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Drug Fulfills Promise Of Research Into Cystic Fibrosis Gene

Jan 2, 2013
Originally published on January 2, 2013 7:53 pm

The promise of genetic medicine is beginning to be fulfilled, but it's been a long, hard slog.

Take the story of Kalydeco. It's designed to treat people with a lung disease called cystic fibrosis. While not quite a cure, the drug is extremely effective for some CF patients.

But the success of Kalydeco has been more than two decades in the making.

A good starting point for the story is Aug. 24, 1989. That's the day scientists from the U.S. and Canada announced the discovery of the gene associated with the disease. It was the early days of gene hunting, and the CF gene was a big prize.

CF is the most common genetic disease in Caucasians. When people inherit a damaged form of the CF gene, a critical protein inside cells doesn't work properly. As a result, sticky mucus builds up in a patient's lungs, causing infections and making it hard to breathe.

The announcement was supposed to be made in conjunction with three papers in the Sept. 8 issue of Science, but a reporter for Reuters got hold of the story early. Science took the unusual step of allowing the scientists to speak to the media before publication.

At the time, scientists predicted that a genetic test for CF was just around the corner. But they also thought a drug to treat the disease was in reach.

The first prediction turned out to be right. "But it wasn't until 20 years later that we were able to find drugs that directly target the underlying cause of cystic fibrosis," says Fred Van Goor, who led the team at what is now Vertex Pharmaceuticals that developed Kalydeco. "So it was a long time between the discovery of the gene and the discovery of Kalyedco."

It took awhile to find a drug that would help restore the function of the protein the CF gene makes. "We tested over 600,000 chemicals in cells with the defective protein that causes cystic fibrosis," says Van Goor.

One of those chemicals ultimately became a successful drug, but it had to be modified so patients could take it by mouth, and so it would last the right length of time in a patient's body.

From the start, Van Goor and his colleagues knew there was a problem with Kalydeco: It only works on a small subset of people with CF. They have to have a particular mutation in the CF gene, or the drug is of little use.

But for people who do have that mutation, the drug works remarkably well.

Emily Schaller was in one of the early studies of Kalydeco. As part of the study, researchers first gave her a placebo, then switched her to the active drug. She knew within days that something was different.

"I was with my brother in Florida, and we were walking down the street, and I took a deep breath, and when I took a deep breath in and I let it out, I didn't cough," says Schaller. "But not only did I not cough, but I felt that my lungs were clear, and that something huge had happened. It was just something I had never felt in my life before."

Schaller isn't cured. She still has a damaged CF gene. The only way to fix that would be gene therapy, where a healthy form of the gene would supplant the damaged one. Although it seems simple in theory, in practice gene therapy has been incredibly difficult to accomplish.

Schaller isn't particularly bothered by that. "Everyone talks about curing a disease — cure CF, cure these other diseases. [But] Kalydeco controls CF at the basic defect, so I'm OK with the other 'c' word, control, because I'm living it and I've never felt better in my life."

The time from gene discovery to successful drug may be shortening, but there are only a handful of successful drugs so far, and for a while at least, the appearance of new ones will be slow.

They're also likely to be expensive. Kalydeco costs in the neighborhood of $300,000 per year.

Copyright 2013 NPR. To see more, visit http://www.npr.org/.

Transcript

AUDIE CORNISH, HOST:

A remarkable new drug appeared on the market this past year. It's called Kalydeco, and it's designed to treat people with a lung disease called cystic fibrosis. While not quite a cure, the drug is extremely effective for some patients. NPR's Joe Palca has this story of how Kalydeco came to be.

JOE PALCA, BYLINE: A good starting point for the story of Kalydeco is August 24, 1989.

(SOUNDBITE OF ARCHIVED NEWS BROADCAST)

LINDA WERTHEIMER, BYLINE: Scientists announced at a news conference today that they have found the gene that causes cystic fibrosis.

PALCA: That's how Linda Wertheimer began NPR's coverage of the story. It was the early days of gene hunting in 1989, and the CF gene was a big prize. Cystic fibrosis is the most common genetic disease in Caucasians. When people inherit a damaged form of the CF gene, a critical protein inside cells doesn't work properly. As a result, sticky mucus builds up in a patient's lungs, causing infections and making it hard to breathe.

My colleague Michelle Trudeau did the story of the gene discovery on ALL THINGS CONSIDERED back in 1989. She talked to scientists who predicted that a genetic test for cystic fibrosis was just around the corner. But they said there was more.

(SOUNDBITE OF ARCHIVED NEWS BROADCAST)

MICHELLE TRUDEAU, BYLINE: With the discovery of the gene, different drugs can be tested to see if any of them will get the defective protein to do what it's supposed to do. So an effective treatment is now within reach as well.

PALCA: The genetic test did come fairly quickly.

DR. FRED VAN GOOR: But it wasn't until 20 years later that we were able to find drugs that directly target the underlying cause of cystic fibrosis. So it was a long time between the discovery of the gene and the discovery of Kalydeco.

PALCA: Fred Van Goor led the team at what is now Vertex Pharmaceuticals that developed Kalydeco.

GOOR: We tested over 600,000 chemicals in cells with the defective protein that causes cystic fibrosis.

PALCA: One of those chemicals ultimately became a successful drug. But it was a long slog. The chemical had to be modified so patients could take it by mouth and so it would last the right length of time in a patient's body. From the start, Van Goor and his colleagues knew there was a problem with Kalydeco. It only works on a small subset of people with cystic fibrosis. They have to have a particular mutation in the cystic fibrosis gene or the drug is of little use. But for people who do have that mutation, the drug's impact is stunning.

Emily Schaller was in one of the early studies of Kalydeco. As part of the study, researchers first gave her a placebo, then switched her to the real drug. She knew within days that something was different.

EMILY SCHALLER: I was with my brother in Florida, and we were walking down the street. I was - I took a deep breath in. And when I took a deep breath in and I let it out, and I didn't cough. But not only did I not cough, I just felt like my lungs were clear, and that something huge had happened. It was just something I had never felt in my life before.

PALCA: Schaller isn't cured. She still has a damaged CF gene. The only way to fix that would be to replace the damaged gene with a healthy one, a process called gene therapy. Although it seems simple in theory, in practice, gene therapy has been incredibly difficult to accomplish. Schaller isn't particularly bothered by that.

SCHALLER: Everyone talks about curing a disease, cure cystic fibrosis, cure these other diseases. But Kalydeco controls CF, you know, at the basic defect. So I'm OK with the other C word, control, because I'm living it and it's - I've never felt better in my life.

PALCA: But even finding drugs that control genetic diseases has been extremely difficult, that's why Kalydeco is so noteworthy. Scientists hope there will soon be many more drugs that are based on understanding the genetics of the disease, but those drugs will likely be expensive. A year's supply of Kalydeco can cost around $300,000. Joe Palca, NPR News, Washington.

(SOUNDBITE OF MUSIC)

ROBERT SIEGEL, HOST:

This is ALL THINGS CONSIDERED from NPR News. Transcript provided by NPR, Copyright NPR.