The Antidote: Inside the World of New Pharma Read Free Page B

endeavor that, like drug discovery, resulted in failure more than 90 percent of the time. Right now AIDS and the virus that caused it, HIV, gave the company its best hope for getting a drug to doctors and patients.
    Following Boger’s speech to the executives, senior scientist Mark Murcko delivered a spirited recap of Vertex’s design strategies for a new class of direct-acting antiviral drugs—HIV protease inhibitors—that the company was relying on to catapult it into the ranks of the world’s elite drugmakers. Murcko, thirty-three, was the last of a half dozen major Merck defectors to join Vertex and the one Boger had fought hardest to get, platooning the scientists to call him every other night for three months until he agreed to move. More and more, he’d become Boger’s technological seer, sidekick, everyman, and commentator: a stocky, precocious, deep-voiced, aside-tossing Sancho Panza. At first Boger refused to go into AIDS, but Murcko and a few others changed his mind.
    Murcko peppered his slide presentation of elegant computer-generated three-dimensional molecular models with striking new data and throwaway gibes at traditional discovery methods. He told the audience about a drug hunt of rare effectiveness and speed. Proteases are enzymes that cleave other sections of protein: in the case of HIV,enabling it to multiply. Theoretically, if a small molecule could latch onto the active site, it would block replication. HIV protease offered a promising drug target and Merck and several other companies had compounds in the clinic, although none had yet shown that their molecules were effective in patients. More to the point, the target site was only Vertex’s second project; the first had crashed spectacularly when the mechanism for which it was churning out compounds proved to be biologically irrelevant. Merck was spending more on HIV than on any other research effort in its history, throwing hundreds of chemists at the project. Vertex, Murcko said, had just five.
    Vertex needed to speed up the process of getting its own compounds to patients, something it had never done before and that would not be possible at this stage without another partner. What the company had was Boger, hubris, and a passionate group of mostly ex-Merck researchers as determined as he was to “do it right”—“Merck’s first team making drugs for the hardest diseases with computers,” as Aldrich liked to tell potential partners and investors. Structure-based drug design is premised on having a reliable 3-D computer model of the target molecule in the body, so as to be able to visualize the inmost workings of living matter. Vertex had industrialized its processes for isolating and purifying proteins to the point where it could reliably solve complex structures showing how different prospective drug molecules bound to the business end of a target. Murcko’s group digitally modeled new atomic interactions and suggested improvements based on predicted changes in activity. This “feedback loop,” he told the audience, enabled Vertex’s small group of chemists to make much more informed choices than Merck’s legions about what molecules to make next.
    Not everyone was sold. After lunch, the keynote speaker, Dr. Edward Scolnick, president of Merck laboratories, unfurled himself from a too-small chair on the dais and rose to deliver a talk entitled “Molecular Approaches to Drug Design.” Murcko, sitting just to his right, smiled, amused. Scolnick was notably hard charging. He had driven the billion-dollar drug Mevacor, the first of the cholesterol-reducing statins, to market, devoting a significant portion of his toxicology budget to overcoming concerns about statin toxicity. Merck’s findings convinced theUS Food and Drug Administration that what seemed to be cancerous changes in animals weren’t really cancers and that a resumption of human testing of statins, after a three-year moratorium, was warranted. Now he was driving