A Battle Against Wayward Genes
The story of how ingenious medical researchers and big pharma teamed up to defeat a rare form of leukemia.
More than 50 years ago, scientists working in the City of Brotherly Love discovered a genetic mutation that they called “the Philadelphia chromosome” in patients with chronic myelogenous leukemia, a fatal, spontaneously arising cancer of the blood.In her book of the same title, Jessica Wapner chronicles the ensuing decades of laborious scientific inquiry and industrial ingenuity that led to the discovery of Gleevec, the first drug designed to attack cancer at the genetic level. Its success in beating CML into remission and making the errant chromosome disappear has helped to revolutionize cancer research, unleashing a hunt for the genetic basis of other cancers and opening the door to comparable targeted treatments.
While the money came from drug maker Novartis,NOVN.VX -0.07% the hero of the story is Brian Druker, an oncologist and researcher at Oregon Health & Science University. His unwavering determination kept the development of Gleevec on track against formidable odds, not least of which was the fact that CML, a rare disease with fewer than 6,000 new cases annually in the U.S., seemed to hold little potential for the blockbuster sales that typically attract pharmaceutical-company investment.
Ms. Wapner tracks decades of work by scientists who often had little knowledge of one another but eventually proved that the Philadelphia chromosome was the sole cause of CML. The mutation causes separate genes to fuse and become one, producing an abnormal protein, tyrosine kinase, which causes white blood cells to proliferate uncontrollably. The resulting cascade becomes a “killing machine,” in Ms. Wapner’s phrase. Blood turns into “viscous sludge” as red cells plummet. Meanwhile, platelets become too few to make the blood clot, and severe bleeding precedes death.
Having myself received the diagnosis for CML in 1992, I can testify that it is a fairly terrifying experience. At the time there was no Gleevec in sight. Patients were prescribed the drug hydroxyurea to slow things down, but it didn’t work for long, and another common treatment, interferon, was tough to tolerate and wasn’t a long-term solution in any case. The only possible cure was a bone-marrow transplant, which carried risks—including rejection—and required a suitable donor, preferably a matched sibling. (I was fortunate to have two.)
The Philadelphia Chromosome
By Jessica Wapner
(The Experiment, 303 pages, $25.95)
Surprisingly, Ms. Wapner gives short shrift to bone-marrow transplantation, portraying it as the worst possible option when in fact it has saved the lives of many CML patients, including my own. She also dismisses the side effects of Gleevec as minimal. Having taken the drug as part of treatment for recurrences more than a decade after my transplant, I can attest to its unpleasantness, a reason that some patients have stopped using the drug. Resistance also develops, leading some patients to seek transplants after all.
In “The Philadelphia Chromosome,” Ms. Wapner routinely translates the complexities of science for the lay reader, notably the role of tyrosine kinase and the quest to inhibit its deadly activity. Whenever the details get to be tough slogging, she offers up straight talk to explain what it all means: “In the hunt for cancer’s underlying mechanism, finding tyrosine was like a tracker finding an animal print or a broken branch. They knew they had caught the right trail.”
The narrative picks up steam when Dr. Druker moves from the Dana-Farber Cancer Institute in Boston to a new research job at Oregon Health & Sciences University. He secures several compounds from Ciba-Geigy, the pharmaceutical company, which is also pursuing a drug. He ultimately uses the compounds to find the Holy Grail: an antibody that is able to bind to the errant protein and block its effects.
Dr. Druker found supporters among Ciba-Geigy’s scientists, but it was hardly clear coasting from there, and Ms. Wapner’s tale shifts to the often-frustrating struggle to clear the regulatory, political and financial hurdles that kept popping up. Though the lead compound of the drug that would become Gleevec was synthesized by 1990, seven years later the first phase of human trials had yet to begin.
The turning point came in 1996, after the merger of Ciba-Geigy and Sandoz created Novartis, whose new chief executive, Dr. Dan Vasella, allowed the evidence to prevail over business hesitations within the company. Once human trials were under way, the results were breathtaking: Abnormal white blood cells disappeared, and normal blood cells were not affected.
Soon the Web was abuzz with news of the drug. For patient Bud Romine, it was a miracle. “The sword that had been hanging over his neck, waiting to fall, was now gone,” Ms. Wapner writes. “He’d been waiting to die, and now he knew he was going to live.” After being fast-tracked at the Food and Drug Administration, Gleevec set a record for swift approval in 2001. Gleevec must be taken daily for life and costs about $6,500 a month, though there are programs for those who can’t afford it. From 2001 to 2011, Ms. Wapner reports, world-wide sales were close to $28 billion, and Novartis and others now offer second-generation drugs that may be more tolerable and effective.
Novartis took much of the credit for Gleevec’s success, and Dr. Vasella wrote his own 2003 book about its development, “Magic Cancer Bullet.” Dr. Druker, who did not profit from the drug, did not seem to get the credit he deserved. Thanks to Ms. Wapner, he gets it now. Dr. Druker and Dr. Vasella, since retired from Novartis, strike a conciliatory note at the end of Ms. Wapner’s account, stressing the importance of collaboration between academia and industry, especially when research funding is limited. “The drug companies aren’t evil,” Dr. Druker says from his vantage as a university scientist. “They make drugs, and we should help them.”
Ms. Landro, a Journal editor and columnist, is the author of “Survivor: Taking Control of Your Fight Against Cancer.”