The Antidote: Inside the World of New Pharma

by Barry Werth

  In July the FDA approved the first complete treatment for AIDS taken once a day as a single pill. It combined three drugs already on the market made by two companies, Bristol-Myers Squibb and Gilead Sciences. A fixed-dose cocktail called Atripla—a pink, film-coated tablet with “123” stamped on one side—it was to first-generation protease inhibitors like Agenerase what the iPod was to the Sony Discman. Not only was it an elegant, future-inspiring marvel of miniaturization and packaging but also a triumph of intuitiveness. Not a single drug but an all-in-one therapy, Atripla had all the hallmarks of a game-changing product.

  Gilead sold only two of the molecules itself; the other it licensed in. When it first tried to combine the three compounds, “we had glue on our hands,” an engineer recalled. It took about a year to find a formulation that would produce the same exposures as when the drugs were taken separately, and Gilead had tested five different formulations in volunteers. A midsized Northern California company, it had bootstrapped itself to become the sales leader in AIDS. With a higher valuation now than Sears and rich in cash, it was on a buying spree, aiming to branch out from its historic antiviral franchise into circulatory and respiratory diseases. Of special note to Kwong and her group were Atripla’s targets: none of the compounds inhibited HIV protease. Like AZT, all three blocked reverse transcriptase, the enzyme that enabled the virus to make DNA copies from RNA, and one was a nucleoside analog—a nuc.

  Kwong hoped to determine how the hepatitis C virus progressed in the bloodstream of patients on VX-950, and she had hired a young researcher named Tara Kieffer to build a clinical virology group. Like Kwong, Kieffer was a true believer, her heart deep in her work. In first grade, she fell in love with the structure of the double helix during a visit to her father’s biology lab at Montgomery College in Maryland, made a drawing of it, and had kept it on her wall ever since. While working on her doctorate at Johns Hopkins University, she devised and performed complex experiments to track the development of resistance to HIV drugs; her publications, along with others, helped scientists to conclude that the virus couldn’t be eradicated with one drug by itself.

  Looking at the viral load curves from the second fourteen-day study with VX-950 alone and with peg-riba, Kieffer and her group assessed the overall problem with treating HCV: how to devise a better drug cocktail. They sequenced both the typical form of the virus most common in nature and also numerous mutations—both before and after treatment—and then examined the patient profiles. Kieffer tracked their progress in the presence of the drug. She found that it was powerfully inhibiting the most common form of the virus but that there were variants with specific mutations in the protease that by degrees were less sensitive to the drug. Only with peg-riba were these least sensitive variants suppressed. “We learned that the primary role of VX-950 is to get rid of the wild-type virus, which is the completely sensitive virus, and some low-level resistance,” she recalls. “Then we were really relying on the interferon-ribavirin component to get rid of the higher-level resistance. We were able to look at these profiles and determine how long our drug is needed to do that job.”

  Beyond boosting Alam’s case for shorter-duration treatment, Kieffer’s work gave scientists their first understanding of how HCV responds to direct-acting antiviral medicines. Clinical and commercial interest in her research was keen, and she was asked to give a plenary talk at the Liver Meeting in November at the Hynes. Meanwhile, Vertex signed a broad international collaboration with two Johnson & Johnson subsidiaries to develop and sell VX-950 outside North America and Japan, securing ample financing for its late-stage development and commercialization. Terms of the deal called for J&J to pay the company $165 million up front in cash, with an additional $380 million in potential milestone payments and tiered sales royalties averaging about 25 percent. Wall Street analysts, estimating that the European Union had twice as many patients as the United States and Canada, cheered the collaboration. More than one projected peak US annual sales of up to $3 billion by 2013 and overseas figures cresting at $2.4 billion two years later.

  Smith pounced. After three years of pressing Boger to get the company in shape while insisting to Wall Street that Vertex had not just a breakthrough medicine on its hands but also a true blockbuster, the headwinds had stalled. Like Aldrich, he knew the time to sell new shares to investors was not when you had to but when you could. Smith had converted the remaining debt, and the balance sheet now showed about $500 million in cash. Vertex would lose more than $200 million this year and projected losses of more than $300 million in 2007. With Ken and his legal team filing quickly with the SEC, the company issued nine million new shares, the offering netting about $300 million. Boiling down the math, what Smith realized he could do—now that J&J was footing the bill for Vertex to get through approval to market with its newly renamed HCV protease inhibitor telaprevir (VX-950)—was to fund all the rest of the company’s own R&D for another year simply by minting more stock, which eager fund managers and institutional investors gobbled up in nine days. Perhaps no other biotech had ever been in such a position.

  “When we went out and spoke to investors, we were very bullish,” Smith recalls. “It wasn’t inappropriate—we were basing it on the data—but we were very optimistic. We were very aggressive with what we might achieve with clinical results: the potential and the opportunity. I make no apologies for that. We needed to create a big story with critical mass that caused a Wall Street following. This was a big story. Hep C is a big disease. Nobody had ever seen a result like ours. You’re kind of like the Pied Piper. They start to follow along. There’s also this viral marketing aspect among the investors themselves. There’s a lot of momentum; let’s call it greed as well: ‘I want to be a part of this.’ And then they start to live vicariously through you.”

  From the beginning, science, people, and money had been the vital reagents in Boger’s experiment in building a better company. Throughout the fall, for the first time, a critical mass seemed to be reached. Kieffer stole the show at the Liver Meeting, where a crowd of several thousand packed the main conference hall to hear her explain how telaprevir worked, how it encountered resistance, and how it could be used effectively in a cocktail with existing drugs to cure even genotype 1 patients. Boger, anticipating Vertex’s transformation from a scientific and clinical leader to a commercial one, again turned his attention to a non-obvious foundational issue that felt to him far more urgent even than the singular mission of getting telaprevir to patients.

  Bob Kauffman pressed hard to convince the FDA that in placebo-controlled midstage studies, Vertex could truncate the standard treatment time while also improving cure rates. Long-term safety concerns arose. Telaprevir was highly potent. The longer you took it, the higher the risk to your body, but if you went off it too soon, it could unleash viral resistance. Kauffman partly won over regulators with virology data and modeling. “In the end, the FDA agreed to a multiprong study that allowed us to study shorter duration with some patients,” he recalls. “We were really obsessed about twelve weeks at the time, and the FDA was very concerned. We believed in our modeling. But they did let us do a small number of patients with twelve weeks, and in Europe they allowed us to do more.”

  The race to market was decidedly on, not just with Schering-Plough and Boehringer, but with dozens of other companies, including several that, like Gilead, had started trials with nucs and other polymerase inhibitors that in preclinical assays looked as potent as telaprevir. “We were pushing very hard for an aggressive development program,” Kauffman says. “We knew we were in a competitive area, there were other people working in the field, and it was starting to heat up. We really wanted to both advance our program quickly but also really give patients something that was good at the end—not just higher SVR rates, but higher SVR rates with shorter-duration treatment. All of our advisors kept telling us that would be fabulous.

  “We had a real impetus to stay in the lead. It was frustrating sometimes when it took a few months to nego
tiate a protocol with the regulatory agencies. We were pushing to get stuff done. But you have to see this from the regulators’ point of view. This was a new area, new field. Nobody had ever done this before. Nobody had even shown that you could get an SVR with a direct-acting antiviral until we did it. So they were somewhat skeptical, and concerned. They wanted things tied up well.”

  Within two months of starting Phase II, while Kieffer prepared her slides for AASLD and Smith captivated Wall Street with tantalizing visions of a monotherapy for the leading cause of liver cancer and transplantation, a few patients at different study sites began developing severe rashes. Investigators reported them to Vertex and the FDA. Kauffman, keenly aware that dozens of drugs cause two forms of life-threatening skin toxicities in rare cases, and that a clear correlation can halt a drug from being approved, grew increasingly worried.

  “Things had been swimming along: fabulous swoosh, great data, start Phase II. Then this,” he says. “There was one case, another one, and another one, and we all started looking at each other. You know, the first one, you just go, ‘What was that?’ After three of them, you go, ‘Oh. This could be telaprevir.’ After five of them, you’re pretty sure it really is the drug.”

  During World War II, George Merck made sure that his drug company was central to the war effort. Pharmaceuticals were in low regard—deservedly, since very few of them did anything useful—and profiting from medical research was anathema; an idea whose time had not yet come. Merck, approaching age fifty, chaired the government’s biological weapons program. He also helped drive—and was a prime beneficiary of—Washington’s efforts to marshal the nation’s research labs in defeating the fascist powers.

  President Franklin Roosevelt’s chief science advisor, Vannevar Bush, chose Merck’s top consultant and scientific architect, Dr. Alfred Newton Richards, to chair the Committee on Medical Research—the biomedical equivalent of the Manhattan Project. On August 7, 1941, four months before Pearl Harbor, the CMR heard intelligence reports that the Germans had isolated the active substance from the cortex of the adrenal gland—cortisone—and were feeding it to their pilots to help them withstand the rigors of aerial combat. The committee made cortisone production its highest priority. That evening, after returning by train to Philadelphia, Richards received two visiting researchers from England, Howard Florey and Ernst Chain, who had experimented with a highly scarce mold extract—penicillin—to treat burns and infections, harvesting it in desperation from patients’ urine and reinjecting it until they ran out. By the end of the war, under Richards’s direction, Merck led other drugmakers and federal labs in making enough of the antibiotic to supply the nation.

  Driven to expand his business and assimilate himself and his company at ever higher levels of American life, Merck built deftly on his wartime public service. Bush, forward-seeing architect of the nation’s postwar scientific order, joined the company’s board, soon becoming chairman. In the labs, chemists working under the fiery, protean head of research Max Tishler—Boger’s mentor—labored another decade to develop a synthesis to make cortisone commercially available. George Merck became a spokesman for the industry’s idealistic nature, his company exalted for its scientific leadership and social progressivism. In August 1952 he appeared on the cover of Time over the caption “Medicine is for people, not for profits.”

  Boger had a similar trajectory in mind for himself and Vertex, but the War on Terror hadn’t produced comparable opportunities for drugmakers to pitch in. The only Axis was the name-only “axis of evil,” and the wars in Afghanistan and Iraq offered few opportunities for ambitious, public-spirited company builders to assume national leadership roles against a major threat. Boger seized on an alternative route. Envisioning a leading position for Vertex locally, within the global health industry and with government regulators and payers, he set about building a highly visible web of outside responsibilities, connections, and interests. “Externalities,” he called them. To keep his employees up on what he was doing, he started to blog about his activities internally, for Vertex-only consumption.

  Boger became the first biotech executive in nearly a decade to chair the Massachusetts High Technology Council, and he joined the board of the Biotechnology Industry Organization (BIO), the national biotech trade organization. He sat on the board of fellows at Harvard Medical School and became a major fund-raiser for the Greater Boston Food Bank’s capital campaign. Thinking globally but acting locally, he became a close advisor of Governor Deval Patrick, representing the state’s broad scientific, academic, and business interests, and advising Patrick on how to position Massachusetts for the future. “Unlike many of his peers—who feel that since they represent the future, politicians should come to them—he sees the value of involving himself deeply in Beacon Hill affairs,” Boston magazine noted, ranking him among the city’s power elite.

  He also heartily adopted a few of the trappings of the role, the VIP/inside-the-ropes attention, access, and other entitlements that major CEOs enjoy. In January, a week after returning from the Morgan conference where he outlined Vertex’s plans for the trials of telaprevir and VX-770, he and his wife, Amy, traveled with the New England Patriots to the AFC championship football game against Indianapolis, sitting three rows behind the team’s cerebral head coach, Bill Belichick, during the flight. In March they flew to Mountain View, California, for the XPrize Foundation’s Radical Benefit for Humanity at Google’s sprawling headquarters, special guests of one of the foundation’s board members. With no structure taller than a few floors and “curiously conservative landscaping,” he observed in a ten-page, single-spaced blog post, the campus looked “like an unnaturally clean summer camp for geeks.”

  He was seated at a table with Charles Lindbergh’s grandson Erik, who four years earlier had piloted a replica of his grandfather’s Spirit of St. Louis on the seventy-fifth anniversary of the first solo flight across the Atlantic—a grueling physical and mental feat. Erik Lindbergh had been diagnosed in his early thirties with rapidly progressing rheumatoid arthritis and had been forced to stop flying before he started to take Enbrel, which halted the disease and restored his life, and for which he was so grateful that he’d become a celebrity spokesperson for the product. “And so, I casually asked him,” Boger wrote, “ ‘How important to you would be a once-a-day pill that did about the same thing?’ Unhesitatingly, he jumped forward. ‘That would be great. I hate Enbrel. I’d be curled up in a home without it, but I hate it. The injections: They burn. The new less-frequent injections burn a lot worse than the older ones. The infections. I hate it.’ We talked about Vertex’s decade-plus-long commitment to arthritis. Vertex has a new fan.”

  The Boger Blog recounted in colorful detail the glittering events of the evening: the A-list sightings (Larry Page, Sergey Brin, Richard Branson, Jerry Brown, Arianna Huffington, and Robin Williams, who performed after dinner); the extravagant table setups and posh, all-organic cuisine by Google’s in-house chefs. It showcased Boger’s far-flung interests, erudition, cultural commentary, and own geek “cred”—unscrolling in a rush of asides. About a lackluster finale of “Hallelujah” by singer Rufus Wainwright, for instance, he wrote, “Get the Leonard Cohen version, on his Various Positions album. It’s chillingly superb recitative, a mature creation to Wainwright’s empty simulacrum. (The pop Jeff Buckley version, on the album Grace, is second derivative and even more self-indulgent than Wainwright’s.)”

  During the silent auction, Boger hoped to win a zero-gravity flight with Stephen Hawking. A lifelong space travel enthusiast who views Hawking as the greatest physicist of our time, he was enthralled by the idea of flying weightless alongside Hawking in NASA’s “Vomit Comet”—a specially modified Boeing 707 with a padded cabin where, for twenty to thirty seconds, as the plane flew sweeping parabolas in an invisible, protected corridor above the Atlantic, they would float free. Hawking is as famous for his motor neuron disease, paralysis, electronically modified voice, specially equipped wheelchair, and expansi
ve wit as he is for his theories. Boger confessed to feeling bereft when he at first learned that he’d lost out to another attendee who outbid him, a mix-up that wasn’t resolved until the end of the night. He blogged, parenthetically: “Star Trek fans have already seen Dr. Hawking in space, playing himself (the only person ever to play himself in any Star Trek episode) in Star Trek: The Next Generation episode #252, ‘Descent—Part I,’ first aired 21 June 1993 (Stardate 46982.1). As every fan knows, Hawking, as himself, plays poker with the android Data, in a holodeck simulation including Albert Einstein and Isaac Newton. Actors played the latter two characters. Best episode ever.”

  It would be hard to overstate Boger’s joy and fulfillment on a Tuesday in April, when he flew to Florida to meet up with two dozen other passengers to take the trip on “G-Force One.” Earlier in the month, McHutchison had given a late-breaker presentation in Barcelona, Spain, at the European Liver Meeting on the first shortened-duration telaprevir trial. The results suggested that twelve weeks of telaprevir-based therapy with peg-riba enabled some patients to clear the virus. The company also now had a corrector for CFTR—VX-809—on track for clinical development, the key ingredient in the drug cocktail that could be the elixir of life for the great majority of those with cystic fibrosis. Boger was soaring. “Jet Blue to Orlando,” he wrote. “This was no Mickey Mouse tour. I didn’t go to Tomorrow Land. Felt a little Goofy, but that was understandable. I was headed for weightlessness. Weightless. With Steven Hawking. Weightless.”