Twenty-Five Milligrams

I

On 25 June 1998, in Oregon, a sixty-eight-year-old retiree took the first twenty-five-milligram tablet of a compound still called by a number, “STI 571”.

His name was Bud Romine. He had been diagnosed four years earlier with chronic myeloid leukaemia and given three years to live. He had already gone past them.

The dose was small on purpose, because in a phase one trial what is sought is not to cure anybody. It is to find out how much a body withstands. You start below what is believed useful and go up with the following patients [three per step, if nothing appears].

For Romine, at twenty-five milligrams, it did almost nothing. Within a few weeks his white cells went up again and he had to leave the study.

He went back in later, at a much higher dose, and with that one he did respond. He lived until 2012.

The first patient of the drug that changed oncology was, technically, undertreated.

II

It has to be said why that small dose was not an error, because there you see how the system works.

In a first trial in humans, nobody knows where the limit of toxicity is. The law and ethics oblige you to start far below and go up slowly, in small groups, watching what appears. It is slow and it is frustrating for whoever is inside it, and it is the only known way of not killing people while the dose is being sought.

What is striking about this particular case is how quickly it was seen to work once the correct quantity was reached. When they got to three hundred milligrams, almost all the patients responded [fifty-three out of fifty-four]. Practically all of them.

That never happens in oncology.

III

I have a blood count done every year and it costs twelve euros at the laboratory on the corner.

It is the cheapest and most revealing test there is. One tube of blood, a machine that counts cells by size and by shape, and a sheet with twenty lines of numbers and their reference ranges beside them.

I look at it with the attention of somebody who cannot interpret it. I see whether anything is outside the range and I am reassured or worried, with no further criterion.

What I had not thought about until writing this is that that sheet, in 1960, was what allowed the thing about this disease to be discovered. Two researchers in Philadelphia [Nowell and Hungerford, on a routine preparation] saw that in the cells of these patients there was an odd chromosome, shorter than it ought to be, and noted it down; it took them thirteen years to understand why it was short.

My twelve-euro sheet and theirs are the same sheet [the same twenty lines, in the same order]. What changed is what one knows how to look for in it.

That continuity seems to me the best thing in this story. No new machine and no expensive test were needed: what was needed was for somebody to look carefully at a routine preparation and note that a chromosome was shorter than normal.

IV

Inside, this disease is a wiring accident and that is why it could be fixed.

In the marrow cells of these patients, two chromosomes have broken and stuck back the wrong way round, swapping pieces. At the weld point a new gene is left that exists in no healthy person: half of one gene stuck to half of another.

That gene makes a protein that is also half and half, and that does one very particular thing. It is a switch that gives the order to divide, and being badly welded it stays on for ever.

The cell receives the order to multiply without stopping. That is the leukaemia.

The molecule Romine took is designed to get into the gap of that switch where the piece that gives it energy normally fits. Without that piece, the switch cannot give the order; it stays off and the cell stops dividing.

Notice what that means. The drug does not attack the cells that grow fast, like chemotherapy, nor mark an aerial on the surface, like the antibody of the previous piece. It gets inside and blocks one particular fault that exists in no healthy cell of the body.

That is why the adverse effects are modest compared with what came before. There is not much healthy with that fault to do harm to.

That is also why there is resistance. It is enough for the welded gene to change one letter and change the shape of that gap for the molecule no longer to fit; then you have to move to another of the ones designed afterwards to fit the modified gap.

V

What this drug changed is not the survival of a rare disease.

It is the idea of what a treatment is. Up to here, almost everything consisted of giving something toxic and trusting it would be a little more toxic for the enemy than for you; the whole of chemotherapy is based on that narrow difference.

This is the opposite. There is an identified fault, its shape is known, and a piece is made that fits that shape and no other.

Then came the cascade effect. The same idea, applied to other faults, produced dozens of similar drugs in twenty years, and it also produced the economic problem we are dragging along. Since each fault affects few people, each drug is prescribed to few people, and the price per patient rises to figures no health system had ever seen.

And it changed something else, which is not about money. This disease stopped killing and became a “subscription”; whoever has it takes a tablet every day for the rest of their life, and the day they stop paying for it or stop obtaining it, it comes back. The cure, here, consists of never stopping.

VI

The objection is the price and it has to be put with numbers and without a speech.

This drug came on the market in 2001 costing some twenty-six thousand dollars a year. A decade later —with the same product, the same factory and the patent amply paid off— the annual price in the United States had risen above ninety thousand.

In 2013 more than a hundred specialists in this disease, from fifteen countries, jointly signed an article protesting about that. It was not written by activists: it was written by the doctors who prescribed it.

The prices are public and I add nothing more.

Only one thing of context, which is also public. In India generic versions were made at a fraction of that price, there was a long lawsuit over the patent and that country's supreme court ruled against the company in 2013. The same tablet, the same dose and two orders of magnitude of difference according to where it is prescribed.

Against me: I have told this story as a triumph of intelligence, which it is, and I have taken six sections to say what it costs.

VII

Bud Romine went back into the trial at the high dose, responded for years and died in 2012, at eighty-two [fourteen years after that first tablet], of something else.

Of the first patients of that phase one there are several still alive who see each other from time to time. There are group photographs, taken at anniversaries, with the survivors and their doctors.

This disease, which in 1998 killed in three or four years, has today a life expectancy almost the same as anybody's, on condition of taking a tablet every day for ever.

25 June 1998, twenty-five milligrams.

Three hundred milligrams: the dose at which almost everybody responded.

2001, approval, twenty-six thousand dollars a year.

A decade later, above ninety thousand.

Blood count at the laboratory on the corner: twelve euros.