Types of CFTR Modulators: Correctors, Potentiators, and Amplifiers
Cystic fibrosis (CF) is a disease caused by genetic mutations (changes) in a specific gene called the cystic fibrosis transmembrane conductor regulator (CFTR). When the CFTR proteins do not form correctly, they can cause an imbalance in the salt and fluid levels both inside and outside of cells. The results of these genetic errors cause the symptoms associated with cystic fibrosis.1,2
People with cystic fibrosis have different problems caused by different flaws in the CFTR protein. Current available treatments for CF include the use of medications that target the various defects in the CFTR protein. One class of drugs is called CFTR modulators. There are three categories of modulators called correctors, potentiators, and amplifiers.1-3 These modulators can’t cure CF or restore full function of the CFTR protein, but they are proving to be effective at relieving the symptoms associated with cystic fibrosis.1
A normal CFTR gene sends instructions for making the cystic fibrosis transmembrane conductance regulator.1 This is a protein whose job is to form a channel across cell membranes to carry chloride (which includes salt and water) to produce mucus, sweat, saliva, tears, and digestive enzymes. Cystic fibrosis can develop when the message from the CFTR gene can’t get through and the protein cannot form correctly.1-4
CFTR modulators try to work around the problems in the CFTR protein to improve specific functions. Each of the modulators work differently attempting to fix or improve certain conditions that could reduce the symptoms of CF. Correctors, potentiators, and amplifiers all help to treat different cellular issues in different ways.1
The normal CFTR protein has a particular 3-dimensional shape. Nearly half of all people with CF have 2 F508 del mutations, one from each parent. If the F5098 building block is missing, the instructions cannot be received and the CFTR proteins do not form in the right shape.1 This interferes with the protein’s function.1,4
It is like a puzzle with a missing piece. The mutations affect the folding of the proteins and the ability of salt and water to get to the surface of the cells (this is sometimes referred to as trafficking). Corrector CFTR modulators, like lumacaftor or tezacaftor, attempt to stabilize the CFTR protein so it can work properly.1,2 They help to fix the folding process so that the puzzle pieces of the protein fit together. When the CFTR protein is in the right shape, it is able to move to the cell surface.1,4
When used alone, correctors don’t relieve CF symptoms. Correctors work better when taken in combination with a potentiator, like ivacaftor. There are combination drugs already approved for treating CF. Orkambi® is a combination of lumacaftor and ivacaftor and Symdeko® is a combination of tezacaftor and ivacaftor. They are prescribed for treatment of CFTR mutations. The CFTR corrector helps to fix the problem, the potentiator increases its effectiveness.
The normal CFTR protein has a tunnel shape with a gate. When the tunnel is open, it allows chloride to move through and then out of the cell.1 Potentiator drugs increase the protein’s ability to hold the gate open long enough so the chloride can flow through, creating a channel to the cell surface.3 If the gates of the protein are closed, then there is limited chloride movement into or out of the cell. With improved chloride flow, mucus built up inside the lungs and other organs is rehydrated, it absorbs more moisture and becomes moister. This can reduce blockages in the lungs and other organs.1
Ivakaftor, known as the brand, Kalydeco® is type of CFTR modulator referred to as a potentiator. It targets 10 different genetic mutations in around 8% of people who have CF. Ivakaftor helps improve the gate function and the transport of chloride to the cell surface in those cells where there is not enough normal protein present. Potentiators help open the defective ion channel in CFTR to allow the chloride to pass through.1,3
There are different kinds of CFTR mutations in people with CF. Although some CFTR protein reaches the surface of the cell, there is either not enough or it is faulty and does not allow enough chloride to flow through. Potentiators can bind to the corrected CFTR protein at the cell surface and hold open the gate of the chloride channel long enough to improve flow. This can restore the liquid balance on the cell surface and reduce CF symptoms.1
The third type of CFTR modulator is an amplifier. Amplifiers increase the amount of CFTR protein that each cell makes. This would be helpful for people with CF who don’t make enough of the CFTR protein.1,4 Amplifiers are not yet on the market.
Researchers are presently testing the theory that if cells make more CFTR protein using amplifiers, then by adding potentiator and corrector drugs they could create a way for more chloride to flow through the cells. Amplifiers are in phase 2 drug trials. They are designed to be used as part of a combination therapy.
What’s next? Next-generation CFTR modulators
Personalized medicine may be in the future of CF treatment. Researchers will be challenged to match the right combination of drugs to each person with their own form of cystic fibrosis. There are other next-generation CFTR modulators being investigated. Having multiple drugs including potentiators, correctors, and amplifiers, prescribed in different combinations, could potentially treat different variations in cystic fibrosis.1,2
Triple combination therapies, using each of the CFTR modulators, may improve function by treating the different errors due to the individual mutations in the CFTR protein. These cellular changes which cause the defects, if treated with the right combination of drugs, may result in improved clinical outcomes.2
The goal of next-generation modulators will be to eliminate or improve the defective folding of the protein as well as to improve the surface stability and chloride channel function in cells with CFTR mutations that cause CF symptoms.2
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