The F508del Mutation and How ORKAMBI® Works

Cystic fibrosis (CF) is a genetic disease. A person with CF has 2 mutations in his or her cystic fibrosis transmembrane conductance regulator, or CFTR, gene.

Mutations in the CFTR gene, such as the F508del mutation, can result in missing CFTR proteins and/or CFTR proteins that do not work the way they should. CFTR proteins are found on the surface of cells in certain organs, such as the lungs. These proteins act as channels that allow chloride ions to pass into or out of the cell.

In a person who does not have CF:

  • There are enough CFTR proteins at the cell surface
  • The channels in these CFTR proteins work as they should

Chloride ions are able to pass into or out of the cell. This helps keep a balance of salt (sodium chloride) and water in certain organs. In the lungs, this keeps mucus thin and free flowing.

CF is the result of missing CFTR proteins and/or CFTR proteins that are defective, which means they don’t work as well as they should.

The F508del mutation is complex. It affects CFTR proteins in multiple ways:

  • Primarily, it affects how many proteins reach the cell surface
  • In addition, for those F508del-CFTR proteins that do reach the cell surface, they do not work as well as they should, and they don’t stay at the cell surface as long as they are supposed to

These defects reduce the amount of chloride ions that can pass into or out of cells. This results in an imbalance of salt (sodium chloride) and water, which eventually leads to the symptoms of CF. In the lungs, this can lead to thick and sticky mucus.

ORKAMBI is made up of lumacaftor and ivacaftor.

  • Lumacaftor helps to get more F508del-CFTR proteins to the cell surface
  • Ivacaftor helps the CFTR proteins at the cell surface work better

As a result, ORKAMBI allows more chloride ions to pass into or out of the cells. This may help keep a balance of salt and water in certain organs, such as the lungs.

What is known about how ORKAMBI works was learned from studies conducted in a laboratory. Keep in mind that laboratory studies do not always match how these medicines work in a person. If you have any questions about your treatment, please speak with your healthcare provider.