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A new drug combination treats the underlying cause of cystic fibrosis (CF) in half of all people with this deadly disease.

Thousands of cystic fibrosis patients can breathe easier thanks to the latest breakthrough in CF treatment.

A new combination of drugs that treats the most common form of CF was approved by the U.S. Food and Drug Administration (FDA) in 2015.

Dr. Bonnie Ramsey of Seattle Children’s Research Institute was one of four principal investigators who led international clinical trials that showed a combination of ivacaftor and lumacaftor improves lung function for patients with a specific genetic mutation found in approximately half of all people with CF.

Bonnie Ramsey“This is a huge leap forward in CF treatment because it helps such a large percentage of people who have cystic fibrosis,” says Ramsey, who leads the institute’s Center for Clinical and Translational Research.

CF treatments previously addressed only the symptoms of the disease. The new drug combo, Orkambi, is the second therapy to treat CF’s underlying cause. The first, Kalydeco, helps a smaller subset of patients with a different genetic mutation. Kalydeco (the brand name for ivacaftor) was approved by the FDA in 2012.

Changing the game

Cystic fibrosis causes thick mucous to build up in the lungs and other parts of the body. The sticky mucous makes it hard to breathe and is a breeding ground for bacteria that cause chronic lung infections and progressive lung damage. About 30,000 people in the U.S. have cystic fibrosis. The median life expectancy is 50, but many people die as young adults.

Orkambi and Kalydeco change the game by targeting some of the many genetic mutations that cause CF. Of the 1,400 mutations that have been identified, 10 account for more than 90% of CF cases.

“These drugs are an amazing example of personalized medicine because they correct different genetic defects that cause the same disease,” says Ramsey. “The treatments are new and we’re still writing history, but we expect they will lead to longer lives.”

Going with the flow
Margaret Rosenfeld

Each CF mutation results in a unique defect in a protein that regulates the flow of salt and water across the surface of cells. The defects cause salt and water to flow sluggishly and create the symptoms of cystic fibrosis. In some cases, the protein isn’t made. In others, it either fails to open properly or fails to reach the cell surface – or both.

Ivacaftor treats people with the G551D mutation in which the protein doesn’t open properly. The ivacaftor-lumacaftor combination treats people with the F508 mutation in which the protein neither opens properly nor reaches the surface. Ivacaftor opens the protein. Lumacaftor enables it to reach the surface.

Researchers began to screen for drugs to treat the underlying cause of CF about 15 years ago. The F508 mutation was a prime target because it is the most common mutation, but it was decided to develop a therapy for the G551D mutation first because ivacaftor was further along than lumacaftor and worked without needing to combine the two drugs.

Progress continues

Ramsey has devoted her career to improving care for people with cystic fibrosis. Before working on Orkambi, she helped develop TOBI, a groundbreaking inhalable antibiotic treatment for CF lung infections. She also led the clinical trials for Kalydeco. Ramsey’s election to the National Academy of Medicine in 2015 recognizes her overall contributions to the field.

The clinical trials for Kalydeco and Orkambi were managed by the Cystic Fibrosis Therapeutics Development Network, which is based at Seattle Children’s. The network manages numerous CF trials at more than 70 sites, maintains a registry of patients eligible for trials and consults with study sponsors.

Ron Gibson Two Seattle Children’s researchers are exploring additional ways to treat CF based on the work that led to Kalydeco and Orkambi.

Dr. Margaret Rosenfeld is studying the use of Kalydeco and Orkambi in young children. Dr. Ron Gibson is studying a possible replacement for lumacaftor that may work better in combination with ivacaftor.

Researchers elsewhere are studying how to help patients with a mutation in which the protein that regulates the flow of salt and water isn’t produced at all.

These drugs are an amazing example of personalized medicine – they correct different genetic defects that cause the same disease.
– Dr. Bonnie Ramsey