The Antidote: Inside the World of New Pharma (4 page)

Six compounds in all were still in contention as the council now set about choosing which one to scale up for human testing—a hugely complex and expensive process requiring quantum jumps of activity at every level of the company. Boger had been pressuring the scientists for months to choose a candidate, but the lead chemist, Roger Tung, resisted him, importuning for more time and data. In June Tung would lead a Vertex contingent to the massive annual AIDS conference in Berlin to disclose the company’s work publicly. He wanted to tell a fuller story.

“I’m all for stalking horses,” Boger interrupted, “but when the real horse is ready, I don’t want to keep him in the paddock because the stalking horse is at the last turn and we want to let him finish so that he doesn’t feel bad. I want to go out and shoot him.”

To Boger, there was just one issue: getting the FDA to approve the testing of Vertex’s compounds in humans before Merck announced its first clinical results. Boger believed Vertex had the better drug: smaller, easier to synthesize, more likely to get into the brain, where the AIDS virus can hide. But if Merck’s medicine was highly effective, even in a few patients, all bets were off. The world was desperate for better treatments for AIDS. Other companies—notably Abbott Laboratories, Hoffman–La Roche, Searle/Monsanto, and another structure-based start-up, Agouron Pharmaceuticals—were starting trials with protease blockers. But no one dominated competitive markets better than Merck, and Boger dismissed the others.

“Throw a dart,” Sato said.

The council, after arguing for just a few minutes, picked VX-330.
Boger wasted no time. Dispatching most of the scientists with a hail of laughter, he huddled with Sato and a few senior people on the next set of experiments: toxicological studies, animal studies, multidrug studies with other compounds, one-on-one comparison studies, formulation studies to determine how to get the drug into a pill or capsule, blood assays, ultrapure large-scale preparations of the molecule. By Boger’s timelines, the molecule had to be available for human experimentation in AIDS patients by the end of the year or during the first quarter of 1994. An immense amount had to be known before then.

Thirteen years into the epidemic, the crisis had only spread and worsened, and hopes for a cure seemed ever further away. At the meeting in Berlin, thousands of grim public health officials, doctors, nurses, academic researchers, patient advocates, and journalists heard a drumbeat of reports about alarming infection rates, especially in Africa. The outlook in vaccine research was dismal. Despite its cautiously rising expectations for protease inhibitors, the drug industry’s involvement so far had been suspect, and the most recent studies with experimental drug therapies confirmed the view that the industry was failing to make even incremental progress in fighting the virus.

A new European study, the most conclusive to date, showed that the standard drug AZT, which had raised the first real hope that targeted, effective anti-HIV drugs could be found and developed, did nothing to prolong life for symptomless infected people. They experienced an initial delay before developing the skin cancer and pneumonia that would kill them, but they suffered and died at the same rate as those who didn’t receive the drug. HIV is an RNA virus that uses an enzyme called reverse transcriptase to make DNA copies of itself. Because AZT partially blocks the enzyme, it was widely hoped that adding a second reverse transcriptase inhibitor would boost effectiveness. But in the first American study to evaluate the impact of combining AZT with such follow-ons, not one patient showed improvement.

“Only an eternal optimist,” the
New York Times
reported in the first sentence of a long article that neglected even to mention protease inhibitors, “would have left the ninth international AIDS conference here last week believing that new drugs will be available anytime soon.”

AUGUST 22, 1993

Debra Peattie, leader of the company’s molecular biology group, approached Thomson and Sato about launching a project in hepatitis C, another recent viral contagion where the scale of the medical problem was just becoming clear, and the existing therapies were not good. Unlike AIDS, the epidemic was stealthy, slow moving, and indolent, with symptoms taking decades to show up in most infected patients. The disease was known only since the 1960s, initially as a reaction to blood transfusions, and previously named—“in a less than brilliant foray into nomenclature,” its codiscoverer said—non-A, non-B hepatitis. Only now, more than two decades later, was it becoming a recognized public health threat.

Hepatitis C puzzled virologists, baffled doctors, and had no vocal constituency among sufferers, the vast majority of whom didn’t know they had it. Three years earlier, scientists at the biotech company Chiron Corporation identified the virus that caused it, making a blood test available, and ever since then doctors were discovering more and more people who were infected but had no symptoms. At the same time, nearly 40 percent of carriers reported that they never used intravenous drugs, never received a transfusion, and had no evident reason for contracting the infection by blood-to-blood contact. The scale of the contagion was unknown and, it seemed, given these mysterious discrepancies, perhaps unknowable.

Sato and Thomson were intrigued. The target was another viral
protease. It was a serious unmet medical problem, a wide-open opportunity. Liking the feel of it, they sensed its tractability. But Vertex couldn’t initiate a program by itself; there was simply too little published about the virus, and the company, despite its success with HIV, had no virology group of its own. Peattie, scouring the literature, learned that three labs, all roughly equivalent in their abilities, had begun to map the virus, charting the structure and function of its various domains, and were well ahead of the rest of the world. Two of them already had collaborations, with Merck and Hoffman–La Roche. The third was run by an unattached academic, Assistant Professor Charles Rice of Washington University School of Medicine in Saint Louis.

Peattie flew to Saint Louis in late August. She was pregnant with her first child. Having become enthralled at Vertex with the business of research—“the ability to construct negotiations around science”—she recently had been accepted at Harvard Business School, and she anticipated that Rice, like many academics, might be less than enthusiastic about collaborating with a small, unprofitable partner. On the other hand, she knew he had few other options. The hepatitis C virus, HCV, wasn’t fashionable like HIV. Universities and federal funding agencies avoided parceling grants to researchers in innovative disease areas.

Most academic researchers fall into their fields of interest, or are attracted to them via some mixture of challenge and circumstance, but Rice was called to hepatitis C. He had been the country’s leading expert in yellow fever when an FDA scientist phoned to ask if he could help develop a vaccine against HCV. Because both viruses are so-called flaviviruses—
flavus
means “yellow” in Latin—the caller hoped Rice would find structural similarities. Digging into the biology, Rice’s lab determined that HCV started as a larger precursor, a polyprotein, and cleaved itself into at least ten smaller subunits. He and his group identified the protease, found that its optimal activity depended on binding to a small viral protein, and reasoned that since it cleaves at multiple sites, the virus couldn’t survive if the protease was blocked. They also predicted other possible drug targets.

Rice was stalled. He couldn’t expand his research without funding, and he was finding scant support among the usual sources.
“You bootstrap your way along when you want to start something new,” he says. “After we’d done quite a bit of work on this on the fly, we applied for a pilot internal grant at Wash U. We got the reviews back, and they said, ‘Well, you know this is really important, and you guys have made great progress. But you’re really far enough along to write an RO-1 on this [apply for a US National Institutes of Health research grant], so no money for you.’ ”

Peattie and Rice sketched out a collaboration to determine the structure of the protease, quickly submitted it to their respective licensing teams, and by October the agreement was signed and experiments were being discussed. As Peattie moved to the business side before giving birth to her son, Thomson assumed the lead role on the project. He had recently developed an industry-beating production method for a second protease, ICE—interleukin-1 beta-converting enzyme—a promising target for fighting inflammation. His team’s work had enabled Vertex to negotiate a highly favorable licensing deal to develop ICE inhibitors for patients with rheumatoid arthritis and other autoimmune diseases despite having no drug leads of its own. “All we had,” Sato recalls, “was another of John’s pull-a-rabbit-out-of-a-hat things.” To celebrate his and Vertex’s achievements, Thomson had just bought himself a terrifyingly sleek naked-frame motorcycle, a Ducati Monster—a “rocket,” he called it—and he was ripe to plunge in and go hard against a worthy problem. “All three labs were bogged down, saying, ‘We think the protein is like this, but we don’t know how to make it or get it active out of the cells,’ ” he recalls.

“So it’s a protein biochemistry problem for a protease specialist hot off HIV and ICE. It was right up my alley. Also we were identifying the attractive opportunity of getting the program kick-started in a collaborative mode with Charlie Rice, and the obvious opportunity for us was to say, ‘We can help you move this along and discuss how to get active material.’ So I was the sensible person to brainstorm with Charlie on what to do. Charlie wanted to see his fine work stimulate discovery of drugs. He gave us intellectually a kick start into the field. We gave him some money. He gave us some reagents to get started. And that was the start of it.”

For every development deal they did, Boger and Aldrich talked with twenty to twenty-five potential partners—“kissing a lot of toads,” Sato called it. With HIV, their prospects were limited on the one hand by the small number of companies that knew how to make antiviral drugs and, on the other, by the emerging glut of labs racing to develop protease blockers and numerous other types of treatments. Nestled in the company’s sweet spot was Burroughs Wellcome, which sold the AIDS drug AZT.

The British-owned firm had come of age scientifically by creating the first antiviral drugs. Building upon in-house Nobel Prize–winning discoveries about how nucleic acids, the stuff of DNA, are synthesized, it led the way in developing so-called nucleoside analogs: “nucs.” These are small molecules that mimic the structure of the building blocks of genes; as a retrovirus tries to make more of itself by assembling bits of genetic material inside a cell, nucs insert themselves, breaking the chain and preventing the virus from replicating. AZT is a nuc and, as is typical of such chain terminators, many of which are used to battle cancers, broadly toxic, especially to blood cells, disrupting the structures that energize them to grow and reproduce. And yet because it was the only drug available, doctors prescribed it at high doses to desperate patients. Though resistance developed quickly, and many patients suffered life-threatening anemia and infections, Burroughs was reaping $500 million a year in sales. Determined to defend its franchise, it had become captivated by its own success, insisting that nucs would remain the backbone of any future treatment for AIDS.

“Somebody [at Burroughs] made the error of saying that proteases weren’t very important, so they had been very late to the research party there, where everybody else had jumped on it,” Boger recalls. “As opposed to, say, Abbott or Merck or even Lilly, they were very late realizing that the protease was going to be the mechanism that in HIV would be most effective. They also had some people saying that it was not going to be possible, you can’t make drugs against proteases. Of course they were nucleotide guys.”

As Vertex cranked up its preclinical experiments in the wake of the
Kissei agreement, it approached Burroughs Wellcome with a novel proposal. A key goal at this stage was determining what a human body would do to a small molecule once an individual swallowed it, a science known as pharmacokinetics, or PK. It didn’t matter how potent or specific a laboratory compound was if it wasn’t still around in high enough concentrations, hours later, to be taken up by living cells in the body of a sick person. Vertex offered Burroughs, at no cost, 10 grams of a successor molecule to 330—VX-478—so that Burroughs’s pharmacologists could feed it to ferrets, dogs, monkeys, and other species and see what happened. Boger recalls: “We said, ‘Tell us what you’re going to do. Tell us the protocols. If we say okay, you can do whatever you want with it for thirty days and we get the data. And we can use the data if we don’t do anything with you.’

“They had better PK resources than we did,” he says, “and we wanted to get better information, faster, cheaper, than we could get from the outside. We were pretty sure that this molecule was going to be orally bioavailable but we didn’t have any data that it was. So we gave them 478, and they came back and said. ‘This is really great. This is better than anything we have.’ They had a small protease program, and they said, ‘We’re shutting down our program if we do a deal with you.’ ”