Class Notes

Magic Pills

The story of the making of a miracle drug

By Paula Marantz Cohen | August 20, 2013


Jessica Wapner’s new book, The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level is a riveting suspense story about the development of imatinib (U.S. brand name: Gleevec), a breakthrough drug in the treatment of chronic myeloid leukemia, or CML. Ten years ago, CML was a death sentence. Today, with Gleevec, most of its sufferers lead full and normal lives. Wapner tells the complex story of how this came to be with clarity, eloquence, and balanced insight.

The book begins with the 1959 discovery of the Philadelphia Chromosome by researchers Peter Nowell and David Hungerford at the University of Pennsylvania. They observed that one particular chromosome in the cells of CML patients is shorter than it should be—leading them to the conclusion that part of it had moved to one of the cell’s other chromosomes, where it was able to replicate itself unchecked, over and over.

In normal cells, there are natural checks on cell replication, but in CML, as in all cancers, the on and off switch is damaged. The switch remains on. At some point, researchers began to develop specific protein combinations, inhibitors of the on switch in cancerous cells—an approach known as “rational drug design.” Traditional chemotherapy simply bombards all the cells with toxic drugs; a rationally designed drug focuses only on the specific mutations that need to be controlled or eradicated.

Once the connection between the Philadelphia Chromosome, the mechanism of CML, and the inhibitor became known, the next and most fraught step was getting the new drug tested and approved. Wapner explains the dynamics and politics of this process, and lauds Gleevec’s patron saint, the physician and researcher Brian Druker, for making it happen.  Druker, in the face of opposition and conflict, pushed first for clinical trials and then harder still for quick FDA approval of the drug. Helping him was the then-new tool of social media. Patients used blogs and email blasts to get the word out and push for the drug’s approval.

The tone of Wapner’s book is even-handed. It doesn’t treat drug companies as villains. It makes understandable the rationale for the way drugs are developed, why some are pursued and others not. Developing a drug is expensive. If the disease requiring treatment is not widespread or common, the outlay in time and money may not seem worthwhile. CML is a relatively rare form of cancer, and thus treatment for it was not a priority on the part of the company. Most cancer drugs simply aren’t efficacious for very long.  But because Gleevec is such an effective drug and CML sufferers go on to lead long lives, the company has profited in a way it never thought possible. This has given a boost to the development of so-called orphan drugs, since it is now possible to imagine that a drug for a less common disease could be taken over the course of a lifetime and earn a profit for the company that designed it.

The story of Gleevec is not only a mystery story, but also an intellectual journey ending in triumph. The results of the first clinical trials were breathtaking. Patients in wheelchairs with only weeks to live suddenly saw their white counts plunge, their symptoms disappear, the Philadelphia Chromosome itself evaporate from their bodies. They got well and went to work. The treatment: one, albeit very expensive pill (out of pocket for 400 mg: $311.99), taken once a day, that may cause a bit of a puffiness around the eyes and some leg pain in the early weeks. It seemed like a miracle.

Unfortunately, as the book also points out, the action of Gleevec on CML is a fluke of sorts. Most cancers don’t have a simple, easily targeted mutation—an unchanging Philadelphia Chromosome. Instead, they tend to have many different and changing mutations that frustrate the development of a drug to treat them. The newest work in drug design involves tailoring the drug not to a form of cancer but to a specific patient’s tumor. This may seem fantastic, but the ability to map the genome more efficiently and economically makes it more feasible than it appears.

The story of Gleevec makes clear how science works over time, through serendipity and painstaking follow-through, through practical savvy and ivory tower dreaminess. Pieces are fit together, money raised, and the powers that be prodded into action by impassioned gadflies. It’s a complicated, compelling, wonderful, frustrating, human story—a template for progress and creative thought in any field.

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