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

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.
    More to the point, Searle filed a so-called Markush structure. In the 1920s, chemists, to protect their inventions, sought a way to avoid havingto patent individually each member of a class of compounds that would have a similar function. Eugene Markush, a dye manufacturer, filed for and won a patent for a class of compounds with a replacement group of atoms at several positions, meaning it covered potentially thousands of molecules. Based on the alluring but false premise that combinations of different groups of substituents around a common core generate molecules that have the same activity and biological properties, Markush structures amount, legally speaking, to hurling kegs of nails off the back of a moving truck.
    Boger delayed revealing VX-478’s structure until after the company’s European patent application was made public. Merck, meantime, stumbled. At the retroviral conference in December, attendees had crammed into a presentation in the Washington Sheraton Hotel to hear the company report that patients getting the Merck drug had a 42 percent drop in HIV after just two days of treatment, compared with 1 percent for those on AZT. “We were beside ourselves,” Scolnick would recall. “We thought we had the cure for AIDS.” Then, six weeks later, a molecular biologist examining blood samples from trial participants discovered that the virus had mutated, building resistance to the drug. Another test indicated the virus hadn’t developed resistance. Scolnick called Anthony Fauci, the government’s top AIDS researcher, to get his read. “You’ve got resistance,” Fauci told him. Scolnick protested, bringing up the conflicting data. “I don’t care,” Fauci said.
    “You’ve got resistance.”
    Boger, Sato, and Tung conferred throughout the spring. Formulation and other problems had slowed the work at Wellcome to a crawl. There were so many treatments being tested in humans that it had become difficult to enroll patients for new trials, and it now looked as if Vertex’s molecule wouldn’t be in the clinic until the end of 1994. Pressured to show their hand, they opted to disclose the chemical structure at the Third International Conference on the Prevention of Infection in Nice, France, in June. The audience seemed skeptical from the outset. Despite hoping for a breakthrough, many were eager to see Vertex come down a notch. The compound was a sulfonamide, one of the class of molecules that were the first antibiotics—the sulfas—and now were also soldas anticonvulsants and diuretics. Novel functional groups extended from a core that shared common features with other protease inhibitors.
    Reactions ranged from qualified optimism to mild disappointment. No one felt that Vertex had been blowing smoke, but neither was anyone immediately convinced that VX-478 was all that the