Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that affect the production of the CFTR protein. When the CFTR protein is not made correctly, it affects the balance of salt and fluids inside and outside of the cell. This imbalance leads to thick, sticky mucus in the lungs, pancreas, and other organs.
We support the development of drugs that target specific defects in the CFTR protein. As a group, these drugs are called modulators because they are intended to modulate the function of the CFTR protein so that it can serve its primary function: to create a channel for chloride (a component of salt) to flow across the cell surface.
When proper chloride flow is reestablished, mucus becomes rehydrated inside the lungs and other organs. Although modulators can't yet completely restore proper chloride flow, they can improve the flow enough to relieve symptoms for people with CF.
There are two main types of CFTR modulators:
The CFTR protein is shaped like a tunnel that can be closed by a gate. Potentiators are CFTR modulators that hold the gate open so chloride can flow through the cell membrane.
The drug Kalydeco® (ivacaftor) is a potentiator. This drug can help patients with gating and conduction mutations in CFTR. It also works on residual function and splice mutations where an insufficient amount of normal protein is present. In all these mutations, some CFTR protein reaches the surface of the cell. However, either not enough protein reaches the cell surface, or the protein does not allow enough chloride to flow through. By holding the gate on the CFTR protein open, potentiators allow more chloride to flow through and reduce the symptoms of CF.
The next type of CFTR modulator is called a “corrector.” Correctors help the CFTR protein to form the right 3-D shape so that it is able to move -- or traffic -- to the cell surface.
Nearly 90 percent of people with CF have at least one copy of the F508del mutation, which prevents the CFTR protein from forming the right shape. Corrector drugs help the CFTR protein to form the right shape, traffic to the cell surface, and stay there longer. But, even with correctors, only some of the CFTR protein reaches the cell surface. Additionally, the proteins that do reach the cell surface do not open sufficiently to allow chloride to pass out of the cell.
But, if a corrector(s) 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. In the newest modulator on the market, the correctors elexacaftor and tezacaftor were combined with ivacaftor to form Trikafta®, a triple combination that can be used to treat people with CF who have at least one copy of the F508del mutation (regardless of their second mutation) or at least one copy of 177 specified mutations.
Ivacaftor and lumacaftor, a component of Orkambi®, are sometimes called “first-generation modulators” because they were the first modulators approved to treat people with CF. Tezacaftor, approved in February 2018 as part of Symdeko®, is also considered a first-generation modulator.
Elexacaftor is considered to be part of the “next-generation” modulators, which are potentially more effective than the first-generation CFTR modulators. Other next-generation therapies are in development. They also are likely to be part of a triple-combination therapy to provide more people with CF a variety of treatment options. It is important to have alternatives because individuals respond differently to drugs. In addition, not everyone can take currently approved modulators. This population includes people who experience side effects, have drug interactions, or have mutations that are not responsive.
Individually, each of the three drugs in a triple-combination therapy addresses a different aspect of the defective CFTR protein. When used in combination, the results may be better than using one or two of the drugs alone.
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FDA-approved drug information is available at dailymed.nlm.nih.gov/dailymed.