#NACFC2016 – CFTR Potentiators, Correctors Explored for Rare Mutations in CF

Among people with rare mutations in the CFTR gene, the gene defective in cystic fibrosis (CF), studies are needed to map down which patients may benefit from CFTR potentiators, such as Kalydeco (ivacaftor), or CFTR correctors.

In this way, researchers will also be able to identify those in need of alternative treatments to replace or mend a nonfunctional CFTR protein.

This topic was the focus of a presentation by Fred van Goor, PhD, from Vertex Pharmaceuticals, at the 30th Annual North American Cystic Fibrosis Conference (NACFC) Oct. 27-29 in Orlando, Florida.

The presentation, “Precision Medicine in Cystic Fibrosis: Ivacaftor in Rare Mutations,” was part of a symposium on rare mutations in CF titled “Small Molecule Intervention for Uncommon CFTR Mutations: Achieving Treatment for Every CF Patient.”

Although 90 percent of CF patients carry the F508del mutation in the CFTR gene, there are at least 276 known mutations in this gene that cause cystic fibrosis. As CF-causing mutations often reduce the numbers of CFTR channels at the cell surface, or prevent the protein from functioning properly, treatments that either correct or potentiate CFTR have been proven beneficial.

Kalydeco works by increasing the probability that the CFTR channel is open, allowing chloride ions to pass. In addition to treating people with the F508del mutation, the drug is approved in the U.S. for treating CF patients who are age 2 years and older with the mutations G551D; G1244E; G1349D; G178R; G551S; S1251N; S1255P; S549N; S549R, and R117H.

Orkambi, a drug combination of ivacaftor and lumacaftor, is approved only for patients older than 12 who have two CFTR gene copies with the F508del mutation. Lumacaftor works by increasing the number of CFTR channels at the cell surface, and so the drugs complement each other.

Studies have shown that Kalydeco (ivacaftor) increases the amount of chloride being transported in lab-grown cells with CFTR mutations associated with clinical evidence that CFTR is still working to a low degree. This suggests that Kalydeco could benefit patients with these mutations where at least some CFTR protein is present at the cell surface.

Research is currently ongoing to evaluate which of the rarer mutations can be targeted with combinations of CFTR potentiators and correctors.

Scientists use human bronchial epithelial cells gathered from people with cystic fibrosis and preparations of human gut to use as models for the study of CFTR. Many other types of measurements exist, allowing scientists to evaluate whether a drug, or a combination of drugs, improves the actions of the CFTR channel.

Van Goor pointed out that when studying these rare mutations, it is crucial for scientists to take into account factors such as the onset of disease in different organs, the impact of modifier genes, and limitations of the assays used.

Nevertheless, the types of mutations that do not respond to CFTR potentiators and correctors are likely to require other types of treatment, such as gene editing or mRNA-based therapies.