The Antidote: Inside the World of New Pharma (44 page)

My original premise for joining the [Vertex] board was that I believed the future of medicine was in medicine . . .
Duh
 . . . and that drug companies are called drug companies because you need drugs . . .
Duh
 . . . and the only reason you ever have a product is its perceived value. You can’t jam it with a sales force. Perceived value has to be, basically, inherent in the product. We’re in a market that is now squeezing—monetarily—down on an industry where me-too is not going to make it; incremental is not gonna make it.

I mean, I’m amazed we don’t use generics first in almost every disease. I have high blood pressure. All the drugs I take—four of them—are generic. That’s fine. They work. So we shouldn’t be paying six dollars a pill. What we should be paying for is companies that create a mechanism to continue to bring very, very good breakthrough drugs. If you can’t do that, you shouldn’t be in the business.

The insane thing you’re seeing in the big companies is a lack of sustainability, a leveling; and they’re saying, “Okay, we’re gonna do a stock buyback, we’re gonna pay a dividend, and we’re gonna cut our research.” The market continues to want to see progression of earnings and a progression of dividends, and if you don’t have those two things, the stock goes down. Well, that’s a bad spiral. If you don’t show me productivity in research that’s gonna make the top line go up over time, if you’re burning the furniture to heat the house, then pretty soon the house is gonna get cold and you’re not gonna have any more furniture. These massive research departments have not been able to sustain it.

The pre-EASL buzz on Wall Street wasn’t about Vertex versus Merck but about Pharmasset’s nuc-nuc combination, touted by the company as the most promising all-oral therapy across all genotypes of hepatitis C. Biotech fund managers, having tasted this very magic once before—with Vertex—pounced on the story.

Grabbing a chapter from Vertex’s playbook, it seemed, Pharmasset submitted a research abstract to EASL describing interim results of a small Phase II study in which fifteen of sixteen, or 94 percent, of patients receiving its cocktail had undetectable levels of virus after fourteen days. On March 7 EASL released the abstract online. Though the data were embargoed to the press until the Berlin conference, the abstract, grossly preliminary, sufficed to trigger a land rush. Shares of Pharmasset stock, VRUS, rose 24 percent one day and 8 percent the next, to $66.92.

Pharmasset’s gain was Vertex’s loss, as analysts recalculated the opportunities in hepatitis C. A few downgraded VRTX shares, which fell as much as 5 percent, to $47.07, on the announcement. Vertex’s news at EASL—positive results of a “quad” therapy, combining telaprevir and VX-222 with peg-riba—suddenly looked less than inspired: a limp second-day story off yesterday’s headlines; a placeholder, not an advance, in the race to the promised land of an all-oral therapy. “
A
play, as Cumbo would put it, “but not
the
play.”

Inside Vertex, Pharmasset’s coup registered. Ann Kwong, promoted to lead Vertex’s hepatitis C franchise, worried that Vertex still had no late-stage nuc in its arsenal. So did Smith. But the overall response was notably skeptical: not blasé, but been-there, done-that. “I almost feel bad for them,” Michael Partridge said. “They have no idea what they’re facing.” The more that its drugs were studied, and the more the reality set in of how grueling and risky and time-consuming a series of buildouts Pharmasset now needed to navigate to get its drugs to patients, the less impressive its nucs would no doubt look. Emmens, especially, professed no worries about who would ultimately win the hepatitis C market. He was certain it wouldn’t be one company, like Gilead in AIDS.

Vertex sent an eighty-person contingent to EASL, including the entire ET except Emmens and Ken, to show the flag. “This place eats money,” Emmens noted. “It’s too many people, but we have to hear everything, be everywhere. The company is in the balance.” Emmens normally shows little strain, but he was suffering his third attack of diverticulitis in twelve months. Not too many years earlier, he’d finished marathons ahead of competitors half his age, but now, at sixty, carrying his tray in the cafeteria on the fourth floor of JB-II, he shuffled like a post-op
patient. More and more, he was feeling his age. He planned to take some time off over the weekend.

On
NBC Nightly News
on March 30, the opening day of EASL, anchorman Brian Williams read a one-paragraph health item. “News tonight about hepatitis C, the liver infection that affects more than three million Americans,” he said. “A new drug, expected to be available in the next few months, doubles the cure rate when given along with two other drugs that are already prescribed. In people with the most common strain of hepatitis C, the cure rate goes from about thirty-five percent to about seventy percent when this new drug, called Victrelis, is added to the treatment.”

Victrelis was Merck’s trade name for boceprevir. No drugmaker was mentioned in the report.

APRIL 27–28, 2011

Kauffman would have preferred to go ahead of Merck, to set the tone for what bio-business writer Adam Feuerstein called “Hep-C-apalooza.” The eighteen-member advisory panel, meeting over consecutive days in the Great Room of Building 31 at the FDA’s White Oak campus, would recommend, by vote, whether to approve telaprevir and boceprevir. Since licensure of both products was all but assured, the larger struggle would come down to the relative merits of the package insert, or prescribing information (PI)—the label. More than a point of pride, a label dictates how and to whom a prescription drug can be sold, and Vertex aimed to have its field force launch its medicine with a superior PI. Kauffman believed that going first provided an edge.

Boger still argued that the FDA’s white paper on EPO alone meant boceprevir should be rejected out of hand. But the team, without him, had moved on to the view that it faced a superheated two-treatment market. Vertex’s hearing was scheduled for Thursday. Its forty-plus-person contingent flew to Washington on Monday, checking into the Doubletree by Hilton Bethesda, a forward base to rehearse, rehash, watch Merck’s presentation via webcast, and wait. In Cambridge, Emmens, Smith, Partridge, Ken, and their teams readied for the aftermath.

Mueller was, as always, central to the overall effort, but the hearing had implications for every part of the company. Megan Pace brought a group to handle communications. Wysenski and the entire senior commercial team except Cumbo bird-dogged the on-site preparations, as did
representatives of Tibotec. Amit Sachdev, a former FDA official and now commercial lead for Canada, commuted from home to help navigate issues of history, personality, and political tone. It was a rare week when he didn’t have to be in Cambridge and Ottawa.

On the science and clinical side were two dozen researchers and doctors who had lived and breathed telaprevir—a few, like Kwong, for nearly fifteen years—and whose professional mien did little to conceal their fervor. Dr. Camilla Graham, vice president for global medical affairs, formerly had a busy hepatitis C practice and a position at Harvard Medical School. When she first heard about VX-950, she’d cold-called Vertex, saying: “You have to hire me.” Since at least Sinclair Lewis’s 1925 novel
Arrowsmith
, in which a doctor who goes to work for a drugmaker is denounced as “gone bad,” physicians who work in industry have withstood doubts about their split loyalties between business and medicine. Graham, who still saw clinic patients at a Harvard teaching hospital, saw no contradiction, a positive deviant in both settings.

Weet, as liaison to the FDA and show-runner, so to speak, was attuned to the forces at work and the group’s chemistry, and he worried about overpreparation. “I like to see it buttoned down more,” he says. “I like to see, in athletic terms, a light practice. You don’t have to run five-mile loops the day before the game.” But during rehearsals Tuesday, the presentation was less than crisp, and when he talked with ProEd’s people, they pressed for another full-dress session. “The day of the Merck presentation everybody wanted to kick back and watch the presentation,” he recalled. “We were sitting over lunch, during a break, and ProEd’s leader said, ‘At five o’clock, I want to break out and have another rehearsal.’ Darryl Patrick [head of early drug development] pounded his fist on the table and said, ‘
You’re killing these people! Enough already!
’ If you’re talking about the dynamics in the room, it was just about ready to explode.”

By any measure Merck was enjoying a remarkably friendly day before the committee, stoking Vertex’s frustrations. Before the markets had opened, Merck announced it would buy back up to $5 billion in stock, following the trend of using cash to “return value to shareholders.” Its keynote speakers represented what Wysenski called “the old Schering crowd,” led by Janice Albrecht, formerly vice president of hepatology
clinical research for Schering-Plough. Not the Merck of lore, the team nonetheless had a drug with a 63 percent to 67 percent SVR rate and a reserve of goodwill with regulators; what it couldn’t prove with data it appeared to obscure and evade.

In its briefing document to the panel, the FDA staff had flagged several key concerns. The examiners criticized Merck’s practice of adding EPO during its clinical trials, clouding the dropout rate; its attempt to redefine nulls—those patients who failed previous treatments—as people who failed only to respond to a four-week lead-in with the standard of care; its proposal to allow longer treatment for patients who still have detectable HCV RNA at eight weeks but who go undetectable at twenty-four weeks, a complicated new type of “response-guided therapy” with only scant supporting data that it would result in the patients’ being cured; and the paucity in its studies of blacks, who don’t do as well on peg-riba. As Albrecht and her speakers argued each point, the panelists pushed back, but seldom with anywhere near the degree of outrage the Vertex group thought was warranted.

Merck’s failure to submit important data elicited the morning’s sharpest rebuke. Lynda Marie Dee, a Baltimore lawyer advocating for patients, chided the panel and the FDA for tolerating Merck-Schering’s failure to study how boceprevir affected sick patients already taking other meds, particularly antidepressants, which along with painkillers provided the only way many of them could tolerate peg-riba. “There are no drug interaction studies,” she said. “I’m shocked we don’t have studies on depression. I know there’s a race with all these drugs, but I think it’s irresponsible that these studies haven’t been done before now.”

Despite its qualms, the AdComm voted 18–0 to recommend approval. “To go to sixty percent to seventy percent [SVR] really seems like a dream come true,” said Dr. Lawrence Friedman, chairman of the department of medicine of Newton-Wellesley Hospital, outside Boston. “I think this is a major advance, so I’m very enthusiastic about this drug.” Friedman jabbed lightly at the complexity of Merck’s regimen—the lead-in, the repeated testing of viral RNA, the shifting end points—saying, “You need to be somewhat of a Talmudic scholar to prescribe it.” Patrick Clay, a pharmacist and director of clinical research at the
University of Missouri–Kansas City, vigorously defended Merck’s lapses, declaring he wasn’t worried about its shortage of data. “Given Merck’s history, I have confidence in them,” he said after announcing his vote.

At the Doubletree, the Vertex team stewed. When the AdComm finished its work at about five, a core group broke out for a light rehearsal, then went out for dinner. Weet recalled:

I think that the overall sense was that Merck just got away with murder. The FDA briefing document to the Advisory Committee had all kinds of baggage attached to it. The anemia: they’d confounded their studies by treating patients with an unapproved drug for the anemia so that you couldn’t tell what boceprevir’s impact was on the anemia entirely, because they were treating these people with EPO. You can’t be recommending the use of an off-label drug. We didn’t know how the panelists were gonna handle that.

The drug interactions piece: They had done nothing. So they got this finger wagging: “Shame on you, Merck, we expected more of you.” The whole thing around response-guided therapy. The whole thing around nulls—they didn’t have nulls. They created their own definition of nulls out of this pretreatment; if you didn’t respond, they said, “Well, you would have been a null.” Kauffman’s yelling, “
That’s unethical!
” because we had done a study with people who had actually failed forty-eight weeks of standard of care. Bob was just tearing his hair out, but they got away with it.

So there was a certain view in the room that we were witnessing a crime. The hematology expert, who was there to really interrogate them on the anemia, didn’t say a word, the entire time. They got off scot-free on the anemia. They got off scot-free on the nulls. They got off scot-free on RGT. They got off scot-free on their DDIs except for this finger-wagging. But, they’re Merck. Some ways we were upset, but other ways we were comforted: “Hey, maybe this won’t be so bad.”