CFTR modulators in cystic fibrosis: potentiators, correctors and who they are for

Cystic fibrosis and the CFTR protein

Cystic fibrosis is caused by mutations in the gene for CFTR, the cystic fibrosis transmembrane conductance regulator. CFTR is a channel in the membrane of epithelial cells that moves chloride, and with it water, across the cell surface. When it is missing or does not work, the mucus lining the airways, pancreatic ducts and intestine becomes thick and sticky, which leads to chronic lung infection, digestive failure and the other features of the disease.

More than two thousand CFTR mutations are known, but they fall into a few functional groups. In some, the protein is made but cannot open properly: these are gating mutations, of which G551D is the best known. In the most common mutation, F508del, the protein is misfolded, most of it is destroyed inside the cell before reaching the surface, and the little that does arrive gates poorly. Almost 90 percent of people with cystic fibrosis carry at least one F508del allele.

Potentiators and correctors

CFTR modulators are small molecules that act on the protein itself, and they come in two kinds.

A potentiator increases the probability that a CFTR channel already at the cell surface is open. Ivacaftor is the potentiator in every approved modulator product.

A corrector helps misfolded CFTR, above all F508del-CFTR, to fold well enough to escape destruction and reach the cell surface, where a potentiator can then act on it. Lumacaftor was the first corrector; tezacaftor and elexacaftor followed, and the triple combination of elexacaftor, tezacaftor and ivacaftor is the most effective regimen available for F508del.

The approved products

• Ivacaftor alone (Kalydeco): a potentiator for patients from 1 month of age with at least one CFTR mutation that responds to ivacaftor, originally G551D and now a longer list of gating and residual-function mutations defined in the product information.
• Lumacaftor/ivacaftor (Orkambi): the first corrector-potentiator combination, for patients from 1 year of age who carry two copies of F508del. Its clinical benefit is real but modest, and it is largely superseded where the triple combination is available.
• Tezacaftor/ivacaftor (Symkevi in the EU, Symdeko in the US): for patients from 6 years of age with responsive mutations, with fewer drug interactions and respiratory side effects than lumacaftor.
• Elexacaftor/tezacaftor/ivacaftor (Kaftrio in the EU, Trikafta in the US): the triple combination, for patients from 2 years of age with at least one F508del allele or another responsive mutation, and the current standard of care for most people with cystic fibrosis.

Ivacaftor and lumacaftor/ivacaftor have full medication pages in our catalogue. The approved mutation lists, age thresholds and weight-banded doses differ between the EU and the US and are updated regularly; the product information of the specific product is the authoritative source.

Who is eligible

Eligibility rests on two facts: the patient’s CFTR genotype, established by genetic testing, and the patient’s age. Treatment is started and supervised by a cystic fibrosis centre, which also arranges the monitoring described below. Because responsiveness is defined mutation by mutation, a genotype report is needed before any of these products can be prescribed.

How they are taken, interactions and monitoring

All of these products are taken by mouth, as tablets or, for young children, as weight-banded granules mixed into soft food. Each dose is taken with fat-containing food, because absorption on an empty stomach is poor.

Ivacaftor and its partner molecules are metabolised by the liver enzyme CYP3A, which creates two important interactions. Strong CYP3A inducers such as rifampicin, carbamazepine, phenytoin and St John’s wort lower exposure to the point that co-administration is not recommended. Strong inhibitors such as ketoconazole, itraconazole and clarithromycin raise it, and the product information specifies reduced dosing frequencies for these combinations. Lumacaftor is itself a strong CYP3A inducer and can reduce the effect of hormonal contraceptives and other medicines.

The product information calls for liver function tests before treatment, at intervals during the first year and annually thereafter, and for eye examinations in children, because cataracts have been reported in young patients treated with ivacaftor-containing regimens. Common side effects include headache, upper respiratory symptoms, abdominal pain, diarrhoea and rash; chest discomfort and shortness of breath at the start of lumacaftor/ivacaftor treatment are also described.

Storage and sourcing

CFTR modulators are not cold-chain medicines: the tablets and granules are stored at room temperature as directed on the pack, and they are shipped as ordinary parcels. What matters instead is continuity, because treatment is lifelong and interruptions allow lung function to fall. A request should state the exact product, the strength, the pack size and the treatment period, and it must be accompanied by a valid prescription from the treating physician. Destination-country rules for prescription medicines are verified before dispatch.