Cystic fibrosis is a disease that is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. These mutations compromise the transport of water and chloride ions across the CFTR protein channel, resulting in the production of thick, obstructive, sticky, and dysfunctional mucus within the secretory cells of the body. This disruption of the CFTR protein function across cells that line the lungs, pancreas, intestines, and reproductive organs have several consequences.

Some CFTR mutations can cause problems with protein production and folding, and therefore compromise the amount of protein present on the cell surface, while other mutations can cause a direct functional impairment in chloride transport across an existing channel.

CFTR modulators

To correct defects caused by mutations in the CFTR gene, investigators have developed a range of CFTR modulators to overcome functional disturbances in the CFTR protein. These modulators fall into three categories based on how they work.

CFTR amplifiers act by enhancing the amount of functional protein present on the cell surface, CFTR correctors aim to overcome folding defects within the protein, and CFTR potentiators facilitate the chloride transport by modulating the gating (opening and closing) characteristics of the channel.

CFTR potentiators

CFTR potentiators act by holding open a key gate within the protein in a correct conformation long enough to facilitate the transport of chloride ions across the channel. An important mutation is known to cause gating defects in the CFTR protein is the so-called G551D substitution.

Vertex Pharmaceuticals has developed Kalydeco (ivacaftor), which is a CFTR potentiator now approved for use in CF patients who are 6 and older, and have at least one G551D mutation.

The treatment is also approved by Health Canada and the European Medicines Agency (EMA) for the treatment of CF patients who carry other gating mutations (namely G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, and G1349D).

Approved CFTR potentiator combinations

A combination of ivacaftor and CFTR corrector tezacaftor (marketed as Symdeko) received regulatory approval in the U.S. and Canada in 2018 for patients, ages 12 and older, who have two copies of the F508del mutation, or who have at least one mutation that is responsive to treatment with the combination treatment.

Emerging CFTR Potentiators

GLPG2451 and GLPG1837 are two CFTR potentiators that are being developed by Galapagos in collaboration with Abbvie. The potential new treatments have shown promising results in clinical trials.

QBW251, which is developed by Novartis, is another CFTR potentiator that has been tested in combination with other CFTR treatments.

PTI-808 is a promising CFTR potentiator that is currently being developed by Proteostasis Therapeutics.

Developed by Flatley Discovery LabFDL176 is a new CFTR potentiator that was evaluated in Phase 1 clinical trial (NCT03516331) for its safety, tolerability, and pharmacokinetics (movement in the body) in combination with Flatley’s CFTR corrector, FDL169. The treatment has also been tested on its own in another Phase 1 clinical trial (NCT03173573).

Some plant flavonoids such as quercetin and genistein have been suggested as CFTR potentiators. However, their clinical development for use in CF is still at a very preliminary stage. Some preliminary pre-clinical studies on rattlesnake phospholipase Aand aminoarylthiazoles have suggested their dual roles as potentiators and correctors.

Clinical trials

There are currently about 35 active clinical trials testing ivacaftor alone or in combination with other therapies. Twenty-six of these clinical studies are currently recruiting patients or enrolling them by invitation.

CF patients should consult with their physicians to determine which CFTR potentiator or combination of modulators is right for them.

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Cystic Fibrosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health care providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.