The Antidote: Inside the World of New Pharma (31 page)

Clinical development had advanced smoothly, with few glitches and a strong safety profile. In the fall, the company started a midstage study with VX-770 in twenty patients with the G551D gating mutation. Patients took the drug for fourteen days. Dosages were varied. Expectations were deliberately set low. The company’s chief marker of activity was sweat chloride; if a patient’s perspiration was less salty, it would show that the potentiator was keeping the molecular gates in CFTR open longer and allowing the protein to pump chloride ions across the membranes of epithelial cells just under the skin. Whether that translated also into improved lung or pancreatic function because of a reduction in mucus went beyond the modest goals of the trial. The medical community, as ever, remained deeply skeptical that the compound would work in patients.

At the annual North American Cystic Fibrosis Conference in Anaheim, California, in November, a nurse from one of the trial sites in Iowa had approached Olson and blurted, “I know I’m not supposed to tell you this, but one of the patients in the trial says he hasn’t felt this good in five or six years.” Olson recalls: “I didn’t want to believe it. I said, ‘Listen, I’ve seen this before. People get on drug. There’s placebo.’ ” The brain’s role in improving health during trials is a known clinical effect—often
the only effect—of most experimental medicines, and Olson tempered his expectations. In San Diego, most of the attention was on VX-809, the corrector, still the greater hope for the majority of patients.

In late March Vertex received an interim analysis of the study results. After two weeks, the investigators saw an average improvement in lung function of 10 percent in patients receiving the highest dose, compared to no improvement in those receiving placebo. A few of the patients reported breathing better within days of starting on the drug. The lung-function data were supported by improvements in sweat chloride and another biomarker, nasal potential difference, a measure of ion flow in the nasal lining. In the executive suite at Aurora, site head Paul Negulescu huddled expectantly with project leader Peter Grootenhuis to hear the findings. On the phone was Dr. Claudia Ordonez, a Vertex physician, who, along with Kauffman, monitored the trial.

“We hadn’t heard anything in months,” Negulescu recalls. “The deal for us was we had to show a pretty dramatic effect in a very small number of patients to get excited about this. So Claudia comes on the phone. The data are streaming on the computer, and we’re listening to Claudia’s voice. Before any of the data came in, I remember the first thing she said—and she’s a very conservative person, not prone to exaggeration. She said, ‘Well, guys, this was an absolute home run.’ We looked at each other. We had no idea what a home run looked like in CF. But we had hit everything we hoped and more.

“It answered so many questions. It said CFTR is fixable in people and that it’s been sitting there like a switch that’s off, waiting to be turned back on. That was one of the other worries: you’re born with it defective, maybe your whole system develops improperly, such that even if you fixed it later, it wouldn’t matter, because all the biology has changed. But no, it turns out the biology is there, just dormant, waiting to be awakened.”

Mueller, driving Vertex hard to deliver a second drug, remembers being “incredibly stunned” by the data. Far and away the company’s most seasoned drug hunter, he had seen dozens of proof-of-concept findings over his career, but none remotely as dramatic and powerful as this. Even the Vertex swoosh paled. The implications for patients, for Vertex, for
the possibilities of taking on larger problems and harder diseases—even for the way certain diseases could now be viewed—were epochal, he thought. Mueller recalls:

I think this is the first time ever that any company has had a small molecule that is able to correct—in a subpopulation, at least—the gene defect those people have. It was proof that Vertex is really doing transformational medicine. Cool as HCV is, from a reputation point of view, this drove it home. CF is a lot more complicated in nature than hitting a virus over the head. It shows the commitment and also the capabilities that we have as an organization, to go after problems that nobody else really has ever done. They always stepped away: it’s too complicated, not doable. The seven, eight years of hard science that we did finally paid off.

And that gives you a feel that there is an evolution going on in Vertex that is beyond rational drug design. It’s the new-century approach where biology drives the effort, and it’s not just the chemistry. I believe that the twenty-first century has a mandate, and the mandate is that you make an advance in health, not just a drug. This is what you get with transformational medicine.

It took a few days for the euphoria to recede and the larger reality to hit full-on. Sabine Hadida, the chemistry leader, didn’t sleep for a week, she said. Team members were alternately elated and terrified that they might fail the other 96 percent of patients, that they might never produce a corrector as effective or, apparently, as safe as 770. Olson flew to Washington to tell Beall and the foundation the results before Vertex announced them publicly.

“Bob and I and a few others were on this BIO panel in DC,” Olson says. “We’d gotten the data. They knew the data were coming sometime. Ken wanted me to tell them in person what we had. I said, ‘Bob. Can we go back to Bethesda after the panel? I’ve got some things we need to talk about.’ I think he kind of got a sense, because instead of going back to his office, they had a room at the Hyatt, which was just a few blocks away, and he suggested we go there. So we go into this room. I had a sealed
envelope. They opened it. I said, ‘Here are our first data.’ They were just stunned. Bob was so ecstatic.”

For Beall, the results vindicated a decade of all-out heterodoxy and entrepreneurial risk taking: his determination to push venture philanthropy into for-profit research; his refusal to yield to established opinion that CF drugs could treat only the symptoms of the disease but not its cause; his insistence on going after CFTR; his recruitment of Aurora; his faith in Olson and the company; and, especially, his willingness to foot part of the bill for Vertex’s clinical development. If the determination of an individual to make a big difference can be measured by volume, the significantly improved FEV1—forced expiratory volume in one second—that measured the exhalations of patients taking VX-770 was Beall’s deliverance. Calling the findings an “unprecedented milestone,” he said in a press statement: “The results from this trial are among the most important announcements in the history of the foundation. Although we are still early in the process, we have increased confidence that we can treat the basic defect of CF, and these data show that we are on the right path to cure this disease.”

At the end of April, John McHutchison presented the data from the two PROVE trials at the European Association for the Study of the Liver (EASL) meeting in Milan, Italy. The cure rate rose to 68 percent in one arm of the second study, when telaprevir was given for twenty-four weeks. A tolerable number dropped out due to rash: 7 percent. McHutchison also reported on a Phase I trial evaluating the oral availability of a nuc, a polymerase inhibitor developed by Pharmasset, a ten-year-old New Jersey company with early-development programs in antivirals and cancer. McHutchison told the audience that after four weeks, the Pharmasset compound showed an ability to knock down the virus “similar to HCV protease inhibitors, and [it] has an encouraging short-term clinical safety profile.”

Mueller, like Boger, thought nucs made bad drugs, and so far, that had been borne out by the data. All types of other compounds had failed routinely against the virus: nucs, non-nuc polymerase blockers,
IMPDH inhibitors, humanlike antibodies, gene regulators, therapeutic vaccines. A much higher percentage of follow-on protease inhibitors were still proceeding in the clinic, strongly suggesting that as with AIDS, the protease was the most inviting target. Ann Kwong, keenly aware of Gilead’s conquest of the HIV market, was less dismissive of Pharmasset’s approach. She began to press Mueller to consider nucs more seriously in planning for second- and third-generation cocktails, but Mueller was unimpressed.

With skin rash turning out to be a manageable but not insignificant problem, Kauffman was working with the FDA to shorten telaprevir’s treatment time still further, eventually winning the go-ahead for an eight-week treatment arm. Enrollment in the two late-stage trials was filling quickly as word got out about the Phase II data. Meanwhile, the company was rapidly advancing expanded trials of VX-770 and VX-809, also expected to start by summer.

Alam, after eleven years, put down his torch. He had helped elevate Vertex from a research organization to a clinical leader with breakthroughs against two major diseases, but his relations with the FDA had become a liability, and he didn’t have the “tactical rigor” Boger knew he would need to manage the expanding wheel of Phase III trials and the filing of new drug applications with the regulatory agencies. “I love John to death,” Boger says. In the usual Vertex fashion, personal affection and loyalty were not enough when measured against where the company needed to be in five years. “It came as a shock,” Kauffman remembers. “John came into a staff meeting one morning with a sort of Cheshire cat smile on his face and said, ‘I have news for you.’ ‘What’s that?’ He said, ‘I’m leaving.’ They had been conducting a search, it turns out, that I didn’t know anything about. I had not been told about this at all, nor had anyone else in the room.”

News of Alam’s departure was wrapped inside the announcement that Vertex had hired Dr. Freda Lewis-Hall as executive vice president for medicines development. Formerly of Bristol-Myers Squibb, Lewis-Hall would lead the company’s buildout of its regulatory affairs and medical affairs teams in addition to running all clinical and nonclinical
development, but her real urgency was to improve relations with the FDA’s Fleischer. Tracking him down at medical meetings, engaging him in conversation, she became the company’s “Russ whisperer.”

Since Sato retired, more and more frequent turnovers in senior management had rattled investors, perplexed analysts, and confused employees. Boger believed it was the price paid for forever blowing out functions to create the future. In relentless succession, the company had built a research organization, a development organization, and was now rushing to create a commercial organization to launch two drugs. The ET staggered from move to move. First, Tony Coles had left when Boger hired Victor Hartmann. Then Hartmann left when Kurt Graves joined as the seeming heir apparent. When Boger started at Merck in the mid-1970s, it was assumed that he would retire there, but in biotech, if people didn’t change jobs every five years, they felt they weren’t advancing fast enough. Companies adapted to the abrupt comings and goings like a sloop catching a side gust, entering a state of perpetual disruption where head-snapping departures became the norm. “Thrills and chills,” Ken calls it.

A month later, Emmens retired as CEO of Shire, although he remained the company’s chairman. When he took over in 2003, Shire’s flagship product had been the attention-deficit drug Adderall XR, a reformulated amphetamine under patent threat from generic drugmakers. Soon after, its most promising late-stage-development prospect was rejected for FDA approval. With most of his business in the United States, Emmens moved Shire from England to the Philadelphia area, settled the legal standoff, acquired smaller companies with innovative technologies and franchises in rare diseases, and encouraged them to develop their own cultures and programs. Now Shire ranked near the top of specialty drug firms worldwide.

Emmens, fifty-seven, anticipated getting back to his garage to work on his fleet of restored sports cars, flying around the Caribbean, keeping up with his directorships, visiting his adult children, maybe getting a new dog to train. He thought Vertex’s revolving door belied a larger problem—Boger’s hub-and-spoke leadership model—and he told the
other directors in his firm, accentless monotone that he didn’t think it was a scalable design. Development of telaprevir was ongoing. The company had its first FDA submission coming up. It faced scores of inspections, both of its supply chain and clinical activities. It had no commercial organization. And it expected to launch a drug into a highly specialized market in eighteen months to two years. Without thorough integration and alignment among its senior executives—not to mention the faith of the board—Emmens doubted that Boger could succeed.