The Antidote: Inside the World of New Pharma (22 page)

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.

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.’ ”