How Gleevec changed cancer treatment : NPR

Dr. Brian Druker, director of the Knight Cancer Institute at Oregon Health & Science University, defended the drug that became Gleevec.

Kristyna Wentz-Graff/Oregon Health and Science University

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Kristyna Wentz-Graff/Oregon Health and Science University

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When Mel Mann was diagnosed with cancer at the age of 37, he was told he would have three years to live.

It was January 1995. He was an Army major based in Detroit and thought the back pain he’d been suffering for six months had something to do with training. But an MRI showed there was a problem with his bone marrow. He suffered from an aggressive blood cancer called chronic myelogenous leukemia.

“I was shocked because it was the first time I had to face my own mortality,” Mann says.

“Right away, you’re going to think about your family,” he says of the diagnosis. He realized his daughter would be 8 years old when he died. Her time with him seemed rare. “And, you know, I was trying to negotiate to get more.”

So he volunteered to participate in clinical trials of every possible new experimental drug. Some worked for a few months and then stopped working.

Mann lived longer than doctors expected, but he was not doing well.

“At that point I was really tired,” he says. “You know, I would sleep for eight hours, drink two cups of coffee, wake up and feel like I never went to bed. And I… really lost a lot of weight. So I asked the doctor if there were any other medications?”

There was one: the drug that became Gleevec.

Mann started taking it in August 1998, as part of a clinical trial. The following June, he ran a marathon in Anchorage, Alaska. “I did it in a pretty decent amount of time, too,” he says.

Gleevec will ultimately become one of the first targeted cancer therapies approved by the Food and Drug Administration, helping usher in a new era in cancer treatment. But getting there wasn’t so simple.

The reverse

In the 1970s, oncologist Brian Druker had an idea that was at the time quite new in cancer medicine: what if, instead of just trying to kill cancer cells and hoping that healthy cells were largely spared, you could target the reason why cancer cells were growing out of control in the first place?

“What I saw with chemotherapy was that we were giving patients some pretty toxic drugs,” he says. “We didn’t really know if they would work. And my view was that there had to be a better way. And that better way had to be based on knowledge of what led to the growth of a specific cancer.”

There was an attractive target. Chronic myelogenous leukemia was one of the first cancers to be linked to a genetic abnormality: the Philadelphia chromosome.

Scientists knew that people with this chromosome produced an abnormal enzyme that regulates one of the on-off switches of cell growth. This remains stuck in the “on” position, leading to the uncontrolled growth of chronic myelogenous leukemia white blood cells.

Druker was looking for a drug that would be a switch for the abnormal enzyme.

“The problem was that few people thought it would work,” he says. Oregon Health and Science University was ready to support him, so he left Boston, where he was working at the time, and headed west.

Studies

Six weeks after arriving in Oregon, Druker was in a laboratory testing five compounds from the pharmaceutical company that would become Novartis. One of them was Gleevec – although at the time it was not known by its brand name. It was simply called imatinib, a compound discovered by biochemist Nicholas Lydon.

And it worked – at least in the lab. It was unclear whether it would be successful in patients.

“The reality is that I wasn’t just a researcher,” Druker says. “I also had patients and many, many patients who believed in me thought that this was a potential avenue for them. And that allowed me to have enough courage to be their spokesperson and their voice to push for this drug to go into clinical trials.”

At first, clinical trials were distinctive because they only included patients with that specific type of leukemia.

Within six months, all patients in a clinical trial who took a high dose of the experimental drug responded to the treatment. And the side effects were generally mild. It was unheard of.

And because it was 1999, it was also the beginning of blogs and Internet discussion forums. The patients were talking to each other.

“All of a sudden, I was being contacted by patients from all over the world who wanted to enroll in this clinical trial,” he says.

Everyone involved knew they needed to step up testing and submit the drug application to regulators. Fast.

Approval

The next step would be for the pharmaceutical company to submit this drug to the FDA for approval. But to do this, the company had to gather the data and prepare a whole package.

This is where 25-year-old Insa Gathmann comes in. She was fresh out of school and was hired at Novartis as a biostatistician.

“It was obvious at the time that this was a game changer and that we needed energetic people who could accelerate the development of this drug even further and get it to the authorities as quickly as possible,” she says.

She became statistical manager of the Gleevec project. One of his tasks was to produce graphs showing how long patients lived, called survival curves.

“When I first ran them for Gleevec, I was like, OK, I must have made a programming error. Something is wrong because the curves were right, I mean, they all worked great and they were all alive. And I was like, ‘No, no, no, something is wrong. This can’t be right.'”

But she was right. Gleevec was able to deactivate the abnormal enzyme, stopping cell proliferation and allowing patients’ white blood cell counts to return to normal. And the side effects were generally mild.

When Gleevec was approved on May 10, 2001, it was the FDA’s fastest approval at the time – in just 72 days.

Druker was at home in Portland, Oregon, and remembers the moment: “I kind of felt like I was sending a kid to college and I wanted him to go out into the world and be successful and do great things for the world.”

The meaning

Ameet Sarpatwari, assistant professor of population medicine at Harvard Medical School, says Gleevec’s story is an example of the public and private sectors working together to do their best to advance medicine in meaningful ways.

“You can think of this as the beginning of the era of targeted therapies, targeted cancer and drugs on the market,” Sarpatwari said. “There are now more than 100 targeted cancer drugs on the market, which in many cases have significantly improved overall survival and quality of life.”

However, Gleevec was also considered incredibly expensive when it launched at $26,000 per year. And it got more expensive over time. “So we have this remarkable system for developing drugs, but Gleevec also reflects the problems we have when it comes to pricing drugs and ensuring access to them,” he says.

The drug is now generic and costs a few hundred dollars a year. It has therefore become much more affordable and accessible.

Druker and other oncologists still prescribe Gleevec. And when patients are diagnosed with chronic myelogenous leukemia, it can tell them that they have a good chance of living a normal life.

He remembers a patient who suffered from leukemia as a child and started taking Gleevec before she was 10 years old. Eventually, she was able to stop the medication without her cancer returning. She now has two children. “Her parents thought she would never live long enough to graduate from high school, and here she is with us today,” he says.

The epilogue

Biostatistician Gathmann stayed at Novartis and rose through the ranks. She is about to retire.

“I’m very grateful,” she said. “I’m lucky to have been able to participate in the development of this drug. Not everyone gets a chance. I mean, we work on good drugs, but Gleevec, surely. I mean, it was a game changer.”

As for Mel Mann, the dad who had three years to live in 1995 is 69 years old. He was able to see his daughter grow up. He even went back to school and earned a second bachelor’s degree. He wants to run the Boston Marathon next year.

“I’m just grateful to the doctors I know who had to spend a lot of midnight oil to make this happen,” he says. “And the researchers and the people who were involved in the whole process, you know the people at the sites, the people who did the numbers and so many people that I have to be grateful for. And so that means a lot. You know, I got a second chance at life.”

Druker has seen people on death row go on to live normal lives. For him, Gleevec’s 25th anniversary is an important milestone.

“It’s a remarkable and magical moment of reflection because some of the patients from that first phase of human trials are still with me,” he says. “And they’ve seen weddings, births, graduations, grandchildren – all the things they never thought they could imagine happening.”