The Antidote: Inside the World of New Pharma by Barry Werth Read Free Book Online Page B

protease might not be as tractable as the company’s earlier targets. “We knew enough about the polyprotein that gets made by the virus that it was not a dead ringer for HIV,” he says. “It had some funny new funky ways for creating proteins, including this little cofactor that was essential. It was very conspicuous that there were two adjacent regions that interacted with one another very significantly, and then another third piece thatwas key to the activity of the protease. And it was a puzzle as to what the architecture was going to look like in the end. More particularly, it gave us this chicken-or-the-egg problem of: we couldn’t make the protein, and we didn’t have a reliable assay to test whether we had made protein. That was really the bind that kept everyone on the planet anchored in the early days.”
    Throughout 1995, the pressure mounted to solve the structure. Merck, Roche, structure-based rival Agouron, and many others were pouring major resources into the race. Meanwhile, public health officials were reaching the conclusion that many more people were infected with HCV than previously predicted, perhaps twice as many as with HIV. Vertex’s attempts at protein production stalled, cycling blindly in a cul-de-sac; the scientists didn’t know what material they had made and couldn’t test it to determine what to do next. With a reliable assay they could try hundreds of subtle changes in conditions to isolate more protein, but that wasn’t an option. “The Dark Ages,” Thomson called it.
    “Everyone along the way had some different cross to bear,” biophysical chemist Ted Fox, who led the lab effort, recalls. “Those project councils were really tough. You got a lot of really energetic people, excited passionate scientists, and you’re getting beaten over the head week after week. I remember at one point, we finally had some active enzyme—doesn’t look good, not very much; maybe we have an assay—and Josh saying, ‘My God. This thing wouldn’t survive if it were this inefficient in the real world. Guys, you’ve got to work harder, or you’ve got to do more.’ ”
    It was Thomson again who broke the logjam, though others at Vertex were thinking along the same lines. He asked Rice’s group to calculate the space between two regions by mapping the interceding genes, then asked the chemists to synthesize chains of amino acids that could be whittled, atom by atom, roughly to that same length. The chemists fashioned tiny artificial spanners, ten or twelve residues across, to form the most intimate molecular “embrace.” The exercise worked. “You took your protein from the bacteria that were engineering it, then you mix it with this little synthetic peptide, and bingo, you’ve got active protease,” he says.
    As Murcko anticipated, some targets are much harder to isolateand purify than others. Nearly two years after receiving Rice’s clones, Fox’s group delivered the first Thomson Unit of HCV protease to the crystallographers.

    In February 1995, a year later than Boger had predicted to Wall Street, VX-478 was given to eighteen AIDS patients in a Phase I clinical trial, a dosing study of oral availability, pharmacokinetics, and tolerability—not its effect on HIV. Less than three weeks later, US regulators cleared a merger between the Burroughs Wellcome Company and Glaxo, creating the world’s largest prescription drugmaker. During the next fourteen months, Aldrich and Boger’s brother Ken, the company’s lead outside counsel, joined with Glaxo Wellcome’s lawyers to try to convince Searle to come to a reasonable solution over its patent claim.
    “Searle had this guy, total jerk, totally irrational about this stuff, but by virtue of that, he ended up being quite effective,” Aldrich recalls. Early in the negotiations, he and Boger flew to Chicago to meet with a group from Searle. Never one to hide his contempt for the practice among drugmakers of aggressively pursuing patent