The Antidote: Inside the World of New Pharma (20 page)

“I went over there and met with Josh and Vicki,” Garrison recalls. “They kept talking about this communication problem they had with the board. I said, ‘Well, what do you mean?’ They said, ‘Well, they don’t really get what we’re doing.’ I said, ‘So, okay, what
are
you doing?’ Twenty minutes later, I had a little bit of an idea, and I said, ‘I have good news—and good news for me. The first good news is that you do not have
a communications problem. You have a strategy problem. You can’t express what you’re doing. And the second good thing, for me, is I do strategy.’

“I said, ‘Who are your folks?’ My proposition was, ‘Let’s put them in a room together for a day, day and a half, and find out not only what you think but what they think. And what you’ll create is alignment between you and your team, and you’ll have something to tell the board.’ ”

Boger leapt at Garrison’s offer. He believed that what Vertex needed wasn’t management consulting but a homegrown process for navigating the challenges of becoming a world leader while drawing on and renewing its culture—to discover what sort of company it truly could become not by reviewing others’ best practices but through rigorous self-examination. “I was explicitly trying to systemize, institutionalize something that was already there but that was somehow going to get lost unless it had a more explicit verbalization and home,” he says. “When I met Bink, I said, ‘This is the guy. I need
this
person because he understands how to drive that in a nonhokey way, how critically it’s lacking in large companies, and how you can’t retrofit it easily.’ ”

Garrison met one by one with all the members of the executive team. His framework derived from Jim Collins’s breakout bestseller
Built to Last: Successful Habits of Visionary Companies,
the classic investigation into the norms and practices of innovative companies that management gurus and CEOs globally regard as a data-proven tool of what defines corporate culture. It was based on yin and yang: complementary opposites. “On the one side of the yin is core ideology—which is core values, what do we really believe in? it’s not negotiable—and on the other side is core purpose: Why are we on the planet?” Garrison explains. “In a company that’s been around for anywhere longer than twenty-four months, that’s not something you create. It’s an archaeology project, not a creative project. You discover it. The other part of it is an envisioned future—a ten- to thirty-year ridiculous goal. Collins calls it a BHAG: Big Hairy Audacious Goal. What would it be like, the top of the mountain? Describe it.”

On a day in July, Garrison met off-site with senior management and a handful of others, including Murcko and Thomson. His goals were to generate a clear, concise, easily understood description of what Vertex is:
a Vertex “vision, mission, and differentiation” statement, an acceptance that corporate positioning is based on reality and substance and not fluff, and a “perceptible rise in energy based on newfound clarity.” To get them talking, he had them use analogies: If Vertex were an animal what would it be? Or what brand of car would it be? A Ferrari, a Lexus, a Prius? “The whole purpose was to till up the garden,” he says, “to get some action.”

Boger had told Garrison after their first meeting, “I’m gonna hire you away.” Garrison, whose greatest gift may be that top CEOs appreciate him almost as a personal trainer, said he wasn’t looking for a job. Boger replied, “I’m gonna make you an offer you can’t refuse. I’m gonna cut your salary by ninety percent.” Throughout the fall, as Garrison began to probe deeper into the company, Boger showed that he was serious. He made the Vertex Vision Process—a grassroots, companywide exercise to find out what people really believed about who they were and what they hoped to achieve—his top priority.

“This is something I was desperate for,” he says. “We ran it, as usual, as a complete experiment. The intellectual content is, first of all, values are immutable. They’re not something that you can decide to change. If your values are that you’re evil, you can’t decide to be good. Once your value is being evil, that’s your value, and it doesn’t matter how many consultants you bring in, you can’t change it. When is that set in stone? Probably much earlier than most people think. I would say in most social and organizational structures it’s set within six months. So we actually went on an exploration. We asked across the entire Vertex world, independently, what were the values. It came down to basically, on our best days, how do we act?”

When Sato first explained the concept of fear and fun to the researchers at Aurora, many recoiled. It troubled them that fear was an articulated component of Vertex’s culture. “It’s not fear of being chained to the galley oars,” she explained. “It’s about fear of not rising to the challenge of what the world needs. It’s the fear of being mediocre.” In that sense, there was no distance between Cambridge and San Diego; aspirations were equally high at both sites. Tung had moved from Massachusetts and now co-led with biologist Paul Negulescu a Left Coast version of Vertex, one where
the ambition and drive were the same, but half the scientists also participated on weekends in CF walks, and more than a few took a couple of hours at dusk to surf at Torrey Pines State Natural Reserve before grabbing some fish tacos at a stand and returning to the labs. Project leader Eric Olson, a clear-thinking and adept strategist, uprooted his family to Cambridge, where he could represent Aurora and drive ahead the CF clinical program. At his send-off in the cafeteria, his colleagues gave him an enlarged photo of the panoramic view from the boardroom, a snow shovel, and other necessities for winter in Massachusetts.

With the added funding from the CF Foundation, Negulescu, Olson, and the project group pushed more deeply into the problems of trying to correct broken CFTR in the epithelial cells of patients. These are the cells that line cavities in the body and also cover flat surfaces. The new team leader was Peter Grootenhuis, a Dutch medicinal chemist and deft scientific manager, a recent veteran of a rapid M&A mash-up at another firm that left him working at the same site but for four different companies in four years. Grootenhuis, a part-time virtual professor at Dutch universities, guided the incorporation of Aurora’s cell biology into the overarching methodology of making drug compounds, which is improvement through modification. He inherited a familiar standoff. The chemists needed better assays to tell if their molecules were working; the biologists were impatient with the chemists for not delivering more potent molecules. Though the group had several hits from three different screens, progress had stalled in developing leads. Without better assays, there was no way forward.

“I had to first make sure that we work well together as a team,” Grootenhuis says. “The thing about CF is that there was no animal model, so all we had were assays that we ran in different cell lines. We expressed human CFTR in mutants, but there was no way of knowing how reliable or predictable of a read that was. The view in biology was that if we can base our assay on human bronchial epithelial cells from CF patients, that was about the closest we were going to get.”

As leader of CF biology, Fred Van Goor set about conceiving of a model system, one that would convince them that they were on the right track. A deliberative thinker with a laid-back quality belied, at age
thirty-six, by a mane of gray hair that seemed to balloon when he was deepest in thought, Van Goor had done his PhD thesis on ion channels and then spent another five years at NIH studying endocrinology. He recognized that everyone with defective CFTR had the same array of symptoms, but CF was not a singular disease. It resulted from a myriad of different mutations causing two main types of defects: either not enough properly folded protein gets to the cell surface, or there’s sufficient protein at the membrane but with channels that don’t remain open long enough to allow salt and water to pass through. In the lungs, the trachea (windpipe), and the sinuses, this retarded flux allows mucus to build up and cake, providing a fertile field for bacteria and gunking up the cilia, the fine hairlike projections that sweep away detritus and help keep the airways clear.

Van Goor’s group had run the screens that yielded molecules that increased both the amount and functioning of CFTR, but not within human cells, much less cells that might provide a clue as to whether they would work against disease.

Sabine Hadida, who headed the CF medicinal chemistry group, had joined Vertex from the same orphaned San Diego outfit as Grootenhuis, though they hadn’t worked together. As a postdoc at the University of Pittsburgh, Hadida had invented a widely adopted synthesis, and she had an ability, like Tung, to go into areas where the chemistry was thought to be well understood and discover new angles of approach. As her group tried everything it knew to improve on its hits—and as she sensed that the biologists, unaccustomed to working with chemists, weren’t helping—her dismay at not having a more representative assay flashed over. “Number one, we had to convince Fred that we knew what we were doing and that this assay was not really helping us,” she recalls.

“Number two, we had to convince the whole biology group that those hits were not really going anywhere. We were able to eliminate the activity, but we were not able to improve it. Everything we would do would keep it the same or worse.”

Van Goor reasoned that human bronchial epithelial (HBE) cells from patients with CF could provide a solution. A few academic labs had cell lines, and with the help of the foundation, he recruited collaborators
to help test several groups of compounds. While they were looking both for corrector molecules to fix misfolded CFTR and for so-called potentiators to open the channels longer, the team found itself reckoning with a startling new reality: that far more CF patients had folding mutations and thus would be helped only by correctors, which were much harder to find and develop. “The rate of finding a corrector is 0.002 percent,” Van Goor says. “Then you have to make it a drug.”

Here was the emerging dilemma of twenty-first-century drug discovery and development, of medicine itself. Among CF patients, the most common defect is the deletion of three bits of genetic code in the F508 region of the gene for CFTR—delta-F508. Half of all patients have two copies of the delta-F508 mutation and up to 40 percent have one, meaning that the great majority of patients—those who by and large, because they have almost no functioning protein, suffer the severest symptoms—would need a corrector for any hope of relief. Meanwhile, only about 4 percent of patients—around three thousand worldwide—were known to have the G551D mutation, a gating defect that had yielded Vertex’s most promising hit for developing a potentiator. How did you decide what to pursue, the greater need/opportunity or the path likelier to succeed? For sick patients and their families, personalized medicine couldn’t be more personal.

“In CF you’re talking about eighteen hundred different mutations,” Van Goor says. “That’s like eighteen hundred different diseases. It’s a real research, then development, then regulatory, then marketing challenge. Everybody says they know all about it, but how are we going to develop medicines for that? Because that’s the future. The future is to know somebody’s genotype—modifier genes or mutations that cause disease—and then make drugs that are tailored to those. How do you work in that new world? How do you evaluate it? It doesn’t cost any less to develop a drug for five people than it does for a hundred thousand: same preclinical studies, clinical studies, it’s all the same. What we’re trying to do is use biology to provide a reasonable rationale for how different classes of mutations are distinguished from each other, so it’s not eighteen hundred, it’s three.”

In August Hadida’s group made a potentiator that Van Goor
personally took up to the lab of a collaborator at Stanford, who had developed a line of delta-F508 HBE cells. The compound was ten times more potent than the starting point. “We had not seen that in all these years,” Hadida recalls. The goal and philosophy of everyone on the project remained to go hardest for a corrector, but the gain in activity was a milestone, affirming their approach. It convinced them to press harder on both fronts. “We said, yes, now it’s real,” Grootenhuis says. “The problem with that molecule is that it was a brick. It was completely insoluble. It had bad pharmacokinetics. A bunch of things were wrong, but we loved the activity.”