A properly functioning cystic fibrosis transmembrane conductance regulator (CFTR) protein forms a channel that allows chloride (a component of salt) to move in and out of cells lining the lungs and other organs. The CFTR protein is shaped like a tube that goes through the membrane surrounding the cell, like a straw goes through the plastic top on a cup.
Different CF mutations cause the protein to malfunction in different ways. New and potential therapies target these specific problems, sometimes by using more than one drug, to restore CFTR function and help improve key symptoms of CF.
Ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi®), and tezacaftor/ivacaftor (Symdeko®) make up the first generation of CFTR modulators, which seek to restore function to the CFTR protein.
Watch this animation to see how CFTR modulators known as correctors and potentiators work to make the CFTR protein functional.
There are several next-generation modulators currently in clinical trials, including two triple-combination drugs made up of ivacaftor, tezacaftor, and either VX-445 or VX-659. Results from both Phase 3 clinical trials for these triple-combination drugs are expected by early 2019. Previous clinical trial results have indicated that these triple-combination modulators will likely be more effective than current modulators and could potentially treat a much larger population of people with CF.
The goal is to find a treatment that would help all people with CF. The first-generation modulators could benefit 61 percent of people with CF in the U.S. if all age groups are approved. Next-generation triple-combination therapies could help people with just one copy of the F508del mutation, potentially increasing the number of people who could benefit from modulators to more than 90 percent.
In this video, George M. Solomon, M.D., assistant professor of medicine and director of the adult CF program at the University of Alabama at Birmingham, explains what researchers are doing to try to develop CFTR modulators that can treat a wider variety of mutations.
It is estimated that 5 to 7 percent of people with CF will be unable to benefit solely from CFTR modulators and will require different therapies to fix the underlying cause of their disease. We are funding research aimed at discovering new treatments for these individuals with nonsense and rare mutations that do not produce CFTR protein.
Preclinical work is being done to screen for compounds that could enable the protein-making machinery of the cell to override premature stop signals caused by nonsense mutations so that a full-length protein can be made. These compounds would be known as readthrough agents because they could “read through” the premature stop signals.
Watch this animation to see how nonsense mutations might be corrected to make normal CFTR protein.
The multiple approaches reflected in the Drug Development Pipeline include increasing the amount of CFTR protein that reaches the cell surface, stabilizing the protein so that it functions better, and repairing or replacing the CFTR-encoded messenger ribonucleic acid (mRNA) that is used as a template to create the CFTR protein.
The latter treatment is known as RNA therapy, and it could potentially benefit everyone with CF regardless of their mutations. For RNA therapy, the Foundation is pursuing two different approaches in parallel. The first approach would replace the defective mRNA by delivering normal mRNA to cells. The second approach is to repair the defective mRNA responsible for producing the CFTR protein. Both strategies would enable full-length, functional CFTR protein to be made.
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