The Antidote: Inside the World of New Pharma (5 page)

Throughout the fall, Vertex positioned itself to partner in HIV while it also sought to raise its visibility. Several other companies had now shown that blocking HIV protease remained the likeliest hope for stopping the virus from spreading. Merck enthusiastically released early clinical data showing that blood tests from four patients taking its inhibitor showed dramatically reduced levels of virus for several months. In the HIV project council, Boger, Sato, Roger Tung, and a few other scientists plotted strategy for the next major medical meeting, in mid-December in Washington, the First National Conference on Human Retroviruses. It was at such meetings that the business of AIDS, as much as the science, was now conducted.

Vertex so far had refused to release the chemical structure of VX-478, raising doubts outside the company both about how effective and unique it was. Unlike the big players, it didn’t have its own patent lawyers and was relying on outside counsel, who was proceeding slowly. In Washington,
all the other companies would promote their molecules even if they reported no new data. Vertex needed to present something to prove it was in the race. Boger suggested a signature solution. Chemist Dave Deininger synthesized the compound and gave it to Eunice Kim, who quickly solved the costructure. At the conference, after Merck’s scientists conceded that they didn’t know how their drug worked specifically at the molecular level, Tung concluded his own talk with a slide showing how Merck’s drug sat in the active site of the protease, in effect answering the question for them.

Boger and Sato reveled in such in-your-face diversions; they were good for morale, good for the dinosaur-slayer story the company was crafting for itself. But Vertex couldn’t maintain its secrecy with Burroughs Wellcome, which, only after seeing how VX-478 bound to the active site of the protease, agreed to collaborate. A few days after the conference, the two companies announced that they would jointly develop HIV protease inhibitors for Europe and North America. The deal, which would eventually bring Vertex $42 million, was in fact worth several times that, as Wellcome agreed to pay the full cost of development—perhaps $200 million—and Vertex won the right to copromote any drug, enabling it to start building a marketing arm. Aldrich negotiated royalties that climbed from the midteens, rare if not unheard-of for a preclinical compound. Vertex’s stock rose $2 on the news, to $17.50.

Boger was pleased with the arrangement. Burroughs was the industry leader in HIV. It also had been the target of damaging protests for charging patients $10,000 for AZT, a compound it licensed from the National Institutes of Health, where the molecule was discovered and developed by government scientists. With multidrug therapy sure to be the future—unless one of the protease inhibitors was so superior that it could vanquish HIV by itself—Boger looked forward to bringing his compound quickly to patients in conjunction with the one indispensable agent in the field, AZT; yet skirting that drug’s heavy political baggage, which in the current grim environment, and with the threat of price controls looming larger now that the Clintons had uncovered their health care plan, guaranteed controversy and, most likely, a media circus. He could easily imagine enraged AIDS activists resuming
round-the-clock pickets and returning to the New York Stock Exchange to pour sheep’s blood on investors, chanting “Sell Wellcome!” and “Fuck drug profiteers!”

“I’m glad,” Boger said, “our money comes off the top.”

Boger and Aldrich agreed that the time to raise money on Wall Street was not when you had to but when you could. One day after the Wellcome deal was announced, Vertex filed a fast-track stock offering that would yield, six weeks later, another $62 million. Though it remained a treacherous period for biotech and drug stocks, the offering built from start to finish, with shares trading at $16 on the day they started their road show in Europe and $18 two weeks later when they ended it in Boston and New York. It would still be years before Vertex might have a drug, but with three deals in 1993, the company was momentarily in the black, declaring a fourth-quarter profit of more than $2 million. It had put $120 million in the bank. Aldrich was promoted to senior vice president, by title and, in fact, the second most valuable person in the company.

Vertex issued hefty stock options to most of the original scientists to keep them from defecting, although with the labs starting to click, and intriguing new targets sprouting across the spectrum of diseases, none of them had any real mind to leave, not soon. Boger deliberately hired people who, like him, craved the chance to compete at the forefront. Yet when the first researchers arrived in Cambridge, they discovered an atmosphere of almost willful anarchy, an antiorganization—“chaos,” says Sato, whose job it became to bring order. For two years, the scientists had no offices, lugging their backpacks and briefcases from one communal desk to another to use the phone. There was little rank or hierarchy; decisions were made by the project councils. During its initial public offering, launched during a speculative bubble, the raw, head-snapping speed and intensity of the chase and the relentless pressure to do important science while cutting corners overwhelmed the principles of an idealistic young crystallographer, who smashed a chair in the lunchroom in a fit, screaming, “
You will all be stricken down
!” He left the company soon after to attend medical school.

Boger’s “social experiment” was designed to encourage self-selected
leaders who not only would do excellent science but also grasped viscerally that the decline of Big Pharma was due less to cluelessness at the bench or fecklessness on the executive floors and in the boardroom than to the immobilizing sludge of middle management in between, which even at Merck had led to project heads prioritizing how many compounds a group made over whether or not they did anything useful. Boger wanted champions, people who would passionately disagree with each other and with him, who in the end would push groups and projects ahead because they had smarter ideas, worked harder, generated more compelling data, and persisted when others would quit.

Mainly through their association with HIV protease, Murcko, Thomson, and Tung emerged from the founding group to become the company’s rising stars. Statistically, most pharmaceutical researchers work their entire careers without helping to produce a drug that makes it all the way to market. That meant that even if Boger was right and Vertex could improve its odds from 1 in 30 to 1 in 10, most Vertex scientists were subject to the same sobering reality, a career-long string of failures where you best found your job satisfaction in something other than success. For most, it became the daunting challenge itself. VX-478 was not a drug, but it looked as if it would be, and those who led in bringing it out of the lab enjoyed a surge in influence, credibility, and prestige.

Each, in his way, spread his wings. A computational chemist and molecular modeler by training, Murcko stood between the structural biologists, who churned out torrents of data about the smushy interdigitation of atoms, and the chemists, who designed and made inhibitors. He considered VX-478 a tipping point, absolute confirmation of Vertex’s superior strategy for discovering major drugs. “For me the bottom line was: five chemists, eighteen months, two hundred six compounds. It all played out according to script. It was the project from central casting.”

Murcko’s intellectual curiosity rivaled Boger’s and he was often, in the project councils and at Friday afternoon beer hour, the first and most effective to challenge him; “Joshua the Indeflectable,” he once mused. Nearly a foot shorter than Boger, he was built like a catcher, mustachioed. Like Boger, he liked to tweak the mighty, and he thought as deeply about the iterations of the discovery process and the interactivity
of people and ideas as he did about the forces of atoms. Murcko had come to biochemistry through high-speed computing. On his first day at Vertex, he flew to Boston from Philadelphia rather than waste the time driving and worked that night until three in the morning, hands flying over his keyboard. In the early days, he often “pinned” the company’s supercomputer with his experiments; asked how much computing power he could use to do simulations, he deadpanned, “Infinite.”

Awaiting a crystal structure for ICE, Murcko started transforming his research group into a nascent skunk works, hiring several new people who knew both biology and computer modeling and encouraging them to broaden their thinking about what more was possible. He authorized his scientists to invent new technologies and write their own code if they couldn’t find outside collaborators or buy what they needed. The spark of innovation is asking questions; Murcko questioned everything.

“The software at the time didn’t take into consideration any of the downstream physical properties of drugs,” he recalls. “How soluble is a compound? If it’s not soluble, it can’t get into cells. Could you use computers to predict not just the lock and key—how does the drug bind to the active site—but go a step further, to see how one molecule might be better than another because it has better physical properties? We ran computer simulations on hundreds of associated molecules and asked, ‘If I was just going to change one atom, could I increase its solubility?’ For VX-478, one small change predicted to be at least a hundredfold more soluble turned out to be even better: five hundredfold more soluble.”

In January biophysicist Keith Wilson finished the crystal structure of ICE. It was a big protein for the day, a complicated piece of architecture with two domains, and it would receive much glowing press when it was published in the journal
Nature
. Murcko and his modelers went to work. Sitting at aging Silicon Graphics workstations in a darkened room, they wore clunky wraparound 3-D glasses. Chugging Diet Coke, unshaven, they resembled cave-dwelling ancestors of the LeVar Burton character in
Star Trek: The Next Generation
. On the screen, stick diagrams of hundreds of connected atoms in brilliant reds, purples, and blues rotated gently, like hair-thin Tinkertoys, in a fathomless black sea. Within hours, the scientists recognized that although the overall folding was different
from other protein structures, “down deep” ICE resembled a familiar type of protease with a similar cleaving mechanism. Fortified by what they trusted was an original conceptual breakthrough, since no one else had the structure, they started pulling hundreds of scaffolds from chemical catalogs and Vertex’s relatively tiny compound library and docking them in the binding pocket. Five weeks later to the day, running round-the-clock simulations, they chose a core for a new class of molecules that, once synthesized, would prove so much more potent than any other inhibitor that it leapt instantly to the lead in the combined drug discovery efforts with Vertex’s European partner.

Tung took the AIDS compound VX-478 public. As lead inventor on the patent application, he became the face of what Boger called Vertex’s first “real major scientific publicity blitz.” Describing himself as “a sort of first-and-a-half generation, mixed background, American-Japanese and -Chinese,” Tung was thirty-four, deep voiced and serious. His sobering intensity masked a fiery ambition to aim high, discover drugs, and avoid ever becoming subordinate on a project. In his second year at Vertex, toiling for several months on a grueling synthesis, often until midnight, he started to sprout grey hairs, singly at first and then in clusters. After leaving the lab, he and the other chemists drank most nights until they closed the bars in Central Square—a rite at several local start-ups. Unlike Murcko he wasn’t yet entirely sold on the value of structure-based design, though this could also be attributed to a near-universal skepticism of bold claims based on partial data, even when the claims were his. “I live to be proven wrong,” he said.

A year earlier in Berlin, Tung was taken to task for not disclosing the molecule’s chemical structure, and bravura gimmicks like embarrassing Merck at the Washington retroviral conference, while satisfying, only invited more doubts about what Vertex must be concealing. The issue was its patent position. The delay in filing its US application put the company two weeks behind Searle, which had made a molecule with a similar core that appeared to have, like VX-478, exceptional bioavailability.