CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. Because different mutations cause different defects in the protein, the medications that have been developed so far are effective only in people with specific mutations. There are three CFTR modulators for people with certain CFTR mutations: ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi ®), and tezacaftor/ivacaftor (Symdeko®).
The CFTR protein regulates the proper flow of water and chloride in and out of cells lining the lungs and other organs. In people with CF, mutations in the CFTR gene result in either a defective protein being produced or no protein at all. This leads to the buildup of thick, sticky mucus, which can lead to infections in the lungs and damage to the pancreas. It can also lead to problems in other parts of the body.
The following video shows what it looks like when the CFTR protein functions normally in the lungs -- hair-like cilia move mucus and germs out of the airways -- and what happens when the protein doesn't work.
In people with certain mutations, CFTR modulators help the defective protein move to the cell's surface and function properly once it is there. For some, the problem is only at the cell's surface, where the defective protein disrupts the flow of water and chloride. For example, in people with gating mutations, the “gate” to the chloride channel at the cell surface is locked.
Ivacaftor, a CFTR modulator, helps people with CF who have gating mutations. Ivacaftor binds to the defective protein at the cell surface and opens the chloride channel (holds the gate open) so that chloride can flow through, regulating the amount of water at the surface of the cell. The following video shows how this happens in people who have the G551D gating mutation.
Lumacaftor/ivacaftor is a combination therapy that works in people with two copies of the F508del mutation. Lumacaftor is a modulator known as a corrector. It helps the CFTR protein form the right shape, traffic to the cell surface, and stay there longer. But, even with Lumacaftor, only about a third of the CFTR protein reaches the cell surface, and those proteins do not open enough to allow chloride to pass through the cell membrane. But, if a corrector is used in combination with a potentiator -- such as ivacaftor -- to hold the gate on the CFTR protein open, enough chloride can then flow to reduce the symptoms of CF.
Tezacaftor/ivacaftor is another treatment option for people with two copies of the F508del mutation who were unable to take lumacaftor/ivacaftor. Tezacaftor, another corrector, acts in the same way that lumacaftor does, but the tezacaftor/lumacaftor combination does not seem to cause the chest tightness or drug interactions caused by lumacaftor/ivacaftor. In addition, tezacaftor/lumacaftor is approved for people with a single copy of one of 26 specified mutations.