CFTR Modulators for Cystic Fibrosis
The symptoms of cystic fibrosis (CF) are caused by mutations in a gene called the cystic fibrosis transmembrane conductor regulator (CFTR). People with CF inherited two copies of the defective gene -- one copy from each parent.
Mutations in the CFTR gene mean that CFTR proteins are not made correctly. The faulty protein does not provide a channel for chloride, an element of salt, to move through cell walls which creates a thick, sticky mucus that clogs the lungs, pancreas, sinuses, and more.
What are CFTR modulators?
A class of drugs called CFTR modulators target specific defects in the CFTR protein so that the protein can work properly. CFTR modulators do not fully restore chloride flow, but they do improve the flow enough to help lessen CF symptoms.
There are currently four types of CFTR modulators
- Potentiators (ivacaftor)
- Correctors (lumacaftor and tezacaftor)
- A corrector/potentiator combination (elexacaftor/tezacaftor/ivacaftor)
The four different types of CFTR modulators work on distinct parts of the CFTR protein to help it work better. The CFTR protein is shaped like a tunnel with gates that open and close, offering access out of the cell. Potentiators help chloride move through the CFTR protein, providing a channel to the cell surface. Potentiators hold the gate open. Potentiators work on gating, conduction, residual function, and splice mutations. Ivacaftor (brand name Kalydeco) has been approved for use in the U.S.3,4
Correctors help the CFTR protein form the right shape so that it is able to move to the cell surface and stay there longer. Two correctors, lumacaftor (brand name Orkambi) and tezacaftor (Symdeko), have been approved for use in the U.S. These correctors are used in combination with the potentiator ivacaftor to increase their effectiveness.3,4
CFTR correctors, like elexacaftor and tezacaftor, help the CFTR protein channel work better. CFTR potentiators, like ivacaftor, help keep the corrected channel open so chloride can pass through. The medication that is the combination of elexacaftor, tezacaftor, and ivacaftor is the brand name Trikafta.
One amplifier, PTI-428, is currently being tested so this drug is not yet available. Amplifiers increase the amount of CFTR protein that a cell makes, which should help those people with CF who do not produce enough CFTR protein. The theory is that if the cells make more CFTR protein, the potentiators and correctors could allow more chloride to flow through the cell membrane. Research continues on many other next-generation CFTR modulators.
Which CFTR modulator is the best for treating cystic fibrosis?
Not all CFTR modulators work for all CF patients. That is because different genetic mutations cause different types of CFTR protein defects. Each CFTR modulator is designed to correct specific problems caused by the mutated CFTR protein. The current crop of CFTR modulators work on 65 different types of CF mutations, including the most common: two copies of F580del.1
What are the risks or common side effects with CFTR modulators?
Side effects of CFTR modulators vary according to the drug taken, but nausea and sinus congestion are common to all three types of therapies. The long-term risks of taking this new class of drugs is unknown but since the medications cause such dramatic improvements in symptoms, including lung function and body mass index (BMI), CFTR modulators are considered game-changers for the future of people with CF.
Help paying for CFTR modulators
CFTR modulators are expensive, even with insurance coverage. If you are having trouble paying for your CFTR modulator, the manufacturer Vertex offers patient assistance services at 1-877-752-5933 (press 2).5 The CF Foundation offers the Compass service, which offers personalized, one-on-one support for insurance, financial, legal issues related to cystic fibrosis.
Contact the CF Foundation compass service at:
Phone: 1-844-COMPASS (1-844-266-7277)
Monday - Friday, 9 a.m. - 7 p.m. ET6