The Antidote: Inside the World of New Pharma (21 page)

On November 1 Vertex reported at the Liver Meeting (AASLD) that VX-950 was well tolerated and had favorable PK properties in healthy volunteers, according to Phase Ia clinical results; Alam announced that the company would begin testing the drug in infected patients within a few weeks. That morning’s
Wall Street Journal
featured a front-page investigation into Merck’s four-and-a-half-year rearguard action to conceal what it knew about the safety of its blockbuster painkiller Vioxx, which it recently had pulled from the market after studies tied it to heart attack and stroke risk. “By 2000,” the paper reported, “one email suggests Merck recognized that Vioxx didn’t merely lack the protective features of old painkillers but that something about the drug itself was linked to an increased heart risk.”

On March 9, 2000, the company’s powerful research chief Edward Scolnick e-mailed colleagues that the cardiovascular events “are clearly there” and called it a “shame.” He compared Vioxx to other drugs and wrote “there is always a hazard.” But the company’s public statements after Dr. Scolnick’s e-mail continued to reject the link between Vioxx and increased intrinsic risk.

As academic researchers increasingly raised questions about Vioxx’s heart safety, the company struck back hard. It even sued one Spanish pharmacologist, trying unsuccessfully to force a correction of an article he wrote. In another case, it warned that a Stanford University researcher would “flame out” unless he stopped giving
“anti-Merck” lectures, according to a letter of complaint written to Merck by a Stanford professor. A company training document listed potential tough questions about Vioxx and said in capital letters “DODGE!”

Reputation, vital in any business, counts even more so in medicine, where it correlates to a rare degree with trust, market muscle, and influence. In Boger’s analysis, Vioxx was a case study in how to destroy an organization’s image. First comes a problematic product, then executive hubris, then foot-dragging, and then finally the thuggish self-deception that you can beat the rap with cover-up and intimidation. One decade you’re on top; the next you’re acting like a tobacco giant. Boger was more saddened than surprised by Merck’s spate of reversals: its new-drug pipeline was nearly bare, and within two weeks, three hundred personal injury lawyers would gather in a ballroom at the Ritz-Carlton Huntington Hotel and Spa in Pasadena, California, for what the
Times
called “a combination strategy session and pep rally on Vioxx claims” estimated at up to $10 billion. As always, he believed the only way to avert such a downfall—beyond having a robust portfolio and high wattage across the functions—was through organization and culture.

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 spreading 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.