The Pill That Could

Prologue: A Patient in Portland

Brian Druker is thirty-seven years old in the autumn of 1993, in his first months at Oregon Health Sciences University, newly running his own lab, and he is sitting across from a patient he cannot save.

The patient has chronic myeloid leukemia — CML. He has been told this already; that is why he is here. Druker is rarely the first oncologist a CML patient sees. People with rare cancers tend to make their way around the country, looking for someone who knows something the last person didn't, and a few years out of fellowship Druker has begun to acquire that kind of reputation. He has spent his postdoctoral years thinking about this exact disease at the molecular level. If you have CML in 1993 and you read journals, you might end up in his clinic.

What Druker has to offer, though, is the same thing every other oncologist has to offer in 1993, which is not very much.

He has hydroxyurea — a pill that brings the white blood cell count down by interfering with DNA replication. It is not a treatment for CML in any meaningful sense; it is a way to hold the line. The disease keeps progressing under it, just more quietly. He has interferon-alpha, which patients inject several times a week, which makes them feel as if they have the flu more or less constantly, and which produces a deep and durable response in something like ten or fifteen percent of patients. Most of the rest get the side effects without the benefit. And he has, for the patients who are young enough and lucky enough to have a matched donor, the option of an allogeneic bone marrow transplant — wiping out the bone marrow with chemotherapy and radiation, replacing it with cells from someone else, hoping the new immune system kills any remaining cancer without killing the host.

The transplant works, sometimes. It is also one of the most dangerous treatments in mainstream oncology. Roughly a quarter of patients who attempt it do not survive the procedure itself.

That is what Druker has on offer. A pill that controls counts but does not change the course of the disease. A weekly injection that helps a minority and exhausts almost everyone. A cure that kills one in four.

The patient, like most CML patients in 1993, is in what doctors call the chronic phase. He feels mostly fine. He noticed something — fatigue, maybe, or a fullness on his left side where his enlarged spleen has begun to push against his ribs — and he saw a doctor, and the blood work came back wrong, and now he is here. He looks well. He probably is well, in the immediate sense; the chronic phase can last months or years. But the disease is going to progress. The chronic phase will give way to an accelerated phase, and the accelerated phase will give way to what oncologists call blast crisis — the bone marrow flooded with immature cells, an acute leukemia in everything but name, and untreatable. The median survival from diagnosis is something like four to five years.

This is what Druker has to tell him, and tell him in a way that leaves room for hope without dishonesty, because there is a thing Druker has not yet said and is not sure when to say.

The thing is this. He knows what is wrong with this man's blood.

* * *

Not in the way doctors usually mean it. Doctors mean they have a name for the disease, a sense of which cells are involved, a notion of how it tends to behave. Druker means it the other way. He means he knows the specific molecular event that has gone wrong inside one stem cell in this man's bone marrow — the broken switch that is stuck in the on position, telling that cell and all of its daughters to grow and divide and refuse to die when they should.

By 1993 this is not even controversial. It is in the textbooks. Two chromosomes, the ninth and the twenty-second, have swapped pieces. The swap happened once, in one cell, possibly years before the patient noticed anything was wrong. It produced a fused gene that should not exist in nature, made of part of one normal gene and part of another, and that fused gene produces a fused protein, and the fused protein is an enzyme. A kinase — the kind of enzyme that puts a small chemical tag on other proteins to relay signals around the cell. The fusion has broken the regulation that normally keeps this kinase quiet most of the time. The kinase is on. It is always on. The cell receives, continuously and without pause, the molecular equivalent of grow, divide, survive. So it does.

The cancer is, in a real sense, a single broken enzyme.

* * *

If you are a particular kind of person — and Druker is — a fact like that is not just a fact. It is an invitation. If we know the disease is one broken enzyme, then in principle we know what would fix it. We would need a small molecule that fits the active site of that specific kinase well enough to block it, and that does not fit the active sites of the many other kinases the body needs in order to function. We would need, in the language of pharmacology, a selective inhibitor.

In 1993, “selective kinase inhibitor” is something the field talks about the way an earlier generation of physicists talked about controlled fusion: as a thing that would clearly be wonderful if it existed, and that there are real reasons to suspect cannot. Kinases share a common architecture. The pocket where they bind their fuel — a small molecule called ATP, which every living cell uses to do work — is broadly similar across the human kinome, the set of all human kinases, of which there are over five hundred. The conventional wisdom is that any drug small enough to fit the pocket will fit too many pockets, and that hitting them all will be either useless (because the cell finds a workaround) or lethal (because some of those kinases are doing essential work). The pharmaceutical industry, in 1993, has been trying to make selective kinase inhibitors for years, with limited success. There is a strong professional opinion that it cannot quite be done. Or that even if it can, the resulting drug will be too toxic, or the cancer will adapt around it, or the development cost will not be recoverable from a disease as uncommon as CML.

Druker does not believe any of this. Or rather, he believes the technical objections are real and he believes the conclusion that follows from them is wrong.

He has reasons. During his postdoctoral years at Dana-Farber Cancer Institute, in the lab of a biochemist named Tom Roberts, Druker had spent his time developing tools to study kinases in living cells — antibodies that could light up exactly the chemical tag a kinase leaves on its substrates, so you could tell when the kinase was active and how active it was. He had used those tools to look at the BCR-ABL kinase, the fused enzyme made by the broken chromosome, and seen how distinctive its signature was and how cleanly you could read it. Cells that have BCR-ABL look different from cells that don't, in a way that a good antibody can detect at a glance.

He has also been talking, on and off for several years now, with a chemist named Nick Lydon at a Swiss pharmaceutical company called Ciba-Geigy. Lydon's team has been making compounds aimed at one kinase or another, more as research tools than as drugs, and some of the compounds they have made are interesting. One of them, a molecule with a code number rather than a name, is interesting in a particular way: in early tests it inhibits a small handful of kinases and ignores the rest. The selectivity that the field considers impossible is starting to look, in this one molecule, like an engineering problem rather than a law of nature.

The molecule has not been tested against BCR-ABL. There are reasons to think it might work — the kinases it does inhibit are structurally related — but no one has done the experiment.

Druker is going to do the experiment. He has the cells, he has the antibodies to read out the result, and Lydon, who has his own reasons for caring about whether the molecule does anything useful, is willing to send some.

* * *

This is the situation, then, in 1993. The patient sitting across from Druker has a disease that is going to kill him in roughly four to five years on the current standard of care, or possibly faster, or possibly with a one-in-four chance of being killed by the cure. The cause of his disease has been worked out at the level of single atoms. A molecule that might address that cause exists, in milligram quantities, in a freezer in Switzerland. And the gap between those two facts — the distance between knowing what to do and being able to do it for the man in the chair — is the entire subject of this book.

It is a wider gap than it sounds.

The molecule has to be tested in cells. If it works in cells it has to be tested in animals. If it works in animals it has to be made in larger quantities, and then tested in the first humans, and then in more humans, and then in many more humans, and at each stage it can fail, and at each stage someone — usually a committee — has to decide whether to keep going. Most molecules that get this far do not become drugs. Most drug projects that get this far are abandoned. The molecule under discussion has, in 1993, a number of features that the people whose job it is to decide whether to develop drugs find unattractive. CML is uncommon. The class — a kinase inhibitor — has a poor track record. There are, in any committee meeting where the molecule comes up, more reasons to walk away than to keep going.

The patient does not have a few years to spare on committee meetings.

* * *

Druker, in the clinic in 1993, does not know what is coming. He does not know that the company he is about to start working with will merge with another company and become an institution called Novartis. He does not know that the molecule will be given a new code number, and then a new code number after that, and finally a name. He does not know that the first phase 1 trial — the first time anyone takes the drug — will not begin until June of 1998, five years from now, three years too late for some of the people in his clinic. He does not know that when the trial does begin it will produce results so striking that the doctors running it will spend the first weeks not believing what they are seeing. He does not know that the FDA, when it finally sees the data, will approve the drug in roughly ten weeks, faster than any cancer drug had been approved before. He does not know that some of the people in his clinic in 1993 — the ones who survive long enough on the inadequate options he has to offer them — will be alive in 2026, taking a pill every morning, watching their grandchildren grow up.

What he knows is that he has a patient he cannot save, and a molecule he has not yet tested, and a hypothesis about how cancer might be treated that the field largely does not share.

The question, at the end of his clinic day in 1993, is the question this book exists to answer.

It is not, despite how the story is sometimes told later, whether the science was right. The science was right. By 1993 the science had been right for several years, and a small number of people had already begun to act on it.

The question is what it takes — in time, in argument, in stubbornness, in luck, in the unglamorous labor of running an experiment and then running it again and then running it a third way because the second way did not convince anyone — to move a fact about a disease from a journal article to the cabinet of someone who has the disease.

It takes, in the case of this molecule, eight years from the beginning of Druker's collaboration with Lydon to the day the FDA approves the drug. It takes longer than that if you start the clock earlier, in the Philadelphia laboratory where the first piece of the puzzle was found in 1960. It takes a number of careers, a number of arguments inside a number of companies, a small group of patients willing to take a drug no one had ever taken before, and several pieces of luck that could easily have gone the other way.

This is the story of how it happened, and what it meant, and what it did not quite manage to do.

It begins thirty-three years before Druker's clinic, with two men in Philadelphia looking at a chromosome that should not have been there.

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