The Pill That Could · Approval

Approval, part 4

The arguments against the price went something like this. The drug had been developed on the back of decades of basic science largely funded by the public sector — the work of Nowell, Hungerford, Rowley, Bishop, Varmus, Hunter, the BCR-ABL groups in Rotterdam and elsewhere, all of which had been done in academic laboratories with public money. The pharmaceutical industry's contribution had been important and necessary but it had been the final segment of a long relay; charging the public many times over, through both taxes that funded the research and prices that funded the marketing, was double-billing of a particular kind. The patients who needed the drug — in the United States, with American insurance — might mostly be covered, but patients in lower-income countries would not be, and the price would effectively put the drug out of reach for most of the world's CML patients. And the broader signal, that an effective drug for a small disease justified an annual price north of twenty-five thousand dollars, would set a benchmark that other cancer drugs would race to meet and exceed in the years to come.

Both arguments were correct, in their own frames. Both arguments would echo, in different forms, through the next two decades of debate about cancer drug pricing.

What is worth saying, looking back, is that Gleevec at thirty thousand dollars a year in 2001 looks, in 2026, almost charmingly cheap. By the mid-2010s, list prices for new oncology drugs had climbed past one hundred thousand dollars a year as a matter of routine. Some climbed past two hundred thousand. The number of cancer drugs entering the market at price points that would have shocked the industry in 2001 is, by the standards of 2001, very large. The Gleevec price was, in retrospect, the lower end of a curve that the industry then climbed for two decades. Novartis itself raised the price of Gleevec several times during the period the drug remained on patent, eventually reaching list prices well above one hundred thousand dollars a year before the patent expired and generic versions entered the market in the mid-2010s, at which point prices for the molecule fell sharply.

We will come back to the price question in chapter eleven, when we look at what targeted therapy did and did not deliver across the broader landscape of cancer. For now it is worth registering: Gleevec was, in May 2001, the first drug of its kind, and the price it was launched at — controversial at the time — became the floor for a generation of similar drugs that would mostly be priced higher.

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What did the approval mean for the patient sitting in Druker's clinic in 1993?

The 1993 patient is, in this book, slightly composite — standing in for any number of CML patients Druker saw in his early years at Oregon. But the question is concrete enough. A specific patient, diagnosed with CML in 1993, faced a specific clock: somewhere between three and eight years before the chronic phase ended, give or take. A patient diagnosed in 1993 who lived through 1999 — six years — was at the long end of the range, but not impossibly so. A patient diagnosed in 1993 who was still in chronic phase in 2001 was lucky, but not miraculously lucky.

Such patients existed. They had been on hydroxyurea, on interferon, on whatever combination their oncologists had been able to assemble; their blood counts had been managed, more or less, by the inadequate tools of the era; their disease had progressed, more or less, on the timeline the disease tended to follow. Some of them had been on the phase 1 trial since 1998 or 1999 and were doing well. Some of them, on May 10, 2001, called their doctors to ask how they could now get the drug.

Many of them did get it. The shipment of Gleevec into clinics through May and June of 2001 was, in CML practice, the largest treatment switch in the history of the disease. Patients who had been managing on the older drugs transitioned to imatinib, often within a few weeks of the approval. Their blood counts came down. Their bone marrows cleared. The Philadelphia chromosome, in many of them, went from being detectable in essentially every dividing cell to being detectable in only a few cells, then in none.

Some of those patients are still alive in 2026. They are in their sixties or seventies or eighties now. They take a pill in the morning. They get blood drawn every several months. They live, by every measure their oncologists can apply, more or less normal lives.

What Druker had not been able to give them in his clinic in 1993 — a treatment that targeted the specific cause of their disease without poisoning them — he could give them in his clinic in 2001. The patients who had survived to 2001 transitioned to the drug. The patients who had been diagnosed since 1998, and especially since 1999, mostly went onto the drug as their first or second therapy and never spent significant time on anything else. The disease had not been cured — we will come to what “cure” means in this context in chapter ten — but it had been, for the patients on the drug, transformed into something that could be managed.

* * *

The story this chapter has just told is, in its broad shape, a triumph. A drug worked. A regulator moved quickly. Patients lived who would not have lived otherwise. The cover of Time magazine appeared, and was not wrong.

It is also, the rest of this book is going to argue, only part of the story.

There is, first, the question of how the targeted-therapy paradigm extended beyond CML — whether the success in this one disease was a template that could be applied across cancers, or a beautiful exception that turned out to be hard to repeat. The next chapter looks at a parallel case, in a different cancer, that was developed during the same years and approved a few years before Gleevec: Herceptin in breast cancer, where a different kind of drug aimed at a different kind of target produced its own version of targeted therapy. The two stories together — small molecule for leukemia, antibody for breast cancer — set the shape of what targeted therapy was going to become.

There is, second, the question of resistance. Gleevec worked beautifully in chronic-phase CML. It worked less well, and less durably, in patients with more advanced disease. The reason, when researchers looked carefully, was that some CML cells were evolving — acquiring specific mutations in BCR-ABL that prevented imatinib from binding — and the cells with those mutations were the ones that survived and grew. Resistance was, in 2001, a small cloud on the horizon. By 2005 it was a serious clinical problem. Chapter nine looks at how the field responded, and at what the resistance story tells us about the limits of going after a single molecular target.

There is, third, the question of cure. Gleevec controlled CML, in most patients, very well. It did not, in most patients, eradicate it. The Philadelphia chromosome, when measured at the level of molecular response — the most sensitive techniques the field had — was almost always still detectable in some small fraction of cells, even in patients who looked completely healthy. Most patients who tried to stop the drug, after years of apparent remission, relapsed. CML had become, for most patients, a chronic disease managed with a daily pill rather than a fatal disease cured outright. The distinction between cure and control turned out to matter, in ways that took the field a decade to fully appreciate. Chapter ten is about that.

There is, fourth, the question of what targeted therapy did and did not do across the larger landscape of cancer. Gleevec worked in CML because CML had the unusual property of being driven by a single molecular event in a way most cancers are not. Many subsequent targeted therapies, aimed at other mutations in other cancers, would produce real benefit; some would be transformative. Some would not. The dream that every cancer would yield a targeted therapy — the dream the Time cover, in retrospect, slightly overpromised — turned out to be more complicated than it looked in 2001. We come to that in chapter eleven.

And there is, fifth, the patients themselves — the ones who entered Druker's clinic in 1993 with three to five years to live, and who are now, twenty-five years after Gleevec's approval, sitting in clinics getting routine blood draws and going home to their grandchildren. Chapter twelve is about them. It is the chapter the book has been moving toward from the start.

But first: a different cancer.

Different decade, different molecular logic, different kind of drug. Same fundamental insight: identify the driver, build the inhibitor, test it carefully, give it to the patients who need it.

Genentech. Breast cancer. Herceptin.

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