The Antidote: Inside the World of New Pharma

by Barry Werth

  “This disease does not take a day off,” he says. “It’s very persistent. So as an Art of War type of thing, that’s your adversary. You have to match or exceed its effort if you want to win, and that can be mentally and physically very draining. If you’re going to live with CF and get what you can out of life, you have to be realistic about things. If you wake up every day disappointed that you didn’t run a marathon, I don’t think you’re in the right place mentally.”

  Johnson and his family rented a town house near the Hudson River in Westchester County. He played in a pickup weekend soccer game, usually becoming too winded to run during the second half, walking the field, bent, tugging at his shorts, gasping. He loves golf, struggling a couple of dozen times per year around Hudson Hills, the premier local public course. On the day in February 2010 that Johnson started taking two unmarked tablets daily, along with his usual treatment regimen, as part of the randomized sixteen-week study, he “blew” 52 percent. A patient’s FEV1 can easily vary from day to day; Johnson’s baseline for the trial hovered in the low 50s.

  The second week in March, on a warm afternoon, Johnson played Hudson Hills with a friend. The eighteenth hole is a 403-yard par four. Climbing to the green after slicing his drive, when normally he would be “huffing and puffing,” he had little trouble breathing. “I felt amazing,” he says. “I felt cured. I hadn’t allowed myself to think that anything like this was possible. I could not believe that someone had figured this out.” A few weeks later, he blew 58 percent. When Johnson returned to the adult unit of the CF center at Beth Israel Medical Center in Manhattan, one of several study sites, at the end of June, he was tested again. His FEV1 measured 60 percent.

  “I knew it when I blew it,” he recalls. “I could just feel. Within ten days, I would say that my life turned upside down for the positive. Not only did I feel that this was working, but that this opens up a whole new life, one that I wanted but that I hadn’t allowed myself to hope for because I just didn’t want to go through the disappointment.

  “I was seeing everything completely different—at work, the possibilities. It was the most productive time ever for me workwise. I never made as much money. I was winning every deal. The guy I work with said, “Dude, what is up with you? I can’t even keep up with you when we walk around the city.’ I couldn’t wait to wake up in the morning, to live life.”

  Keith and his wife, Adrienne, had avoided discussing the future; the subject was too frightening. They had backed into family life without sharing any larger ambitions for how they hoped to live. Adrienne had wanted children; Keith, like most men with CF, was sterile. Yet they had found a doctor who reasoned that since his CFTR malfunction was in the vas deferens, the tube that transmits sperm to the ejaculatory ducts, Keith might have what he calls “swimmers,” and after eight attempts at extracting cells from his testicles and using in vitro fertilization, he’d become a biological father—twice. Still, the couple had never really looked ahead. “Life was like you were living from paycheck to paycheck, not in a monetary sense but ‘How Keith was feeling,’ ” he explains. “Not reliable. It was not reliable to make plans.

  “Adrienne and I completely recalibrated our conversations. What is it that we can accomplish in life now? Moving into a better school district? Getting a second car? We were actually making plans.”

  After the sixteen-week comparative study was completed, subjects who met prespecified criteria were eligible for an “open-label extension” or rollover; that is, everyone who wanted to continue on the drug was given free multimonth supplies, pending the outcome of the trial. Johnson recalls signing for boxes of VX-770 and greedily stuffing them into his backpack. His company was sold at a premium after a bidding war between Hewlett-Packard and Dell, and he and Adrienne started looking at split-level houses in Irvington, New York, near a school with an excellent reputation. He started showing up both weekend mornings for soccer, exercising so much that he lost weight—a curious anomaly, since his digestion was the best it had been in decades. “My exercise tolerance was so high, I was finding any excuse I could to do any type of cardio.”

  Johnson blew 62 percent in November. He took his doctors out to celebrate. He and Adrienne bought a house, making a deposit with the proceeds from his stock options, but had no money left for living room furniture—the “Gift of the Magi” room, he called it. His daughters, Claire and Danielle, called it their indoor soccer field. He began, in a dream, to feel unchained from the rigid sense of responsibility that he could never miss a treatment. “You know what?” he says. “I could miss a TOBI [tobramycin, an inhaled antibiotic for treating pseudomonas infection]; I could miss an albuterol. I could go out at night and come home and not do my meds. And it was not being irresponsible. It was just this freedom. I . . . I just couldn’t believe it. It was just so powerful.”

  “There’s no way,” Johnson told himself, “I ever not want to have access to this med.”

  The second mock was held farther off-site, not in a distant city but at the Hyatt at Boston’s Logan International Airport, overlooking an isolated runway where the previous night Air Force One remained parked, bathed in klieg lights, surrounded by sharpshooters, while a hundred-vehicle motorcade swept President Obama in and out of downtown for a school appearance and a fund-raiser. In addition to making it more convenient for the company’s consultants, the move lowered the number of senior executives in the guarded conference room, though not the tension.

  The speaker slate was reshuffled from a month earlier. During that first grilling, Vertex had lost a keynote speaker when ProEd’s statistician attacked his credibility. The company was relying on a highly regarded expert in the treatment of hepatitis C and liver cancer to deliver an overall assessment at the end of its presentation, but the consultant, pelted with allegations that he’d compromised his professional integrity by speaking on the company’s behalf, abruptly gathered his papers, stood, and said, “I think I have a plane to catch.” Every company needs independent experts to support its claims, but now the team would rely solely on the testimony of Dr. Ira Jacobson, the principal investigator on the ADVANCE trial, who agreed to address the burden of the disease and the need for new medicines, but not telaprevir. Chief of the Division of Gastroenterology and Hepatology and a distinguished professor of medicine at New York–Presbyterian Hospital Columbia University Medical Center and Weill Cornell Medical Center, Jacobson had replaced John McHutchison in the ambiguous role of lead clinical investigator/paid ally when McHutchison, lured finally into industry, went to work for Gilead in 2010. Lest there be any question of Jacobson’s impartiality, he enjoyed a similar relationship with Merck.

  Kauffman delivered the introduction. Emmens had noted that when speaking with Wall Street, Kauffman was almost preternaturally calm and unruffled—an informed senior figure who never got defensive or strayed from his data, conveying honesty and patience no matter how aggressive or trivial the challenge. Kauffman briefly outlined the contours of Vertex’s presentation. Jacobson, he said, would offer a brief background of the disease and the current treatment landscape. Next, he—Kauffman—would return to provide an overview of telaprevir’s development: how it was studied, first in the lab and then in nearly four thousand patients. Two other Vertex physicians, Dr. Shelley George and Dr. Priya Singhal, would then discuss the drug’s efficacy and safety, respectively, before Kauffman provided the risk-benefit assessment himself at the end.

  Sponsor presentations invite obvious skepticism, and Kauffman was eager to show not only that Vertex had produced a breakthrough medicine but also that it took very seriously its commitment to transparency—up to and beyond the requirements set by regulators. Drugmakers are expected to study drug-drug interactions, or DDIs, the myriad ways in which medicines combine to produce additional effects in the body. Patients with hepatitis C, especially those whose livers are already cirrhotic or who have cancer or have received transplants, take numerous other drugs; those coinfected with HIV take even more. Many develo
p ascites—their abdomens fill with fluid—requiring diuretics. The disease also correlates with an increased risk of adult-onset diabetes. As specific as a drug might be, it is no match ultimately for the devilish intricacies of whole-animal biochemistry, and many new drugs come to grief because they can’t be administered with the other medicines that a patient is already being prescribed.

  Kauffman told the panel that Vertex had conducted a comprehensive clinical pharmacology program characterizing the potential for DDIs with telaprevir. He showed a slide—one of sixteen hundred prepared for the mock—listing DDIs with more than fifty other prescription medicines. It had studied cross-reactions with opioids (narcotic painkillers) and immunosuppressants. It found that telaprevir interacted with the estrogen component of oral contraceptives, possibly reducing their effectiveness. Though the company’s thoroughness was laudable, Weet and others worried about the risk of being too diligent. “It was positive that we had done a lot of DDIs,” Weet recalls, “but you could also say it was negative that we had done a lot of them. We saw a lot of interactions, and it caused a lot of concern.”

  It was up to Singhal to present Vertex’s case regarding telaprevir’s greatest safety risk and clinical vulnerability: rash. Whether the discussion of rash at the AdComm remained scientific and grounded or, as Emmens put it, became “emotional,” would reflect on Singhal’s presentation, and she faced potentially the toughest questioning. A recent immigrant from India, poised and precise, she had arrived with her husband, a fellow doctor, to study at Harvard, and then joined Vertex as senior director of worldwide patient safety. Now she delivered a case history, with graphic slides, of the company’s response to the rash issue, with special emphasis on the most severe skin reactions.

  After the first cases were reported, Vertex had appointed an outside adjudication panel to investigate. In parallel, the company launched several investigations to try to understand what was causing the rash and how it could be managed. A special search category was established to ensure that all severe adverse events were thoroughly characterized. Singhal noted that the external panel in three cases suspected Stevens-Johnson syndrome (SJS), a life-threatening and horrifying skin condition in which cell death causes the top layer of skin to die and shed. Only one case was definitive, although it occurred eleven weeks after the last dose of telaprevir, while the patient was still on peg-riba as well as other drugs, and the panel considered it unrelated to telaprevir. The team, led by a Harvard dermatologist who would be available for questions at the AdComm, also investigated eleven suspected cases of another severe skin reaction given the acronym DRESS syndrome. Again, only one case was considered definite, its etiology unclear.

  Science, Murcko likes to say, is an interactive process. The second mock played a lot better than the first, but there was endless room for improvement. The slide deck for the AdComm, already bulging, grew as the session proceeded. Each slide was prepared to answer any question that could possibly be asked, but as new people were brought in to hear the presentation, new questions arose, or there was a new spin on an old issue, and people chased off in search of more data to put together new slides—slides that Kauffman and the team would have to be able to summon instantaneously.

  The problem was the wealth of information itself. Vertex had done so many experiments over the eighteen years of the program that the scale and scope of its inquiries went beyond the ability of its keynote speakers to stay on top of them all. If they surely had the answers the panelists would be looking for, locating those answers was something else. With a bullpen of up to two dozen other scientists seated in rows along the wall to fill in the gaps, even Kauffman’s, George’s, and Singhal’s careful curating and narrative precision were becoming subsumed in the flood tide of data. It was during the simulated question-and-answer session after Kauffman’s summary, according to Weet, that the problem reached a familiar stress point.

  There were still people brought up to the podium to give detailed answers to questions who Peter didn’t trust to speak. He thought maybe they were gonna give too much detail. Maybe they fumbled over an answer, and he didn’t like that. I was sitting next to him at the time, and he said, “I don’t want that guy on the podium.” And I said, “We’re gonna get Bob to answer as many of these questions as possible.” He said, “Okay. Let’s make sure.” I said, “I’m on it.” Then another question comes up. “I thought you said that guy wasn’t going to be on the podium!” I said, “Peter, there are some questions where we have to have the technical experts. Tox. Clinical pharmacology. Bob can’t answer everything.” He was getting very, very nervous. And, of course, people were nervous because Peter was in the audience.

  Approaching the annual meeting of the European Association for the Study of the Liver (EASL) in Berlin during the last week in March, Emmens was “jazzed.” He had a breakthrough drug, abundantly tested and studied. He had the organization he wanted, and every head was down, focused on the launch. There were no premature high fives, and Emmens could feel the camaraderie surging with the size of the stakes. “When your company’s on the line, and it’s a drug that just about everyone in the company worked on, you become a team,” he said. “A lot of the petty stuff goes away. You don’t have to run around with a vision. You know what our vision is now? ‘Holy shit, we’d better not screw this up!’ Right now the vision is to make the company sustainable, and it’s really simple. In the next couple of years, we have to make more money than we spend. So that’s my financial plan. We have to make enough money to sustain the level of research that we think we can sustain.”

  It was just this singular focus that the board had felt was lacking when it ousted Boger. Yet Emmens’s main concern was that Vertex could become too concentrated on—dependent on—hepatitis C. “That’s the only thing that worries me,” he added. “This is really hard stuff now. You need another telaprevir now, or the sustainability goes away. HCV is a booster rocket, designed to catapult the company into the upper atmosphere, and then dump into the ocean.”

  Toggling back and forth between the reality of Vertex’s situation now and its vision of itself a decade from now, Emmens transitioned smoothly. One moment he was the chief internal cheerleader for the drug, rallying the troops at a lunchtime presentation—webcast companywide—where he showed a stop-action movie of white-coated workers assembling a Boeing 757 from scratch at hyperspeed and then wheeling it onto a runway—the Vertex name and logo Photoshopped in purple on the fuselage. The next moment he was publicly extolling Boger and his vision, rededicating Fort Washington as the Joshua Boger Innovation Center and Fort Washington II as Joshua Boger II, or JB-II. A moment after that, he was waving the banner on Wall Street for Vertex’s high-risk, high-reward, science- and patient-based, anticonsolidation, David and Goliath business plan and company narrative. He explained:

  Every time that I say that this place is about research, it’s not to placate the employees. The only future in this business is breakthrough products for sick patients who aren’t getting adequate therapy. That’s the only thing that’s going to work long term. So from a strategic standpoint, to me, one of the things I love is that that’s a very consistent message.

  I came on the board here because I believed that. When I was at Shire, I felt that search-and-develop was great, having no research was great, but I thought it was something that was not sustainable. You’re going to have to go earlier and earlier to capture your products to a point where you’re gonna pay the same prices as if you had your own research. The only thing you have is that you can be a wide net. So when I came here, my messages were: we need a wide net—lots of different projects, in different areas, in different sciences. But, also, we have to do both things well. We are a science company, but that does not mean that we will not go outside for more science and more projects.

  I think one of the problems with pharmaceutical companies is that they try to narrow that net—we’re going to be in two, three, four areas. When you mess with biology, you don’t re
ally know what you have, and you end up in areas that you didn’t start in. So to say that is crazy. It’s an assembly-line mentality. Nothing squashes creativity more than telling creative people what they’re gonna create. We didn’t go after epilepsy; it just happened. So here’s a drug now in later-stage research that was tried for psoriasis. It did not work well then. But here we are.

  Emmens knew and admired Merck’s Frazier—“a really smart guy”—but doubted that, even with the right CEO and a return to its culture and principles, Merck would survive the giantism afflicting pharma. In hepatitis C, he anticipated that Merck’s strategy would be to “make the two drugs seem the same.” Since Vertex would benefit from the extent to which doctors and insurers differentiated between telaprevir and boceprevir, Merck had an interest in blurring distinctions. Frazier and the company also needed to justify the Schering takeout, so boceprevir was a priority asset. Emmens respected Merck’s commercial organization but didn’t fear it. If he were in Frazier’s shoes, he knew he would be concerned about Vertex, but he’d be worried materially more about his anemic pipeline, the paralyzing scale of his operations, the bureaucratic politics permeating Merck’s labs, the cultural and reputational overhang of Vioxx, and Wall Street. Emmens:

  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.