The Philadelphia Chromosome

by Jessica Wapner

  The speakers repeatedly highlighted the role that collaboration among academia, industry, and government had played in the speedy study and approval of Gleevec. When asked by a journalist how long the drug had been in development, Vasella’s response was “2.7 years.” He was technically correct: The phase I trial had begun in June 1998, and the drug had garnered approval in May 2001, less than three years later, an extraordinary accomplishment.

  Unmentioned, however, was the fact that the trial had started more than two years after the preclinical studies, and that the tyrosine kinase inhibitor project had actually begun in the mid-1980s. So not everyone shared Vasella’s view. “It took eighteen years, which is ridiculous for such a project,” said Alex Matter. But Matter’s estimate includes the years of toxicology studies and the many years it took to create the compound. That extended timetable was now a chronicle of the broad changes in thinking that had accompanied the development of Gleevec: the unwillingness of industry representatives and the oncology community at large to give credence to the notion of targeting a single kinase with a compound synthesized in a laboratory, the slow acceptance of dedicating resources to treat a rare disease, and finally the breathtaking clip of the studies once the drug maker had fully committed to the mission. Those eighteen years traced a new idea from birth through adolescence, with all the accompanying struggles, heartbreaks, and achievements. In eighteen years, a vision had been wrestled into reality.

  If there was any remaining tension in the aftermath of approval, it was between Druker and Novartis. Druker’s name had been mentioned only in passing at the approval news conference. Now, Vasella heard rumors that Druker felt shafted because he wasn’t being given the recognition he deserved. Vasella was not surprised. He had seen people fight for credit after previous successes, and he believed his experience with Druker to be yet another example. “Each time you have a success, everybody’s a father and a mother,” Vasella said. The company had not publicly acknowledged the scope of Druker’s contribution. But considering the company’s financing of the drug—Novartis had covered nearly the entire development cost, save for some grants Druker had received from the Leukemia and Lymphoma Society—and the fact that it had, after all, been created and developed by Novartis, Vasella didn’t think such acknowledgment was due. And, because he’d joined the kinase inhibition effort in the middle of the toxicology studies, he was unaware of all the work that had preceded it. “For me, he’s an unknown,” Vasella said.

  Druker readily acknowledges Novartis’s ownership of the drug. “They made the drug and did the toxicology testing. They financed the clinical trials,” he said. “So from their perspective, it’s theirs.” He has a harder time with the notion that the drug would have been made even in the absence of his efforts. “They never would have done the clinical trials,” he said.

  Miffed as Vasella was by the whispers that Novartis was not giving enough credit to Druker, others were equally puzzled by how much credit Vasella was taking for himself and Novartis. Shortly after the approval, Vasella wrote Magic Cancer Bullet, a book chronicling the development of Gleevec (coauthored with a named ghostwriter, Robert Slater). Druker was interviewed extensively, though the book makes little mention of his efforts over the years. Nick Lydon declined to participate in interviews for the book because he considered it to be a sham. “If it weren’t for Brian’s efforts, the compound would likely have disappeared,” said Lydon. “If anybody at [the company] should have written a book, it was Alex Matter. He had been involved from the start and deserves a lot of credit for supporting the kinase program through many years.” For his part, Matter was not chagrined to see Vasella’s take on the story. “Victory has a lot of fathers,” says Matter, “and so this is fine.” John Goldman, who had to wait for two years after the phase I trial opened to give the drug to his patients in the United Kingdom, holds a similar perspective. “Without Vasella, Novartis would not have made the drug,” he said. But the glory reaped for Novartis and Vasella went beyond what was justified. “I don’t think it was inappropriate,” he said of the credit Vasella and Novartis had claimed in Magic Cancer Bullet and in general. “It was just sort of disproportionate.”

  Druker continued to work with Novartis, tracking the progress of the patients from the phase I, II, and III trials. In 2008, he received funding from Novartis that enabled him to establish one of the first molecular testing facilities in the country. Vasella and Druker have not worked directly together since the approval of Gleevec. They met for the first time in 2009, at the ceremony for the Lasker Award, the highest honor in the field of cancer research, given jointly to Druker, Sawyers, and Lydon that year. Although OHSU has served as a trial site for other Novartis drugs, Druker has not been part of their development. “At times, I’m at peace with my relationship with Novartis. We have a drug that’s helping lots of people. That’s great,” said Druker. “Could they have been better early on and gotten an earlier start, and could there have been a simpler path to clinical trials? Sure. Did they make up the time? Yeah, they probably did. Have they been gracious afterwards? No, they really haven’t. Have they looked at what we’re doing and said, ‘We did this once, why can’t we do this again?’ No. But again, I’m at peace with that, and that’s their business. They do their things their way, and I have to do what I need to do.”

  FOR DRUKER, THE actual moment of the approval was one more gust in the whirlwind of 2001. His passport from that year marks the trail of talks he was giving around the world—Italy, Germany, Australia, Japan. Oncologists everywhere wanted to know all they could about the drug. They wanted to learn how to give it to their patients, what kind of monitoring was needed, how to decide on the exact dose, what information patients needed to take care of themselves outside of the clinic. After all, the idea of taking a cancer medication at home was relatively new. Most drugs were given intravenously in hours-long injections at the clinic, where nurses were standing by, ready to address the side effects that were bound to arise. With Gleevec, patients were away from professional supervision, and doctors needed to know what to tell them to watch out for, when to take the medicine, whether to take it on a full or empty stomach. That situation might be normal for the majority of prescription drugs, but cancer had never been treated at home. And oncologists near and far wanted to meet the doctor who they believed was largely responsible for bringing this drug into the world. “I was in pretty high demand and I wasn’t very good at saying no,” said Druker.

  That was also the year that Druker and Hardy fell in love. After all the years of 90-hour work weeks, all the pushing to get the drug made, all the time spent caring for patients on and off clinical trials, Druker now found himself in an entirely new situation. For the first time in his life, he had a family of his own. He and Hardy married the following year. He became a stepfather to her first child, and they would soon have two more children together.

  PART IV

  Aftermath

  • • •

  Every day that the phase I trial patients swallow their next Gleevec pill tests the notion of treating cancer as a disease driven by genetic abnormalities. For as long as they live, they will be part of an experiment that has transformed cancer care. Their continued health proves the principle behind targeted therapy, bringing hope not only to people stricken with CML but also to the world at large, anxiously awaiting the day when cancer will no longer claim so many victims.

  But is the success in treating CML a one-off case, the likes of which are unlikely to be seen again? Or are we indeed standing at the precipice of a new era still in its infancy? Treatments tailored to the genetic drivers of cancer may be the future, but there is no telling how or when that future will take shape.

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  A PRICE TO PAY

  With the approval of Gleevec came a price tag. In setting the price, Novartis decided to match the cost of interferon at the time. For the 400-milligrams-per-day dose level, the price was set at $2,000 to $2,400 per month
. For 600 milligrams per day, the typical dose for accelerated and blast crisis patients, the price was set at $3,500 per month. For the average CML patient, the annual cost of care—medication plus clinician visits—came to just under $33,000.

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  The price was not higher than interferon’s, and interferon hadn’t been criticized for its cost. Still, the Gleevec price drew criticism because so many people couldn’t afford it. Medicare’s lack of coverage for oral cancer medications didn’t help. Until then, cancer treatment was predominantly given by injections, and the formulation of a drug (by needle, by pill, by patch) factored into how much coverage Medicare provided. Cancer drug injections were given at a hospital or clinic under close supervision, and it was that whole system that Medicare covered, with code numbers for each aspect of the treatment. Oral cancer drugs that could be taken at home were something entirely new. Medicare’s lag time in covering Gleevec stirred up trouble, generating a short but potent spurt of worry and outrage that CML patients on Medicare would not be able to afford it. That problem was later remedied, although Medicare’s infrastructure for oral cancer drugs remains highly convoluted and often requires a period of hefty out-of-pocket contributions. But the issue exacerbated objections to the price. Novartis needed to make sure that everyone who needed Gleevec would get it starting immediately after approval.

  The company decided to try a sliding-scale assistance program. Anyone with an annual family income of less than $43,000 could get the drug for free. For those with a family income between $43,000 and $100,000, the total amount paid for Gleevec would stay within 20 percent of the annual income. If the family’s annual income was more than $100,000, patients would pay the full price.

  The assistance program was innovative and helped a great many people obtain an otherwise unaffordable drug for free in the United States and, as global approvals began to flow, internationally. Yet not all the problems were solved. A patient whose family income landed them just on the 20 percent side of the equation could still end up with medical bills too high to cover. Co-pays were often steep, so that even insured patients felt the pinch.

  Despite consternation over the cost, it was much too soon to accuse the company of excessive profits. The question of how much Novartis would earn from the drug was still unanswered. The fact that patients took the pill daily had been a revelation, not only because of how unusual the approach was but also because of the financial windfall such a regimen promised. But the long-term benefit of the drug was still uncertain, and therefore so were the long-term profits. There were patients who’d been on the drug for almost three years, but no one knew what the average duration of life would be. There was no predicting what turn of events the next day might bring, and still no knowledge of how long the responses would last.

  For this drug without a history, every day was fresh evidence. The first trials may have been completed, but Gleevec was still an experiment. There were no signs that patients would suddenly take a turn for the worse, but there was no proof that they wouldn’t.

  And Novartis still had to cover the expense of the drug for many trial patients, who were doing far better than anyone expected based on previous experience with cancer treatment and clinical trials. “We phase I patients are provided the drug for life, right?” Judy Orem recalled asking Vasella around the time of the approval. “Yes,” she recalled him replying. “But we never expect phase I patients to live very long.” The response was tongue-in-cheek. Vasella was beyond thrilled that the trial patients were doing so well, and he knew that the company had an obligation to cover the cost of the medication for those who had willingly subjected themselves to an untested drug. But no one had factored the possibility of a normal lifespan for the patients into the trial budgets.

  A year after the drug’s initial approval, it was clear that Novartis had nothing to worry about. In 2002, worldwide sales of Gleevec totaled more than $900 million.

  ALTHOUGH THE LEADERS at Novartis may not have recognized Druker’s contribution, recognition seemed to come to him from every other direction. Alongside the continuous stream of speaking invitations, Druker has also received a series of prominent awards since the approval of Gleevec, including the Lasker Award (which led to a television interview with Charlie Rose), and the Japan Prize, a science award second only to the Nobel in global prestige, awarded in 2012 to Druker, Lydon, and Janet Rowley. His office is lined with commemorative plaques, pictures, and fancy cups that trace the history of his renown over the past decade. In 2007, Druker was asked to take over as director of OHSU’s cancer center.

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  His investment in the clinical research of Gleevec has not brought him wealth, however; he does not own stock in the drug and, to preempt any trouble with insider information abuse, stopped investing in biotech and pharmaceutical companies in 2000. Druker was paid by Novartis for some of his early Gleevec talks, though he notes that the payments were small and that he always used his own slides, never those prepared by the company (avoiding a common practice that has raised suspicions about biased information being used to influence medical professionals).

  But the drug’s success has helped pay for his research endeavors. His lab receives annual funding that ranges from $900,000 to $1 million from the Howard Hughes Medical Institute (a portion of which covers Druker’s salary). He also has a long-standing grant from the NIH that amounts to about $200,000 per year for his lab, and research funding of about $250,000 annually as part of a $1 million multilab collaborative grant from the Leukemia and Lymphoma Society that has been ongoing for about fifteen years.

  And then there’s the gift from Phil Knight, founder of Nike. In 2008, the stock market crash in full effect, Druker received a call from Knight, who said he wanted to donate $100 million to the cancer center at OHSU. “I want to invest in your vision,” Knight told him. The gift was one of the largest donations ever given to a US cancer institute. At OHSU, the cancer center was promptly renamed Knight Cancer Institute. Overnight, Druker went from being the head of a modestly successful cancer center to being the head of one of the most well-funded medical institutions in the world.

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  SHOWING A WEAKNESS

  Following the approval in 2001, the relentless pace of Gleevec development continued. Novartis still had several clinical trials on the go. The phase III IRIS trial had completed enrollment in January with more than 1,000 patients spread across several countries. The drug was also being given to patients with other types of cancer. CML was the only cancer found to express the mutant Bcr/Abl fusion protein, but the other tyrosine kinases inhibited by Gleevec were present in other malignancies. PDGFR, another tyrosine kinase inhibited by Gleevec, was associated with a type of brain tumor. And researchers had also found that gastrointestinal stromal tumors, a rare type of stomach cancer, are driven by mutated Kit, a kinase against which Druker had screened the first experimental compounds sent to him by Nick Lydon back in 1993. Now the time had come to investigate whether the drug was any good at thwarting cancers operated by these proteins.

  George Demetri, from Dana-Farber Cancer Institute, and Charles Blanke, from OHSU, were leading a phase I clinical trial investigating the use of Gleevec for gastrointestinal stromal tumors, or GIST. After the investigators tried the drug on a single patient in March 2000 and the disease slowed down, a phase I study opened in July 2000. By May of the following year, just as Tommy Thompson and Richard Klausner were preparing their remarks for the Gleevec approval news conference, Demetri and Blanke were preparing a presentation for the annual meeting of the American Society of Clinical Oncology, the single largest professional gathering of oncologists worldwide.

  The results of that first study were published in the summer of 2002 in the New England Journal of Medicine. The outcomes weren’t as jaw-droppingly impressive as those seen with CML patients, but the drug worked. None of the 140 patients experienced a complete disappearance of the disease, but more than 50 percent had a
partial response, the tumors shrinking by at least half their original size. The drug caused more side effects in these patients, with swelling, nausea, diarrhea, and a rash occurring in many. But as with CML, the side effects were mostly minor, not crippling, though five people had serious hemorrhaging. No other treatment existed for GIST aside from surgery. So Gleevec wasn’t just an advance in treatment for GIST; it was the creation of a treatment for GIST.

  In time, Demetri and other clinicians would see that GIST patients tended to not respond to Gleevec for as long as CML patients did. Even during the ten months of that initial phase I study, twenty patients became resistant to Gleevec. The drug would be approved for GIST—it was far superior to the previous standard therapy. But why did some become resistant so soon?

  While Demetri puzzled over the resistance he observed in GIST patients, Charles Sawyers, one of the three phase I investigators from the CML trials, was still haunted by the sight of the blast crisis patients responding so dramatically to Gleevec and then relapsing just as quickly. Witnessing patients with advanced CML rise from the nearly dead and then crash so spectacularly had driven Sawyers back to the laboratory. Why would patients respond so vigorously and then return to the same condition they’d been in before the treatment? Why did some patients not respond to Gleevec at all, even during the chronic stage of the disease? Sawyers had to know what was going on.