The Antidote: Inside the World of New Pharma Page 16
The factual turning point was one slide. At the end of two weeks, patients receiving 750 milligrams every eight hours had a median drop in HCV RNA of more than 4 log—a 25,000-fold reduction in viral levels. The compound drove the virus down hard and fast, and then kept it down; the viral load in some patients was below the detectable limits of the most sensitive assays. BILN-2061 had been given for only forty-eight hours, after which viral levels rose, but this was the first demonstration anywhere of, as Kauffman says, “a really potent antiviral agent that could make viral loads just go down, amazingly and dramatically.” Hartmann, the most experienced drugmaker in the room, said the last time he’d seen a result as profound was with Novartis’s revolutionary cancer treatment Gleevec.
Boger could see the way ahead, and it was both daunting and massively expensive. Most often clinical results have to be subjected to statistical analysis to determine incremental value, but the effect of data like this was deep and visceral. He instantly reordered the company’s priorities around the slide’s swooping silhouette, which was dubbed, for its steep dive and hockey-stick leadout, the “Vertex swoosh.”
“Up until we saw that, that wasn’t the number one program,” Boger recalls. “We were still trying to keep pralnacasan alive. It was our other HCV program which was going to lead. As soon we saw the swoosh, it took over, since then you knew you were on the fast track. You knew you had all that work to do, and you knew you had the molecule to do it, so it changed things a lot. And it became substantially the solution to Ian’s problem.”
Smith relished the swoosh as salvation, nothing less than the key to the company’s future, which it well might be, as well as for the magnitude of the story he could now tell to Wall Street. He announced within days a fast-track stock offering that would yield, less than a month later, $175 million. As Smith, Alam, and others went on a hastily assembled road show, confidently touting VX-950 as the molecule that would transform the treatment of hepatitis C, several analysts raised their ratings to “outperform.” Porges was the most bullish, despite the dilution of stock and management’s boosterism, advising in a research note: “We . . . believe the stock is likely to continue to strengthen as investors recognize the size of the opportunity and the significance of the Phase 1b data recently released.” Boehringer finally halted development of its protease inhibitor due to cardiac toxicity, leaving the biggest outstanding question, Porges warned, a possible challenge from Schering-Plough.
Alam reeled from the reversals. In late May he flew to Chicago for the Digestive Disease Week conference, where Dr. Henk Reesink, author of the European study, presented his findings. “We blew it out of the water,” Alam recalls. He and Kauffman discussed what the data revealed about viral dynamics, the complex interplay between virus and host, and they began to model treatment regimens to improve SVR rates in patients. Several weeks later, Alam joined Smith on the road show. He called his mother from an airport and learned that the low blood flow during his father’s heart surgery had caused his liver to fail. “I finished the road show, flew back to Washington, and buried my father,” he says.
Hurter’s group reworked the VX-950 formulation over and over with different polymers and conditions. Anticipating the start of new and bigger trials in the months ahead, she drove her fast-growing team to emulate her own breakneck pace. By May, they were able to make 60 kilograms for advanced animal toxicology studies; with a better powder and a better suspension vehicle, the drug substance remained stable for two days. They turned immediately to figuring out how to make the new material into a tablet by combining it with other inert compounds that acted as stable carriers for the active ingredient. By July, they had a pill formulation for the Phase II clinical trial scheduled to begin in October.
“After we figured out what the amorphous formulation looked like, we got some stuff made,” she says. “It took us less than a month. We made the stuff in England, where they have a place where you can manufacture and dose at the same facility. You can literally make the tablet upstairs and take it downstairs and give it to patients. We were waiting on the data, and Josh was being all gung-ho. I was getting worried because, ‘Okay, I think it’s going to be good, but it’s not a slam dunk.’ I was saying something to Josh at the beer hour, like, ‘I hope you don’t think this is totally bomb-proof. And I’m glad you have faith.’ And he looked me in the eyes and said, ‘Trish, I have the appropriate amount of faith in you.’ ”
Boger at last had a molecule powerful enough to foil the “constant headwinds of doubt” that had buffeted the company for the past four years. His ebullience soared. After Sato left, he took back the position of president, and with the organization maturing around him, he plunged further into making Vertex the model twenty-first-century life sciences company he’d dreamed of creating ever since he decided to leave Merck. Soon enough, that would mean engineering and running a competitive commercial organization built for expanding success across the globe. But first Boger felt he needed to ensure that Vertex was prepared to become such a company by cementing its culture, building its reputation with doctors and regulators, and raising its—and his—visibility in the industry and internationally.
Garrison’s work captivated him as it progressed from fifteen focus groups involving about a third of the company’s employees across all the sites, to a smaller team that would distill all the discussion and testimony and draft the core purpose and values. Figuring out a distinctive shorthand for the company’s unshakable mission was not hard, relatively speaking, and the team soon arrived at the prosaic “Innovate to redefine health and transform lives with new medicines.” It sounded exactly like the statements of hundreds of other companies, but with three disruptive verbs—innovate, redefine, transform—they thought it made the point. Developing the values was harder. After asking them to find out what inspired them, Garrison now pushed them to focus on a few taut phrases: “It’s a giant regression, basically. A lot of companies do values that are aspirational: we wish we were more collaborative, so we’re gonna make collaboration a value. Unnh. Error. No good. If you do values that aren’t true, the employees say bullshit. The other thing we said is, ‘Here’s how many you get. Three.’ You go to companies all the time, and they have nine, ten values. They might as well have none. When there’s three, there’s nowhere to hide.”
In July Hurter’s team was deep in the final challenge of a commercial formulation. “We were really in the thick of things,” she recalls. “I was going completely nuts. We were called to some all-employee meeting at Le Méridien hotel. I remember I was walking down there, speeding down Sidney Street. I’m ranting and raving, ‘I don’t have time for this!’ I get down there, and there’s all this loud music playing, purple balloons everywhere, and it’s very festive.”
The packed scene was the introduction ceremony for Vertex’s values, a mini-launch that within weeks would be reprised at the two other major sites. Determined to build on Garrison’s work, Boger devoted major resources to the effort, putting key people in charge of Vision into Practice (VIP) teams and initiating a three-phase implementation plan. The company adapted the familiar branding elements of clinical trials, where phases are named in series with slogans. Boger now explained Phase I—AWARE—six months of internal messaging that would include the inevitable banners, desk tchotchkes, and coffee mugs but also off-site brainstorming sessions to ensure that everyone “knows it and gets it,” Garrison recalls. Boger put up a slide of the three values, arbitrarily ordered.
Fearless pursuit of excellence
Innovation is our lifeblood
“We” wins
Here was an expression of corporate excellence that thrilled Boger. Not only were the values the actual values that had driven him and the other founders out of Merck and into the marketplace, and had coursed through the organization for sixteen years, but they were also cleverly turned to differentiate themselves from the commonplace themes of excellence, innovation, and teamwork that most companies adopt. “ �
��We’ wins,” for instance, despite its slight grammatical awkwardness, is more than the sum of cooperative endeavor. It claims that at Vertex if you have a job that you know you can complete on your own with 100 percent certainty, you’d rather enlist others even if your chances of success diminish slightly, since the benefits of interdependence always outweigh the risks. Fearless pursuit of excellence, Boger says, was “a demand for excellence always in the face of something that had to be scary. It almost had to be scary before it would warrant our attention.
“Innovation is our lifeblood,” he says. “What we found was, it wasn’t a choice. We didn’t choose to be innovative. What came up from the Vertex conversation was that to not be innovative would be to have the blood sucked out of you. It was a physical need. It is what keeps us feeling alive. And so, it isn’t that we’re innovative because we care about others. We’re innovative because we care about ourselves. We would die if we couldn’t be innovative. We can’t stand it. It makes us ill if we don’t innovate.”
Hurter was far from alone in becoming an instant evangelist. “I’m gullible,” she says. “I soaked it all up.” Her chief job now involved hiring people for entirely new functions during a growth spurt, and she found it invaluable to have a succinct statement of what sort of place candidates would find if they joined. “We can say to people, ‘This is what we’re about. If it sounds cool to you, you should be here. If this sounds dopey to you, you should not be here,’ ” she says. “I also tell them it’s a very chaotic atmosphere. Ultimately, we still change our minds a lot, and yank people around, and change priorities, and change our minds to try to do something better—and, oh yeah, it’s due last week. And if you find that frustrating, you really shouldn’t work here.”
In December Vertex announced it was initiating a program of midstage clinical trials with VX-950. The first twenty-eight-day study would test the safety, tolerability, and pharmacodynamics of the compound when combined with pegylated interferon and ribavirin, the existing standard of care. A few days later, the FDA granted the molecule Fast Track designation—expedited review, since HCV infection was a serious, life-threatening disease with an unmet medical need for shorter, more effective, safer regimens. Garrison, after struggling for a final few weeks against Boger’s reality distortion field, joined Vertex to see the vision process through. Boger convinced him that only by coming inside the organization would people take him seriously enough, and trust him enough, to help them do what needed doing, which was to weave the values and vision into the fabric of a breakneck expansion as Vertex “scaled.”
Garrison was first given the title of senior vice president for organizational development—E-level standing. But as people started meeting with him, it was clear to everyone that building a chain of command wasn’t his field. After a few weeks, he realized it would be useful to have a more descriptive title. He went to Boger, who told him to come up with one. A friend made a suggestion: senior vice president and catalyst. Boger, his social experiment now morphing into intensive culture building, told Garrison he couldn’t imagine a more “pregnant” description.
CHAPTER 7
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JANUARY 9, 2006
Boger began his talk on VX-950 at the Morgan conference by showing a picture of the Apple iPod. “Every so often,” he said, “there’s a game-changing product—one that transforms a product category, one that transforms a company, and one that transforms an industry.” He went on to compare Vertex to Thomas Edison’s Menlo Park invention factory. It was impossible to be too bald here, and Boger deployed a prized talent for predicting a future that at once seemed over the top, yet sensible and within reach. And yet as he now stepped onto a broader stage, he carried the extra weight of sixteen years of making grand claims that hadn’t panned out, a reputation for overselling, and losses approaching $1 billion. An investor leaned over to a reporter and whispered, “He certainly doesn’t lack for confidence.”
He’d reached the point where, from now on, the company’s—and his own—evolution could be classified pre- and post-swoosh, and he foresaw seismic changes at every level as Vertex ramped up to deliver the drug. “It’s a tremendous responsibility to live up to a molecule like VX-950,” Boger told the audience, adding, “This astounding data can actually be a bit terrifying.” As if to hammer home the message, Vertex simultaneously issued a press release announcing interim findings from another small Belgian study done by Henk Reesink. In a blinded, placebo-controlled trial of just twenty patients testing the combined effects of VX-950 and pegylated interferon, half of those taking both drugs had no detectable virus after two weeks. They had a median 5.5-log drop—a 300,000-fold reduction—in viral RNA.
The speed of the viral response was breathtaking. But as with HIV, the central issue was resistance; there would be variants that VX-950 wouldn’t hit, and another drug, or drugs, would be needed to achieve a cure. Alam—driven in equal parts by the data and a grim certainty that a shorter-duration treatment against HCV could have saved his father—believed beyond a doubt that the interim findings made a convincing case for shortening the course of treatment from a year to as little as three months. That all the patients in Reesink’s study had the most resistant, hardest-to-treat genotype of the virus—genotype 1—ratcheted up company, and investor, interest in launching such trials as soon as the FDA would approve.
Publicizing the results from a tiny European trial to coincide with a key investor event helped Boger grab added attention on Wall Street, where the share price had nearly tripled since May, and where even small studies in carefully selected patients can spark what Smith calls “the magic” of soaring expectations among investors around a promising stock. It also was guaranteed to irk the FDA, which, more than any other federal watchdog (with the possible exception of the Nuclear Regulatory Commission), defines and controls the process by which a product gets to market. Emerging out of the Progressive Era mission to “civilize capitalism,” the agency defends very seriously both its responsibility to protect the public and its prerogatives, which include deciding how much, how long, and under what circumstances an unproven treatment can be tested on experimental subjects. “Because we sent kind of the wrong message,” Alam recalls, “when we got on the phone with the FDA examiner, he just screamed at us, ‘You guys believe in your drug too much. You’re irresponsible.’ From that day on, we basically severed any kind of relationship.”
If Boger, Alam, and Vertex had a fatal blind spot, this was it: a faith in themselves and in data so blazing that it eclipses other sensibilities. Getting on the wrong side of regulators just as Vertex was at last moving up to become a true drug company so deeply troubled some board members that they began to discuss among themselves the need to rein in Boger. But he and Alam saw no other course. “In every division of the FDA, they’re completely rabbinical; it’s all about precedent,” Boger recalls. “It has nothing to do with any information that you bring them. So we—Vertex, who they don’t know from Adam—come with a drug and we say, ‘Look, we know there’s an existing cure for this disease. We want to add our drug to the existing drugs. And we think we can show you—the way this is going to be used is—we’re going to shorten the treatment of those drugs that are on the market’—in the FDA’s language ‘change the label’ of those drugs. And ours is a new chemical entity that goes by a new mechanism.
“They go, ‘No no, no. That’s not the way you do it. You’re going to dose your drug for twelve months with interferon-ribavirin and see what improvement you get. And then we’ll talk about shortening treatment.’ And we say, ‘There’s no reason to dose our drug for twelve months. Its effect will be one hundred percent done in some number of weeks’—we thought eight weeks—‘at which point we need these other drugs to sort of sweep up.’ And they were just completely against that.”
In the realm of clinical trials, a lucrative hybrid industry—part academic, part commercial—had lately started to ply the gulf between drugmakers and regulators. Companies now outs
ourced the management of large worldwide clinical trials to outside investigators and contract research organizations (CROs), committing significant portions of their R&D budgets to specialty services that line up doctors and patients, publish studies in medical journals, and add a patina of independence and prestige. For its Phase II trials to show how VX-950 could be an effective drug, Vertex had hired as its principal investigator Dr. John McHutchison, internationally recognized for coordinating major clinical trials in liver and gastrointestinal diseases and associate director of the Duke Clinical Research Institute in Durham, North Carolina.
A droll, wiry Australian, McHutchison had moved to California in the late 1980s to study liver disease, began working in HCV, and never returned Down Under. With a large operation and a panoramic view of the treatment landscape, he consulted with dozens of companies focusing on numerous different approaches—anything with a biological rationale. But Alam had also hired McHutchison to help educate investors and analysts about hepatitis C, and since 2003 he’d assisted Vertex by giving an overview of the disease and the market opportunity at major investor events. Hepatitis C was still poorly appreciated even by doctors, most of whom seldom saw a case. When they did see any, they tended to refer their patients to specialists before they developed cirrhosis or liver cancer or went into full-blown failure requiring a transplant, the hallmarks of the epidemic. In most cases hep C presented as an invisible, symptomless, slow-motion buildup until it flashed over into a racing downward spiral in late middle age. The disease confounded investors, who could only guess at the size of the problem. McHutchison told them that in the United States alone, the costs would be equivalent to those of asthma. Around the world, where up to two hundred million were infected, the ramifications were geometric.