Further, the liver problems occurred most often when the dose was 2,000 milligrams per day or more. Druker knew from his preclinical studies that the ideal dose of the drug would probably end up being much lower. So he wasn’t bothered by liver toxicity. The point of doing the toxicology test was to see how the drug affected the liver, not to kill the animals by giving them excessive amounts of it. He knew that if he saw elevated liver enzyme levels in people with CML, he would stop giving them the drug. There were concrete warning signs that any oncologist would heed, so the risk of liver failure was extremely minimal.
The company didn’t see it that way. “Their view was, nope, we’re going to have to go into monkey studies, and that will take another couple of years,” Druker recalled. He was told that once the results from the monkey studies were in, Novartis would then decide whether to launch a clinical trial.
The company feared that the FDA would see the liver data from the canine studies and forbid the clinical trial out of safety concerns. In fact, a member of Novartis’s oncology division had previously worked at the FDA, and he insisted that the drug would never make it through their review of toxicology data. To Druker, that concern seemed overblown. After all, the standard medication for CML at the time, interferon, did not work for many patients, and those whom it did help often suffered terrible side effects. Bone marrow transplantation, the only true cure for CML, was an option for only a fraction of CML patients, who first had to survive the harrowing and dangerous procedure before they could be assured of living CML-free. With such a paucity of therapeutic options, would the FDA really thwart a trial of a new drug because it might cause liver toxicity, an easily identifiable problem that could be stopped long before it became life threatening? “That just didn’t make much sense to me,” said Druker. Plus, a colleague later told Druker, dogs have particularly sensitive livers, and so are far more prone to side effects in that organ than are other lab animals, or humans.
Inside Novartis, concerns about toxicity seemed prudent and warranted. Having seen a severely toxic side effect in an animal, could the company really move forward with treating patients? “If we do so and then a patient dies, we will be in deep, deep trouble,” said Zimmermann. “The company can lose its reputation when you make a mistake.”
That concern was far from hypothetical. The damage seen in the dogs could have been a sign of what was to come in CML patients. If it were, patients were going to die from the drug. The shadow of thalidomide, the drug used by pregnant women in the 1950s that turned out to severely deform the limbs and organs of fetuses, with 40 percent of “thalidomide babies” dying within their first year of life, still hung over the pharmaceutical industry. Prior to its use in people, the drug had been given to rodents only, and the disaster was one of the reasons the FDA started requiring animal testing on multiple species. (Today, thalidomide is used in the treatment of multiple myeloma, another type of blood cancer, but that benefit was discovered only decades after this initial debacle.) The possibility that STI-571 could be such a calamity was very real. “Then you’d have to go back and say, ‘Why did we risk it?’” said Zimmermann.
With Lydon gone, Druker knew that it was up to him to fight for the drug. “Brian was extremely focused on his patients,” says Lydon. “He felt it was a pretty hopeless and depressing situation in the clinic at the time for CML, basically watching them progress and not much you could do about that.” Druker understood the need to be cautious, but only to an extent. Unlike the industry representatives hesitating in Basel, he saw dying cancer patients every day. He knew that alongside the safety concerns, the marketing hesitations lingered. Was the company being cautious, or was it hoping to use the results as an excuse to not move the drug into costly clinical trials?
He also knew that the potential impact of this drug stretched far beyond CML. If STI-571 proved that the principle behind kinase inhibition—that cancer could be stopped by selectively targeting a single haywire protein—was an effective way to treat cancer, then other such drugs could follow for other cancers. STI-571 was the first drug targeted against an abnormal protein resulting from a genetic mutation. If it worked, how would that change the direction of cancer care? How would that change our understanding of the underlying cause of cancer? What powerful medications for cancer or other serious diseases might then be possible? Druker knew his vision might seem grandiose or, at the very least, decades away from becoming a reality. But the current chemotherapy had evolved over at least fifty years. Maybe this drug was the start of the next fifty. As unlikely a dream as it was, it didn’t seem completely impossible.
At some point, the decision makers at Novartis told Matter that if his discovery team could find another use for the drug, then they would consider a clinical trial. Matter and the team knew that STI-571 had shown activity against two other tyrosine kinases, PDGFR and Kit, when the compound was first developed. Now it was time to see if those targets might have any clinical usefulness. Matter turned once again to Chuck Stiles at Dana-Farber, who quickly showed that the drug was active against glioblastoma multiforme, a type of brain tumor that expresses PDGFR, in rats. Years earlier, Lydon, Buchdunger, Zimmermann, and Matter had fretted about whether to try to eliminate the activity that STI-571 had against PDGFR, wondering if it might make the compound a stronger inhibitor of Bcr/Abl. Now they could only be thankful that they’d left well enough alone.
Their requirement satisfied, the company still resisted initiating a clinical trial. Druker called colleagues who he thought could weigh in on the value of the toxicology studies. He suggested to Novartis executives that they call the FDA to ask whether their toxicity data were sufficient to submit their request to run a clinical trial. “We can’t do that, we don’t have permission,” Druker was told. “What if I talk to the FDA?” he asked. “You can’t do that,” he was told. “So,” said Druker, “I did it anyway.”
At Novartis, the monkey studies—the seventh toxicology test—commenced. To further explore the liver toxicity and other potential problems, a group of cynomolgus monkeys, macaques found in southeastern Asia, Borneo, and the Philippines, were given varying doses of the drug per day for thirteen weeks. None of the monkeys died as a result of the drug. The animals receiving the high dose vomited or had diarrhea, and four from this group lost weight. In several of the monkeys given the high dose, their gums turned pale. Many of them had changes in their red blood cell and white blood cell counts, but all returned to normal after the drug was stopped.
Matter, who had been made head of oncology research when Sandoz and Ciba-Geigy merged, was fed up with the toxicology testing and could not remain silent any longer. He had to do something to put an end to what he considered a ridiculous course of action. He was known for his hot temper—“It was my profession to rant, to wail and to remonstrate, at every level,” he said. When the monkey studies started, Matter met with the top management team at Novartis and “scolded them for half an hour,” as he put it.
When Matter was done, Pierre Douaze, the temporary CEO following the merger, stood up. His response, Matter recalled, was to “congratulate himself for allowing such language in a meeting with top management.” For all of Matter’s ranting, STI-571 remained stuck in toxicology limbo.
Matter’s insistence that the company move the compound forward was leaving its mark, though, however faint. “They knew that I was not going to cave in,” he said. But his efforts did little toward grinding the clinical wheels into motion. Even as head of oncology for what was then the largest pharmaceutical company in the world, Matter was almost powerless. He was fighting a fight that has dogged drug development for ages. Companies want to know whether a drug is toxic because they don’t want to give a dangerous drug to people. Clinicians insist that they will be vigilant and that it’s not right for a company to withhold a drug that could benefit patients immediately.
In the meantime, Druker had gone ahead and called the FDA and was told that Novartis had accrued plenty of safety data to warrant
review for a clinical trial. “You have way more than most companies have for these drugs,” Druker was told by a toxicologist at the agency. He relayed the message to executives at Novartis, immediately drawing their ire. “It didn’t advance anything,” said Druker. “All it did was get them madder at me.”
Druker was running out of steam. If the people at Novartis would not even listen to a message directly from the FDA, how could he possibly persuade them to launch a clinical trial? A patient of his who’d run out of treatment options begged for a sample of the compound from Druker’s lab supply. A few weeks later, the patient died. Desperate to find a way to get this drug to the CML patients who needed it, Druker called Nick Lydon to see if he had any ideas. He did.
Lydon suggested that Druker write a letter to Alex Matter with the forceful request to make a decision: Either go into clinical trials or license out the drug. Novartis could easily sell the drug to another pharmaceutical company. Most of the large industry players weren’t interested in tyrosine kinase inhibition, but the number of small biotechs was increasing. These companies were dedicated to the research and development of innovative new drugs such as biologic-based monoclonal antibodies and small-molecule inhibitors, drugs that were little enough to slip through the cell membrane and attack the cancer-inducing mechanisms from within. A modestly sized company could run on a single promising compound, trying to generate investors with preclinical data, either waiting to hit the big time with a drug that actually worked or hoping the research would garner an offer from a larger, wealthier pharmaceutical company. Any of these companies might be glad for a chance to buy an experimental drug that already had so much data behind it. Lydon had even suggested to Druker that his company could buy the rights from Novartis. They knew Matter was on their side, but he was the person to address in this formal way. Druker should explain to Matter that if the monkey studies show toxicity, all it’s going to tell them is what dose to watch for in clinical trials. If they don’t show toxicity, Novartis will have wasted millions of dollars in two years. Druker had patients who needed it immediately.
Druker followed Lydon’s advice. He told Matter that investigators who’d been through the IND process and representatives from the FDA itself all thought the compound deserved a chance to be studied in a phase I clinical trial, the first stage of human studies. He told him that the ongoing thirteen-week study in primates was a waste of time and resources. The company already knew about the liver toxicity that resulted from continued dosing of the drug. If the monkey test turned out negative, careful liver monitoring would still be required in the human study anyway. If the monkey test turned out positive, then a potentially useful drug would probably be dropped without testing in humans. There were already enough toxicology data to submit the compound for IND approval, Druker insisted.
He also addressed a concern expressed by the toxicology team at Novartis that giving the compound for more than four weeks would be unethical. That perspective was based on a strict interpretation of an FDA rule stating that an experimental drug could be administered in a phase I trial for a third of the duration of the toxicology studies. The animal tests had lasted twelve or thirteen weeks each, so Novartis insisted that the phase I study could give the drug to patients for only four weeks at a time.
In Druker’s estimation, that viewpoint simply did not hold water. The duration of treatment in actual patients depended entirely on how the benefits weighed against the risks. CML patients had a uniformly poor prognosis, and those who would enroll in the study had no other treatment options. Give them the drug, said Druker. If the patients benefit from it and tolerate it, then there would be no ethical reason to stop treatment. Monitoring for liver toxicity was not complicated. Blood tests would reveal any problem, and the investigators could even do liver biopsies if necessary. “It is time to make a decision,” Druker wrote. “Give the drug a chance.” If Novartis did not want to take the compound further, then the company should license it out. He told Matter that Nick Lydon’s biotech company would probably be interested.
Druker sent the letter to Matter. Strengthened in his resolve by Druker’s words and dedication, Matter took a deep breath and dived back in, hoping to persuade the company to finally make the so-called go/no-go decision.
MATTER KNEW THAT if he didn’t fight for the drug, Novartis would shelve it. “We had to champion these programs, or they would die.” The persistent pleading from clinicians on the outside gave Matter the confidence to keep fighting. The letter from Druker and all the other voices in support of the drug gave Matter the boost he needed. “Without [everyone] covering my back, I don’t know whether I would have had the stamina to see this through,” Matter said. It was Druker’s words he would hear in his head—give the drug a chance—when he found himself, month after month, pleading STI-571’s case.
Some weeks after his rant to the executives, Matter bumped into Daniel Vasella in the hallway. Vasella, 42, had replaced Douaze as the permanent CEO and chairman of Novartis, and was still getting to know his employees. Born and raised in Switzerland, Vasella had been a doctor of internal and psychosomatic medicine for eight years when, in the mid-1980s, he started wondering what it would be like to work in the pharmaceutical industry. His wife’s uncle was the head of Sandoz, and Vasella, curious about the business of medicine, peppered him with questions. In 1987, the new head of Sandoz offered Vasella a job in marketing, though it required working out of the company’s New Jersey headquarters. He and his family headed to the United States.
That phase of his career would give Vasella his first taste of patient activism. Sandoz had just launched a drug called Sandostatin, or octreotide, designed to treat a rare tumor that caused severe diarrhea. At the same time, the AIDS crisis was at its peak, and patients, who often suffered from diarrhea, learned that there was a new drug that could help. “They wanted access, and we had to manage it in a way that was sustainable and legal,” recalled Vasella. It was his first confrontation with extremely angry, activist patients, and also his first encounter with a drug created for a single, rare condition that turned out to have multiple applications. The success of the drug was gratifying, and its lessons resonated as Vasella ascended the industry ranks.
Vasella and Matter had met early in the merger process, as part of efforts to integrate the two companies’ teams. “He was the most angry person I ever met,” Vasella recalled. Matter’s first impression of Vasella was that he was a suave businessman whose calm disposition stood in stark contrast to his own more combative temperament. “He was a picture of a hero,” recalled Matter. “He was very educated, elegant, an eloquent new presence.”
In that chance hallway encounter in the middle of 1997, Matter immediately started venting his frustrations about STI-571. “He said he had a promising drug, but we couldn’t get it into clinics,” Vasella recalled. Still familiarizing himself with Novartis’s drug portfolio, Vasella knew little about STI-571 since he’d come up through Sandoz, not Ciba-Geigy. He didn’t know about the basic research that connected the Philadelphia chromosome with CML, and he knew very little about the rationale behind kinase inhibition, though he knew Matter had fostered the initiative within the company. He didn’t know about the cell-line studies or the endless toxicology studies about which Matter was giving him an earful. All he knew at the time was that the person standing before him was insistent about the potential value of STI-571. Vasella asked Matter if he was certain about this compound. “I really believe it,” Matter told him. “Okay,” Vasella said, “then we’re going to do it.”
Vasella’s response was, in part, simply that of a CEO handling a hotheaded employee. “I was basically, I think, coping with it in a way which allowed him to believe that I could maybe listen,” said Vasella. But it was also the first time that the drug was brought to his full attention, and Vasella found he couldn’t ignore it.
As Vasella began investigating the kinase inhibition project, he became increasingly aware of the skepticism surrounding the devel
opment of STI-571. It was the prevailing mood at the company, he noted, not traceable to one person or team. “You will never know who it is because it will be some of the researchers, some of the developers,” says Vasella, “[and] the marketers who think, ‘Well, this will never make any profits.’” Whether from his experience with Sandostatin or solely on the merits of the STI-571 data thus far, Vasella was persuaded to consider moving the drug into a clinical trial.
In August 1997, Druker received a confidential letter from Matter. As Matter put it, Druker’s letter had given him the motivation to go straight to the top. Energized by Druker’s uncompromised belief in the drug and his own convictions, Matter had brought the compound and the flagging clinical development to the attention of the CEO, the global heads of research and clinical research, and the head of clinical oncology research. As far as he could tell, they were willing to listen, and he hoped to have more news in a couple of weeks. “For the time being, I would like to express my feelings of gratitude for your dedication to this project,” Matter concluded.
Four months passed before Druker finally heard from Matter again. Matter divulged that a major battle had been raging over STI-571 among different departments at Novartis. He did not describe the details, but Druker knew what the problems were. It wasn’t only the persistent concerns about the potential side effects of the drug that had resulted in the toxicology team taking a stance against continued development. In addition, the marketing team was still insisting that the drug would cost the company too much money. Using an estimate of the patient population, the assumed duration of treatment, and the extent to which the drug could penetrate the market—some doctors, they assumed, would likely continue to use the current standard therapy—marketing had come up with a projected total sales figure of about $100 million, an amount that was, as Matter put it, “totally beside the point.”
The Philadelphia Chromosome Page 18
