The Antidote: Inside the World of New Pharma

by Barry Werth

  Koppel was “so shocked,” he said, by the Merck-Roche alliance that he felt he needed to hear from Emmens directly. “Can you just help me understand what they’re thinking?” he asked.

  “I believe they’re on their back foot now in the market,” Emmens said. “So they’re gonna attack rash. Roche gives them an additional voice. It doesn’t change the drug. We have the better drug.”

  Koppel was eager to know if Vertex was in the market to buy a late-stage nuc, to counter the threat from Pharmasset, BMS, and Gilead, where McHutchison and the clinical team had several nucs and were running an array of clinical trials, testing them in various combinations. “We won’t discuss business development,” Emmens said. Smith, out of earshot, mentioned that Koppel’s fund also owned 10 percent of a company, Idenix, that was promoting a nuc.

  “Roche doesn’t have any skin in the game,” Emmens told Koppel. “Its reps have no incentive to say boceprevir is better. I don’t think you can take a rep and turn his brain off.”

  Pace ushered Emmens to a small room in the communications suite directly after the call, to begin a round of press interviews. His time in the spotlight had arrived. Whether he truly thought the Merck-Roche tag team represented no real material threat to Vertex or was simply unfazed by a weaker product, Emmens was compelled, as Boger had always been, to challenge industry behemoths. “We be small,” he liked to tell company employees, “but we be fierce.” He told the interviewers what he’d told the analysts: Vertex had the better drug, more effective, simpler to use; the pricing decision was “appropriate” given the relative value to patients, physicians, and payers; the Merck-Roche alliance was bluster. “It’s a relatively small number of prescribers,” he told Reuters. “I don’t think we need to shout too loudly.” Looking ahead, he said, to the next wave of competition for supremacy with an all-oral treatment, Emmens noted that it was easy to lose one’s head over preliminary results and that most experimental drugs fail.

  “The new standard you have to compare yourself to is tough,” he said. “It’s us.”

  “Welcome, everybody, in this evening hour,” Mueller began, addressing an invited group of about a hundred—those who had worked most closely in bringing VX-950 out of the lab, through the clinical and regulatory gauntlets as telaprevir, and finally to patients, as Incivek. He stood near the checkout counter in the JB-II cafeteria, the largest space in the building, hours after the markets had closed. More champagne was passed around. Most of their coworkers were back at their desks or headed home. “I think it is a fantastic event, and I’m so excited I can’t tell you. I cannot still believe that it happened, but it did.”

  “I can’t believed that you hugged me today!” Emmens shouted from the sideline.

  “I think that is the most astonishing accomplishment and achievement that we have as a company, and now we are moving really in the right direction,” Mueller said. “I want to introduce you to a new type of tradition that we will have in the future. This monster is a bell: the transformational life bell.” Mueller uncovered an old firehouse bell, bought on eBay, mounted on a rolling cart, and painted purple. He explained that throughout human history, a tolling bell has signified, among other things, hope, freedom, accomplishment and unity, and that from now on, Vertex would ring its bell whenever it received regulatory approval for a new product.

  “When we really think about what we did with this wonderful Incivek approval today, we gave hope to millions of people who have now the freedom to achieve a better life and a cure. I think that this is really fantastic. The accomplishment I really want to give back to you.”

  No one in the room—not Kauffman, Murcko, Kwong, Kieffer, Hurter, Condon, Weet, or the many others who contributed key insights or volunteered extra weekends when a problem needed solving—no one could say definitively which of them had been indispensable, making the decisive difference, enabling Vertex against withering odds and the best efforts of its many competitors to keep going, push upfield, take its shot on goal, and score. Murcko calculated there were at least fifty major contributors without whose timely work the project might have stalled. In his toast, Mueller recognized them all collectively.

  “I want to say just a couple of words to remind everybody. When we started out it was a very, very difficult active site to approach. Protease inhibitors are a tough thing to do and not many are out there. I think our scientists and our environment did a phenomenal job to tackle that type of approach. Then it looked like you never could make the drug. The first kilogram cost $2.5 million. To do any sort of clinical trials was almost impossible for a small company. It was a bold decision to move forward.

  “And then we learned that nobody can swallow the drug because no one can formulate it. I must say we did a phenomenal job to come forward with the presentation as it is today: two tablets daily three times a day. This was not a given. With the clinical trials we had those long periods in front of us, forty-eight-week regimens, which is a huge, huge problem for a small company to do. It’s costly, it’s time consuming, it’s difficult. I must say the clinical guys revved up phenomenally, to change the treatment paradigm. This is not easy to accomplish. There were tons and tons of interactions with the regulatory agencies needed to accomplish this. We built in the last year the most sophisticated manufacturing network that basically provided us a supply chain that is unheard of in industry. Cost of goods now is orders of magnitude less than it was initially. This is a huge, huge difference.”

  Vertex created Incivek, but Incivek also created Vertex. Mueller was its main beneficiary, inheriting a small world-class research organization with a powerful scientific culture; expanding it in conjunction with a bold, committed clinical group; bringing in inspired CMC and manufacturing; assembling a lean, $500 million-a-year outfit with a record of success and a promising pedigree. He was the scientific leader of a maturing drug company just beginning to make its mark on the world, and he knew the future depended not only on his ability to advance and incorporate new methods but upon the alliances he built. He finished by praising their united spirit. “You cure people,” he said. “This is the high art of what we are in. This is a phenomenal ongoing journey. And it’s not just Vertex alone; it’s Vertex in the context of a broader community. We are all working together in trying to tackle the tough diseases that nobody else can tackle.”

  Mueller pulled the rope on the side of the bell. Its deep, mellow sound filled the cafeteria. He pulled the rope again, beaming, and again, until the sound of the bell was drowned out by the exultation in the room.

  Notable by his absence was John Thomson. He sat at his desk downstairs, plowing through his email. Thomson had just returned from China. He wanted to get home to see his wife, Jackie. In the tolling upstairs, few were reminded that among the major intellectual turning points that resulted in Incivek, it was the initial belief that such a drug was possible and that Vertex, with its severely limited resources, could produce one, that ignited all the others. No one in the early days believed more fervently or worked as hard or proved as much or argued more determinedly against giving up. Thomson remained the truest of true believers in Boger’s original vision, and Incivek was as much his achievement as it was the company’s.

  Thomson had a history of avoiding corporate celebrations, but now, at fifty-three, he had other frustrations just as urgent as when he was a self-described “protein jock” spending long nights in the cold-room on the company’s first project. What he’d signed on to do at Vertex was to build a sustainable organization: a church, so to speak, built on Boger’s vision. “I said, ‘I hear you’re starting a company,” he would recall telling Boger. “ ‘Is it all theoretical, or do you need some scientists?’ ” Vertex had two breakthrough drugs and a standout pipeline, but when Thomson looked beyond the rest of the decade—to where the blockbusters of the 2020s would come from, and how a global Vertex would become the hub of a larger network of interests—he worried that the company was unprepared and too cautious. He especially wo
rried that it was moving too slowly in China and the Pacific Rim.

  Vertex planned to celebrate the launch by bringing together the entire company for an extravaganza in the fall. Emmens wanted a timely, smaller party to reward the Cambridge site. The next Wednesday after work, eight hundred Vertex employees poured into the ballroom of the Hyatt Regency. Confetti cannons stood ready in the corners as the crowd drifted among the bars and food stations. Emmens spoke first, discussing the significance of Incivek to the company.

  “We’re not just launching a drug,” he said. “We’re really showing the world what Vertex is, and who we are, not only what we’re doing now but what we’re gonna do in the future. It’s a big deal. We’re here to become sustainable. That’s when we have income that covers our expenses, which are now $3.2 million a day.” He was quickly becoming admired in the company for his brisk yet thoughtful confidence and understated defiance. With reporters, he had compared Vertex’s battle with Merck to David versus Goliath. Now there were two Goliaths. Emmens retold the biblical story, reassuring the crowd that size didn’t matter—indeed, that they were more agile, more emotionally engaged, better positioned than the Philistines and their legions.

  “David believed and was very good at what he did. He took one stone, and he hit Goliath in the head—well, he also cut his head off. So we’re out there now slinging our stones. They’re big and scary, but we’re very good at what we do, and very focused.”

  Patient activist Kelly Ann Mann-Hester, who spoke so compellingly at the AdComm, nervously walked onstage and took the microphone from Wysenski, who had invited her. Mann-Hester had watched her husband die of hepatitis C in the 1990s and was a mother of four and a grandmother of five. She reprised her story of personal transformation, from living to die to learning how to live until she died. “I’d tried everything,” she recounted. “When I began Incivek, I believed I was doing it for altruistic reasons. I honestly thought, ‘I’m not gonna get cured. I’ve had seven treatments. It won’t be me. Maybe they’ll learn enough from me to help save somebody else.’ ”

  Since being cured in 2010, Mann-Hester had made her mission “testing and treatment.” It didn’t matter if there were new cures for hepatitis C if you didn’t know you were infected, like the estimated three million Americans and hundreds of millions around the world who remained in the dark about their diseased livers. She improvised a group experiment to demonstrate. “Raise your hand,” she said, “if you have had a tattoo or a body piercing; if you’ve ever used IV drugs or if you’ve ever shared a needle with somebody or got stuck with a needle by accident, especially if you were a health care worker before 1990; if you had a transfusion or dialysis, or were born from someone who had a transfusion.”

  Several dozen people raised their hands, but hesitantly, looking around. Even here, announcing you might be infected with HCV posed risks.

  “Now out of those hands, how many of you have been tested for hepatitis C?” she asked.

  Only a few hands went up, a minor fraction. Mann-Hester seized on the troubling disparity. “That’s my point, that’s why I’m here. I’m doing this for that reason. Education starts at home. Test yourself. Treat yourself. Find out you’re good to go so that this company can be good to go further. We have to remove the stigma from hepatitis C because that’s one of the reasons that keeps people from getting tested, and there’s no reason for it anymore. I’m living proof. I’m standing here as someone who was cured by Incivek, so I know. I want you to own your future, and I want you to help people own their future.”

  The last speaker was Boger. Looking over the milling crowd, recognizing only about half of them, he began, “Hi, everybody, I’m Joshua Boger, unemployed person.” Most new hires didn’t get the joke, but they laughed alongside the veterans. Boger was the founder who officially stepped down two years ago but was still a director. The painful circumstances of his departure had mostly healed with the realization that Emmens went out of his way to credit Boger wherever and whenever possible while also successfully sticking to first principles. None of the torchbearers had put out his or her torch. The culture seemed to be holding despite his prior apprehensions. In Emmens’s speeches, internal and external, Vertex remained “Josh’s dream.”

  As Boger had told the field force by satellite during Launch Week, the most common question he heard now from well-wishers was: Did you think this would ever happen? “This is exactly what I thought would happen,” he said. “But I also thought it would take an enormous amount of effort and an enormous number of talented people. And there wasn’t any reasonable expectation that those people would come together to do that.

  “Bringing a major drug forward, bringing it out of discovery and into development, then out of development and into the market, bringing it to patients and changing their lives, is . . . the hardest thing that humans do,” Boger said. “Putting a man on the moon? Not . . . so . . . hard. Engineering is an amazing discipline, but it’s also a discipline that succumbs every single solitary time to time and effort. If you give me twenty years and a half trillion dollars, I guarantee I can put people on Mars and bring them back. I guarantee it. Any of you could guarantee it. But making a new drug that changes people’s lives is almost beyond human understanding.

  “So the second question I get often is, ‘So, what’s next?’ ‘You cannot imagine what’s next’ is what my answer is. You don’t create an organization like this, fall over the finish line, even with a success as big as Incivek, and say, ‘I’m done now, this is it.’ ”

  Whatever the company’s desire to downplay its earlier brashness, Boger felt that now, more than ever, was the time to act and sound bold, both to inspire and intimidate. Was designing and developing and bringing to patients a life-altering medicine—not a cancer “breakthrough” that extended life expectancy in trials by a few months, a drug that cost too much and did too little, but a novel compound that actually saved a life or restored a quality of living that had seemed beyond dreaming about—the hardest thing that humans do? Maybe not. But it was impossible for any of them to name anything harder. Who, at such a moment, would want to try? They burst into thunderous applause. A blizzard of confetti exploded from the corners. Boger, to borrow a famous trope from Jerry Maguire, a film about a high-powered sports agent who crafts the ultimate living room pitch to win over a woman who already has succumbed to his fervent mission and charm, had them at “Hi.”

  CHAPTER 12

  * * *

  JUNE 6, 2011

  At ten o’clock on Monday morning, Ken sailed into the small conference room and took his seat at the head of the table. At the opposite end, poring over his PowerPoint with Smith, was Dr. Christopher Wright, vice president for clinical development. With Kauffman on the road promoting Incivek, Wright was fast being groomed to become Vertex’s top clinician. A neuroscientist by training, he was another defector from the world of Harvard medical research, a muscular MD-PhD in his early forties who sported a modest Afro, long sideburns, and fashionable designer glasses.

  The protocol before the disclosure committee was a twenty-patient, Phase II, double-blinded, multidose study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of the corrector VX-809 alone and in combination with VX-770 in CF patients with two copies of the delta-F508 defect. In other words: the first preliminary data from a tiny cohort on whether combination therapy could do for the great majority of people with CF what VX-770 alone was doing for the small G551D genotype.

  Mueller and Wysenski huddled on one side of the table; on the other, Partridge, Olson, Megan Pace, and Dawn Kalmar, who had joined Vertex from Genentech as a product spokeswoman and who would compose the press release. Anticipation was appropriately high. Failure or ambiguous results in this study would represent a serious reversal, since Vertex had already showed that VX-809 by itself offered no improvement. The hope now was that VX-809 would repair a significant portion of misfolded CFTR and get it to the surface, where VX-770 would then hold open the cha
nnels long enough to substantially increase the flow of salt and water across the membrane, lubricating the airways and other affected tissues.

  “We’re currently scheduled for a premarket release Thursday,” Ken began, putting the team on notice that within the next three days Vertex would have to decide not only what the study had revealed, but, more to the point, what the company could safely conclude from it and accurately say about it.

  Wright summarized the top-line data, reading from his laptop as the others followed along. Well tolerated, the cocktail produced no unexpected safety findings—always welcome news, since the safer the regimen, the more dosages can be increased. The primary end point of the study was to observe a drop in sweat chloride. When VX-809 was first given to patients as monotherapy, there was a significant drop relative to baseline; when VX-770 was added for seven days, Wright said, there was a further reduction consistent with Vertex’s theory that you could double the electrophysiological effect. Clearly the molecules were synergistic. In 20 percent of subjects—two patients—the combined effect was profound, sweat chloride dropping steeply.

  Although not on the same order of potency as the Vertex swoosh or the other company-altering “envelopes,” Wright’s presentation unambiguously proved the concept. The company didn’t know if the combined effects of the drugs could relieve lung disease—the FEV1 data after the one week that the subjects were taking both drugs were scant and inconsistent—but the study provided ample promise for moving ahead, with the potential to increase dosages to gain more potency. The mood of the group was decidedly upbeat but sober: excitement marbled with caution and relief.