The Antidote: Inside the World of New Pharma

by Barry Werth

  He was trying to build an organization that was more capable of carrying out midstage and late-stage development and the transition to commercial operations—without killing off the spirit in research. He had accepted early on at Vertex that the people who seem most essential during one phase of a company’s evolution are not always the same ones to propel you on to the next. He and Sato had structured the company in such a way that program executives reported up the chain to him, while everyone else, including the heads of functions, reported to her. The system was stretched now and would surely be unsustainable once Vertex had several molecules in late-stage trials.

  After bringing in Garrison to probe what made the company tick, he launched several more preparatory moves, starting at the top. A few directors were alarmed that Vertex had done no succession planning. “They kept asking, ‘What if you get hit by a bus? This organization is too big; we have too many bets on the table,’ ” Boger recalls. As he stepped up his efforts to explain to them where he was trying to take the company, they were distrustful, skittish. “I was worried one more jolt and they might panic.” Boger saw no need to groom a successor, but to placate them, he brought on a new non–executive director who he thought shared his vision and could show them the kind of person they should consider if and when he could no longer run the company.

  Matthew Emmens, fifty-three, was chairman and CEO of Shire PLC, a midsized English firm rapidly building on a diversified roster of specialty drugs to become a successful, research-driven multinational. In the mid-1970s, after graduating from Fairleigh Dickinson University with a business degree, Emmens started in sales at Merck when it had great products to sell and a reputation for integrity, and its six hundred reps included only one woman. Learning science and medicine from the doctors who were his customers, he absorbed their concerns and affinity for R&D, and after rising through the ranks to lead a new joint venture to promote a heartburn drug called omeprazole (Prilosec), one of the biggest-selling drug franchises of all time, he ran Merck KGaA, known as “German Merck,” and established EMD Pharmaceuticals, its US prescription drug business. Medium built, fit, white haired, circumspect, a mechanic since high school who flew his own turboprop, Emmens had a passion for taking things apart, fixing what’s broken, and reassembling them for optimal performance. He knew how to set goals and build a team.

  “I introduced Matt as our get-hit-by-a-bus guy,” Boger recalls. “I wanted a smart commercial guy on the board, but even more so, I told them, ‘This is the guy who can be the temporary CEO while you take a year finding a new one.’ He was my archetype. He was a guy I knew and trusted.”

  Boger also started to identify experienced, high-level veterans of Big Pharma to run Vertex’s expansion and restructuring. After searching for more than a year for someone else to manage the program executives and move projects to a commercial footing, he hired Dr. Victor Hartmann, a former head of business development at Novartis, giving Hartmann the title of executive vice president for strategic and corporate development and the clear impression that he expected him, as Boger put it, to “shock the system” and “get development to deliver.” Boger recalls, “When Victor came in, he could deliver the message, ‘I don’t care how you work it out internally in your development function, but here’s what you need to deliver. Here’s what a clinical package needs to look like. Here’s what the documentation needs to look like. Here’s what the backup needs to look like.’ But he wasn’t in charge of development. In classic Vertex fashion, we were trying to get people to change their behavior voluntarily.”

  A week after AASLD, Vertex announced that it was beginning a Phase Ib study with VX-950 in patients infected with hepatitis C. The study would evaluate three different doses of the drug over fourteen days of treatment. Results were anticipated in the first half of 2005. Meanwhile, Hurter’s formulation group got another 20 grams of the molecule—“floor sweepings,” she says—and began experimenting with different polymers and conditions to try to improve stability. Garrison traveled to Oxford and San Diego to run focus groups with employees, to get them talking about what drove them ahead.

  At a meeting with the board, Boger put up an enlarged photo of a bus. Borrowing from Ken Kesey and the Merry Pranksters, he invited them one by one to post a picture of themselves on the bus. For Boger’s generation, “You’re either on the bus or off the bus” was a handy metaphor for commitment, for being all in or else left behind. The directors all put up their pictures. For Boger, the best way to avoid being hit by a bus was to be driving it, fast and supremely sure of his sense of direction, like legendary Magic Trip driver Neal Cassady, who also inspired the Dean Moriarty figure in Jack Kerouac’s On the Road. Boger neglected to make much effort to ensure that the board was happy with him. Nor did he pay much attention to managing them.

  “Completely not,” he says, “but it’s a two-way street. They hadn’t added much value in the last few years. So why should I manage them well? And what am I getting out of this? In a list of problems of trying to build a pharmaceutical company, managing the board because you serve at their pleasure can’t be high on your list because it doesn’t solve any real problem. It can create a problem if it gets out of control, but it doesn’t solve a problem. You toss the lions some meat so they don’t cross over the fence, but it doesn’t build anything.”

  Sabine Hadida’s chemistry group produced another tenfold leap in activity by improving the PK, formulability, and synthesis properties in a potentiator, VX-770. A senior researcher named Tim Neuberger, frustrated by the difficulties their collaborators were having trying to isolate and grow HBEs, pressed Van Goor to bring the model in-house. Over the years, everyone on the team had gotten to know patients, many of whom had died or were dying, and the team felt a degree of urgency that seemed to go beyond the normal bonds between researchers and the people they hope to cure.

  Their efforts had proven the concept that a small molecule that targeted CFTR could reverse the damage from mutation. Van Goor had made comparison videos, taken through a microscope, of live cells from the lungs of CF patients. In untreated cells, the cilia rotated aimlessly; slow and uncoordinated, they failed to move mucus off the cell membrane. The second video showed cells treated with a corrector. The cilia, synchronized, beat faster, like wheat raked by a breeze, showing how in the body they potentially could sweep bacteria and mucus from the airways. The images were powerful, but without its own cell lines, Vertex was stalled. With lung transplants having become a last resort, Beall brokered an agreement in December for Van Goor and Neuberger to receive a lung from a CF patient with the delta-F508 mutation.

  The lung arrived at midnight from the East Coast. Neuberger drove in an hour later to begin the work of harvesting cells. He had never done a dissection before. Having read a couple of papers describing extraction methods, he assembled forceps, scalpels, tweezers, scissors, and buckets of liquid in a biosafety cabinet. Taking the package from its cooler, he teased apart the wrapping to discover an organ both healthier and smaller than he’d anticipated. “There was just this tiny little lung in there,” he recalls. He could think only of his own children. A thirteen-year-old boy had died of an anaphylactic reaction to a new antibiotic. Lungs from very sick patients are scarred and saturated with mucus and pus as dense and black as tar balls. This lung was pink and smooth.

  Neuberger examined the lung with an eye toward cutting away tissue he was certain wasn’t part of the branching system of airways. Grabbing the bronchial tube with a forceps, he sliced down deeper and deeper to isolate the airways as much as possible. He carefully cut away the stiff cartilage tubes that support the upper bronchia and the softer rings that surround them as they branch into the lobes. Then he snipped the airway tissue into smaller pieces, rinsed them out with enzymes to get rid of the gooey mucus, performed a series of washes, and then treated them with a bacterial enzyme called pronase. Active cells like HBEs are held together and supported by an extracellular matrix, which also prevents bacteria from spr
eading through the body. Pronase evolved in bacteria to chew through that barrier.

  After thirty-six hours, Neuberger pulled out the pieces of tissue and put them into petri dishes with a medium fortified with vitamins, minerals, and amino acids. After slicing open the airways, he scraped and filleted sheets of cells, collected the sheets under a microscope with a pipette, transferred them to another vial, and spun them down. He added another enzyme that clips intercellular adhesion molecules, and the sheets fell apart into smaller groups of differentiated HBEs. Under a microscope, he could see the cilia still beating. He transferred the smaller groups to flasks, where, he hoped, he could coax them to reproduce, grow, mature, and form cilia of their own. The first set of experiments would take six weeks. Though the process would work the first time, it would fail the second and third times, and Neuberger would work to find optimal conditions for growing HBEs for the next three and a half years.

  Mueller visited Aurora in January to review the site’s progress. Negulescu and Tung, adjusting to the recent lurching in Cambridge, were determined to advance a compound into clinical development, and Tung had led the chemistry effort against sodium channels. They had made promising molecules against chronic pain caused by injuries to the nervous system. Negulescu recalls:

  In those days, the program that we always expected to bring forward first was our pain program. We thought this was the one that was gonna deliver for the site. So all our agendas, for all our meetings, always had sodium channels first, then a couple of other things we were doing, and then CF, trailing—so that if the meeting went long, it got cut, or pushed to the very end.

  The meeting with Peter was a classic case of that. We had an all-day meeting. Around four o’clock, he started to get antsy; he had to get a car to the airport. And so Fred gets up and starts talking about the CF program. Peter’s mumbling. He’s starting to put his papers away. Fred’s looking at me: “What do I do? What do I do? I can’t go through my whole forty-minute presentation.” So Fred showed his movie, and out of the corner of his eye, Peter saw it. He started watching it. He stopped fiddling with his briefcase. And he sat down. And he said, “This is freaking amazing.” It convinced him, like it convinced many people, that this was a real effect.

  For Sato, the progress in CF affirmed that the Aurora buyout was working much as she and Boger had hoped. It also signaled a threshold for her and for Vertex’s research organization. Its AIDS medicines were discovered before she arrived, but HCV and CF were diseases she had championed. Now Mueller and Hartmann would build the company as it moved into late-stage development with compounds brought out of research under her lead. As Vertex took shape as a commercial organization, she could only be drawn further from science if she stayed. Sato retired, returning to Harvard to teach. What she’d found in fourteen years of leading Vertex in an I formation with Boger—besides the necessity of fear, fun, and passion—was that the perseverance required to make a drug was being strangled by the controlling view on Wall Street that the only measure of a company’s success is the extent to which it enriches investors. “The mantra of shareholder value is putting at risk the kinds of qualities that competitive innovation really requires,” she says. “There was a time when people were looking at Vertex and saying, ‘Another example of two billion dollars in shareholder equity flushed down the toilet.’ Innovation has lots of parents. It requires not just capital. It requires certain personal attributes. It requires patience.”

  In late February 2005, a couple of weeks after Vertex announced Sato was leaving, a federal district court threw out what the company’s press release called the “purported class action lawsuit” filed against her, Boger, and others soon after 9/11, the crash of the p38 kinase inhibitor, and lawyer Andrew Marks’s ill-timed margin call.

  Even before the Valentine’s Day meeting a year earlier, clinical virologist Dr. Robert Kauffman had become VX-950’s most ardent champion; also, elliptically, its most reserved. Kauffman, fifty-seven, was dark browed and meticulous, an inward-seeming physician who throughout his career had alternated between studying viruses in the lab and studying them in patients, at Harvard’s teaching hospitals and with other companies. He’d known since second grade that he wanted to be a research scientist, then discovered in his late thirties that his unique talent wasn’t in the lab but in clinical experimentation. At Syntex Laboratories, he had driven the development and approval of an immunosuppressant, CellCept, a major organ transplant drug. With a low-key, just-the-facts affect and a serious, inquisitive, and respectful manner, he brought a seasoned maturity and bedside equanimity into the company’s deliberations: ballast to Alam’s cerebral self-assurance.

  After joining Vertex in 1998, Kauffman had fleetingly believed that merimepodib would enable him to retire in less than a decade, but as he’d grown more and more aware of its shortcomings, he grew more forceful in pushing VX-950 ahead. “To give an immunosuppressive drug to someone with a viral infection is a little bit of a tricky thing to do because there’s a fine line between making the infection worse and curing it,” he recalls. “You had to thread the needle, and it’s pretty hard to do that without getting into trouble. The company was under a lot of pressure to bring a drug into Phase III. I basically said, ‘It’s fine to develop merimepodib, but you can’t do that and not develop VX-950.’ Nobody would understand why you failed to develop a direct-acting antiviral and yet you were developing this mechanism that a lot of people didn’t believe in. It just wouldn’t make sense as a company.”

  Since the start of the Phase Ib trial—the first study in a small number of patients diagnosed with hepatitis C, and designed to confirm the hypothesis that Vertex’s protease inhibitor could lead to improved clinical outcomes—Alam had largely stayed on the road promoting Vertex’s combination approach to controlling HVC. After Eli Lilly dropped out, it had become much harder to sell the idea to investors. Boehringer was steaming ahead with its compound and Alam worried that VX-950 might not be competitive—another too-weak molecule like pralnacasan. Perhaps more than anyone else at Vertex but Boger, he badly needed a success.

  “We spent the six months from an investor relations standpoint between November and May having meeting after meeting where everyone said, ‘There’s no way you’re gonna match BILN-2061 because it’s a hundred times more potent. 950’s a dog,’ ” he recalls. “So we’d have to go through the whole rationale why 950, dose for dose, was, in fact, going to work. There was a whole bunch of people we just had no impact on. Internally, the team set up a baby hurdle—a 2-log drop at two weeks. That was the hurdle for going forward because no one felt that we could come close to BILN-2061, even internally. People were worried. The team didn’t want to put it out that we would stop the program if it wasn’t as good as 2061. They didn’t trust management to make a wiser decision, so they set low expectations.”

  Alam’s father, a retired FDA pharmacologist, was gravely ill, and most weekends Alam flew to Washington to join his mother at the hospital. His father’s medical history was of more than incidental or merely personal concern. Now seventy-two, he’d been diagnosed with non-A, non-B hepatitis in the 1960s and then was confirmed to have hepatitis C in the 1990s. He also had type 2 diabetes and atherosclerosis, leading to a three-vessel coronary artery bypass surgery in 2002. Typically, when he was in his late sixties, his liver disease had worsened. He’d considered being treated with interferon and ribavirin, but, according to Alam, his doctors told him, “First of all, you don’t need to be treated, and second, you’re not gonna tolerate twelve months of therapy anyway, because you have cardiovascular disease.” Now he was back in the hospital for a “redo” and an aortic valve replacement, and his liver was failing.

  Clinical trials aren’t run by drug companies themselves but by independent investigators. They’re conducted in stages. Before a drug is studied in large groups to see if it is effective (Phase II), then compared with commonly used treatments (Phase III), you must prove that the idea behind it works and that what
you’re seeing isn’t an artifact. Patients are assigned randomly to different groups and investigators are “blinded”—kept from learning any information that might bias results. The VX-950 trial was again being run in Belgium, following the common practice, especially among small companies, of testing products overseas before approaching the FDA.

  Kauffman faced a worsening dilemma. He was sensitive to the fact that Alam couldn’t have an inkling of how patients were doing on the drug, since it would put him in an untenable position of having either to lie to investors or breach securities laws. Kauffman also knew that to move ahead with the project, Alam, his boss, needed to authorize major new expenditures as the company accelerated into the next phase.

  “We didn’t know who was assigned which treatment, but it was awfully obvious after a very short time who was getting which treatment,” Kauffman says. “We would look at each other and say, ‘Oh my God.’ There was nothing we could say. It got to the point where we could see viral resistance. Ian, of all people, was interested in these findings. It was very difficult at times to maintain a completely neutral appearance. But we did, very successfully. Nobody knew anything.”

  At Vertex, as at other companies, trial findings are first revealed internally at confidential disclosure meetings. Legal, ethical, and scientific safeguards are crucial. Ken ran the meetings, deciding who, for corporate reasons, should attend, and managing the struggle over how to interpret new data. On a day in April, he convened a group including Boger, Hartmann, Smith, Mueller, Coles, Alam, Kauffman, and others around a double-wide table in the Frankfurt conference room in Fort Washington to review the Phase Ib two-week dosing data with VX-950 in patients infected with HCV.