today.

Maraganore also remembers spending summers as an adolescent working in his father’s pathology lab testing patient samples. He learned a lot of lab basics—pipetting, what to do and not to do with blood—and performed radioimmunoassays (tests to measure, say, hormone levels in the blood) and serum chemistry tests.

“[That was] one of the great things about having a pathologist for a father,” Maraganore says. “It was just a great learning experience.”

Maraganore became a certifiable science geek. His favorite class was biology. He volunteered at his high school biology lab, staying late to set up experiments for the next day, or stocking and maintaining the lab’s saltwater fish tank. He’d visit Chicago’s Museum of Science and Industry and speed to the human biology exhibit. He’d collect water samples from different places and bring them to his microscope to look at paramecia or hydras.

“[I’d] look at the microscope, and sort of look at these little tiny organisms and so forth, or a slide and look at cells, and it’s just fascinating, right?” he says. “It’s so beautiful.”

Maraganore’s brother dutifully became a doctor (a neurologist). But Maraganore strayed from the prescribed path. In his sophomore year at the University of Chicago, intending to study medicine, he began doing basic research in a lab under biochemistry professor Bob Heinrikson. He purified and characterized proteins, specifically snake venom enzymes. He recalls being motivated by the idea of exploring things “nobody else in the world was exploring.”

“Just like I enjoyed it when I was a kid, looking at the microscope, I was doing it as an older kid in a basic research lab,” he says. He began to aim for a career as a university scientist.

He sped through grad school, also at the University of Chicago, getting his PhD in biochemistry in just two years, though he claims it was blind “luck” because of 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 an order disguised as a suggestion: take up business development. Vincent was a big proponent of taking young, talented people and rotating them through different areas of biotech—business, strategy, and medicine—to turn them into better general managers. He clearly felt that Maraganore had potential. But Maraganore was dismayed. His heart was in the lab—and he felt ill-suited to trade a lab coat for a suit and tie.

If he wanted to stay at Biogen, though, he had no choice.

“It soon became apparent to me that he wasn’t giving me the option,” he says. “He was like, ‘this is your job if you want to stay here.’”

At first, Maraganore hated it. He’d had no business training. He didn’t think he could make the right judgment calls. But he turned out to be a natural. Within months, “his instincts take over and he becomes one of the best business guys we’ve had in the company,” Starr says.

Maraganore liked how the job was “incredibly linked” to the science, how there were new, different things to learn, and how he could really have a big impact. In retrospect, he says, Vincent’s mandate was an “amazing gift.”

Former Biogen CEO Jim Vincent

Former Biogen CEO and chairman James Vincent

“Like many things in career development, sometimes you have to do something that you’re not happy with or don’t want to do to really learn something new that can help shape you for the future,” he says.

One of Maraganore’s first big tasks—secretly, he says, the thing he cared the most about—was to find a new home for bivalirudin. He went to most every pharma company in the world looking for a deal. They were all skeptical. Why didn’t Biogen want the drug, they asked?

For about two years, no one was even remotely interested. Finally, Maraganore found two venture capitalists, MPM Capital directors Clive Meanwell and Scott Johnson, who were starting up a company called The Medicines Co. (NASDAQ: MDCO) that aimed to buy up drugs from biotech and pharma and develop them. They loved bivalirudin, and bought it in March 1997 for a pittance—$30 million up front, and royalties.

It was a watershed deal for The Medicines Co. The FDA approved bivalirudin in 2000. Now known as Angiomax, it’s been used in more than 5 million people around the world, generates over $500 million annually, and is the core product of a public company worth almost $2 billion to this day.

Maraganore, meanwhile, felt like he’d done his job for Biogen once he’d sold the drug. After a 10-year stint, new science, again, was calling—the early genomics craze started gaining steam. Sequencing technologies were emerging. Biotech companies were looking for novel proteins that could be better Epogens, or G-CSF’s, or interferons. Maraganore was passionate about genomics, but Biogen, he says, was hesitant to commit to a big investment. Mark Levin, then the CEO of Millennium Pharmaceuticals, was vocal about genomics and how it would change medicine. So Maraganore, who’d met Levin through Sato, began having lunch meetings with him. Levin was recruiting him hard, and after bivalirudin was shipped out, Maraganore left Biogen to join him.

The move helped turn Maraganore into a true biotech business executive. He’d spend the next five or so years at Millennium helping to make deals, large (COR Therapeutics, $2 billion) to small (Cambridge Discovery Chemistry, $53 million), to industry-changing (LeukoSite, $635 million). Starr quips even his fashion tastes had expanded from the “J Crew catalog” to items with “a little bit more European influence.” He bought more suits. His personal life took off. He met a new love at a bar in 1999, and married her three years later.

MaranganoreVolleyballStill, the geeky scientist resided underneath. Maraganore was liable to pull up to Jillian’s, a local pub and sports bar in Boston, with a fancy car and a leather bag carrying a custom pool cue. Meeting some buddies like Starr after work, he’d whip a cigar out, put the cue together—and then scratch on the break.

Perhaps the most significant deal Maraganore helped negotiate at Millennium was its buyout of LeukoSite—the deal that turned Millennium into a commercial success. For his part, Maraganore concedes today that this was partly good fortune. Millennium was really interested in LeukoSite for the cancer drug alemtuzumab (Campath) and a second antibody drug. It valued a third drug, PS-341, or bortezomib, “at zero.” The drug had only been tried in a few patients at the time, and was an inhibitor of the proteasome, the cell’s garbage disposal unit—an approach most people thought would be fatal.

“It was a very scary program,” Maraganore says. “As people said back then, it was ‘inconsistent with life’ to [inhibit the proteasome].”

As luck would have it, people were wrong. Bortezomib, now known as Velcade, worked. By inhibiting the proteasome, bortezomib turned out to activate the cell death pathway in some cancer cells. The FDA approved bortezomib in 2003, making it the first proteasome inhibitor ever to market. It’s since become a mainstay treatment for multiple myeloma, bringing in billions of dollars every year. (Millennium later sold Campath, on the other hand, to ILEX Oncology, which was subsequently acquired by Genzyme.) Bortezomib was so successful it ultimately led Japanese pharma giant Takeda to acquire Millennium for $8.8 billion several years later.

Maraganore, however, never witnessed the commercial success of Velcade first-hand. Like many other big names who’ve since gone on to lead other companies or take up other prolific positions in biotech—like Levin, David Schenkein (Genentech, Agios Pharmaceuticals), Julian Adams (Infinity Pharmaceuticals), Alan Crane (Polaris Partners), Nick Leschly (Bluebird Bio), and Starr—Maraganore got a new opportunity off of Velcade’s success. While regulators were considering approving it in 2002, he got a call from Sharp, who had just started a new company with VC firms Atlas Venture, Arch Venture Partners, Polaris, and Cardinal Partners, in an emerging field of science, RNA interference. The company’s name: Alnylam. Sharp wanted Maraganore to come on board as CEO.

Most drugs on the market today are either small molecules or proteins. Around the turn of the century, however, RNAi began to electrify scientists across the globe because it offered, at least theoretically, a way to create a whole new class of drugs that could treat diseases that those other medications couldn’t touch.

The idea: to essentially silence disease-causing genes before they can make the proteins that trigger diseases. The technique—which involves introducing short, synthetic strands of RNA into cells—was first discovered by two U.S. scientists, Andrew Fire and Craig Mello, in 1998, winning them the 2006 Nobel Prize. But a team led by scientist Thomas Tuschl at the Max Planck Institute for Biophysical Chemistry in Germany became the first to publish a peer-reviewed paper in Nature, in 2001, describing how to introduce synthetic RNA molecules into human cells. Other labs around the globe were following fast.

Maraganore talked with Sharp and with Atlas partner and friend Peter Barrett, and met with then Alnylam CEO Christoph Westphal. He became smitten with RNAi. He remembers days driving to and from work at Millennium where his mind would wander, thinking about the opportunity. Could RNAi be the new monoclonal antibody? The new recombinant DNA? Represent a whole new way of discovering medicines?

“That was an opportunity I just could not walk away from,” he says. “How could you say no?”

Of course, that’s the optimistic dreamer’s way of looking at a new biotech idea. The reality is, Millennium was stable, and Alnylam could only offer an uncertain, long, and difficult journey. RNAi was just a science project, and Alnylam was a startup with six employees, some $17.5 million in backing, and a big idea that it would take years to prove. No one had a clear idea how to effectively get large RNAi molecules into the right tissue, without causing dangerous side effects to healthy cells and organs along the way. In all likelihood, the endeavor would fail.

“My view, quite candidly, was that the technology was too early,” Starr says. “I remember telling him that if he is thinking about doing something else, let’s find him another company. There’s got to be something that’s a little bit more established.”

There was no turning back for Maraganore, though. Challenges be damned: he couldn’t shake the potential. He was named Alnylam’s CEO in December 2002, and the gig has been every bit the roller coaster it was anticipated to be. Maraganore, in fact, breaks his tenure down into three phases:

“Rational Exuberance”

At first, the RNAi field, Maraganore says, was the “wild, wild west.” People were scrambling for patents, and Alnylam, aiming to become RNAi’s leader, “believed strongly” that it had to grab all the IP, he says. On his first day on the job, Maraganore flew to Munich to cut a licensing deal with the Max Planck Institute for a group of Tuschl patents—a tough negotiation, he recalls, because Alnylam had to agree to establish operations in Europe, if not Germany, as part of the deal. It did, and later fulfilled that obligation by buying a company called RiboPharma. Alnylam then proceeded to snap up patents out of Stanford University, the U.K., and elsewhere. But it passed on a key set of additional Tuschl patents Max Planck had licensed to UMass, a decision that would cost Alnylam dearly down the road.

Pharma, too, started becoming enticed by RNAi’s potential. Alnylam went public in 2004, and its scientists published a key paper in Nature showing the RNAi approach could silence a specific gene in mice. Alnylam then cut deals with a number of pharmaceutical companies—among them, Roche and Novartis—that sustained it for years. Meanwhile, Merck bought Sirna Therapeutics, the company that owned the UMass patents Alnylam had walked away from, for $1.1 billion in 2006. Pharmas began throwing billions of dollars at the science.

“Despair and Anxiety”

After the early promise, RNAi’s warts began showing up in the latter half of the decade. Effectively delivering an RNAi drug into humans was proving to be difficult. Then in 2007, the global economy tanked. Big Pharma, facing revenue pressure, started making big portfolio cuts. Making matters worse, a prospective RNAi drug for macular degeneration developed by Acuity Pharmaceuticals (and owned by Opko Health) failed miserably in 2009, headlining a series of clinical failures.

RNAi was put on the chopping block. Pfizer and Abbott Laboratories backed out. Merck closed Sirna’s RNAi lab. Novartis chose not to exercise an option to expand its partnership with Alnylam (though it still pursued the 31 target programs it had licensed in their deal). Roche, perhaps RNAi’s biggest pharma benefactor, fled as well, sending shockwaves through the field and marking the end of what was a potentially $1 billion-plus partnership between the two companies. Roche’s decision stunned Maraganore, who found out via a phone call the night before.

Maraganore says today that he should’ve seen Pharma’s systematic exit coming, and the Roche news in particular. Roche R&D chief Lee Babiss, who led the Alnylam deal, had left the company in 2010, leaving Alnylam without support within the big Swiss company. “We know that in the Roche boardroom they referred to the RNAi investment as Lee’s folly,” Maraganore says.

These were dark days for Alnylam. The company cut up to 30 percent of its workforce in October 2010, and its shares bottomed out at around $6 apiece (just north of its $6 IPO price) some two years later. Investor meetings were sparsely attended. Many abandoned Alnylam. A legal tussle with Tekmira Pharmaceuticals (NASDAQ: TKMR) clouded the company’s future. The prevailing sentiment was that Pharma had lost faith in RNAi, that it couldn’t be used as broadly as once hoped, if at all. A decade in, the field hadn’t yet hadn’t produced an FDA-approved drug.

Maraganore contends, however, that much of the doom and gloom was a media-driven narrative, and that the science was still advancing. Lucky for Alnylam, it had a huge pile of cash—more than $300 million—to fall back on during the tough times. Maraganore had a chance to be proven right.

“We can make drugs out of RNAi.”

Alnylam, and the rest of the RNAi field, began to turn the corner a couple years ago. To solve the problem of delivering the large RNAi molecules to cells, scientists began focusing on the liver, a large organ that can absorb the big molecules from the blood. Alnylam tailored its approach exclusively to the liver, and identified a group of orphan diseases, like Transthyretin (TTR)-Mediated Amyloidosis, that could make for quicker development paths (and can be marketed by smaller sales forces). The strategic shift led, finally, to real data. Alnylam successfully completed a Phase 1 study of patisiran in TTR in 2012. Those results, combined with a successful Phase 1 of a cholesterol-reducing drug it’s developing with The Medicines Co., helped Alnylam’s stock rally from the depths, climbing to around $20 per share late in the year (it’s now worth more than three times that amount).

Alnylam then parlayed that success into additional industry support. It inked a small deal with Genzyme on its TTR program, adding to the partnership with Maraganore’s old friends at The Medicines Co. It started showing signs it might be able to deliver RNAi drugs subcutaneously (rather than through an IV infusion), and added candidates for hemophilia, hepatitis B, and other diseases to its portfolio.

Alnylam’s biggest business breakthrough came in early 2014, when it turned its deal with Genzyme into a major partnership covering several drugs. Genzyme bought a 12 percent stake in Alnylam at a whopping $80 per share. And Alnylam turned around and bought Merck’s Sirna operations—and the IP it could’ve had a decade ago for $5 million—for $175 million.

In the meantime, other companies developing RNA-based drugs, via different methods, made clinical progress. Isis Pharmaceuticals (NASDAQ: ISIS), which uses antisense technology, won FDA approval of an RNA drug in January 2013. A small study from Sarepta Therapeutics (NASDAQ: SRPT) showed that an RNA-based “exon skipping” drug might help treat Duchenne Muscular Dystrophy. Other RNAi companies, like Dicerna Pharmaceuticals (NASDAQ: DRNA) and Arrowhead Research (NASDAQ: ARWR), using different technologies and delivery systems, went public. RNAi firms raised more than $1 billion during the first four-plus months of 2014, Nature recently wrote.

Maraganore speaking at an Xconomy event in April

Maraganore speaking at an Xconomy event in April

Still, the progress has been accompanied by more setbacks. In April, for instance, Novartis threw in the towel on RNAi, citing its “narrow” range of “medically relevant targets.” Shares of RNAi companies took a hit, and skepticism and a whole new discussion of the field’s potential ensued.

“It’s been the classic up and down of a new technology,” Maraganore says. The smooth-talking CEO who’s battled over a decade to validate new science rushed to defend it—and lashed out against its critics. Pharma is “terrible at innovation,” he said at an Xconomy forum on biotechnology held shortly after Novartis’s announcement, raising eyebrows across the industry.

Yet in a few years, a crucial day of reckoning—and another fateful envelope—lies ahead for Maraganore and RNAi. In November, Alnylam began its first Phase 3 study, an 18-month trial of patisiran in patients with TTR. Results are expected in 2017. When the time comes, Maraganore will no doubt have some flashbacks to that tense moment in Kendall Square 20 years ago. But even with the risks, he wouldn’t have it any other way.

“I can’t imagine a more exciting endeavor to be involved with,” Maraganore says. “I pinch myself twice every morning. Once when I get up, put my feet down on the ground, and look across the bed at my lovely wife. And the second time is when I’m going into work.”

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  • Bill Massey

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