CFTR modulators
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CFTR modulators are a class of medication used to treat the genetic disorder cystic fibrosis (CF) in people with specific types of disease-causing mutations.
These therapies work to increase the functionality of a protein, known as CFTR, whose production is disrupted in cystic fibrosis. In so doing, they can help to ease the signs and symptoms of cystic fibrosis, such as lung and digestive issues, slowing disease progression and making day-to-day living with CF easier.
What are CFTR modulators?
CF is caused by mutations in the gene CFTR, which provides instructions for making the CFTR protein — short for cystic fibrosis transmembrane conductance regulator.
This protein normally sits on the cell surface and acts as a gated passageway for transporting chloride across cell membranes. Chloride flow helps control the balance of water on cells and tissue surfaces. Without a proper chloride flow through functional CFTR channels, the water balance is compromised and it is not possible to hydrate cellular surfaces, including the surface of the lung — done through mucus, the slippery substance that coats moist surfaces in the body.
In CF, mutations in the CFTR gene result in faulty or no production of CFTR. As a consequence, instead of a normal slippery mucus, people with CF have an abnormally thick and sticky form, which builds up in the body’s organs and causes damage. The buildup of thick mucus drives most signs and symptoms of CF.
CFTR modulators can bind to specific faulty versions of the CFTR protein to increase the protein’s functionality. This can allow the body to produce a more normal, slippery mucus, which ultimately can ease CF symptoms and slow the progression of damage to the body’s organs. Genetic testing, as part of the CF diagnosis process, can determine what underlying mutations patients have, and the modulator(s) for which they are eligible.
There now are four CFTR modulators approved in the U.S. to treat people with CF caused by specific mutations:
- Kalydeco (ivacaftor)
- Orkambi (ivacaftor/lumacaftor)
- Symdeko (ivacaftor/tezacaftor)
- Trikafta (ivacaftor/tezacaftor/elexacaftor).
All of these approved CFTR modulator therapies are marketed by Vertex Pharmaceuticals.
Potentiators
The CFTR protein normally functions like a gated channel — the gate can open, or allow chloride to flow through the channel, or it can close, or stop the flow. CFTR potentiators are a type of CFTR modulator that work to essentially prop open the gate, so that the channel stays open.
On their own, potentiators are generally most useful for CFTR mutations that allow the protein to get to the cell membrane but reduce its activity once there. That’s either due to less protein than normal, or because the mutation causes the gate to be stuck as if it’s closed.
Kalydeco
A potentiator called ivacaftor, marketed under the name Kalydeco, was the first ever CFTR modulator therapy to win regulatory approval in the U.S., in 2012.
Kalydeco is now approved in the U.S. to treat CF patients as young as 1 month old, and in Canada and the European Union for CF infants as young as 4 months. In the U.S., it is prescribed for patients who have one of 97 genetic mutations that are amenable to potentiator cystic fibrosis treatment. Kalydeco also is available in dozens of other countries worldwide, though specific age ranges and mutations may vary in each nation.
In addition to being used on its own as Kalydeco, ivacaftor is included as part of the other three CFTR modulator therapies approved for treating CF.
Correctors
To do its job, the CFTR protein needs to be transported to the surface of the cell. Normally, the protein folds into a specific shape that allows it to stay stable and be transported to the cell’s surface.
Some CF-causing mutations cause the CFTR protein to fold incorrectly, which makes the protein unstable, so it ends up getting degraded before it gets to the surface of the cell. The most common type of CF-causing CFTR mutation, called F508del, affects the protein in this way.
Correctors are CFTR modulators that help the protein fold correctly into its three-dimensional shape so it can reach the cell surface to function properly.
Two correctors called lumacaftor and tezacaftor are available as part of combination therapies given alongside the potentiator ivacaftor (sold on its own as Kalydeco). The idea behind these combination therapies is that the corrector helps the CFTR protein fold and get to the cell’s surface, and then the potentiator helps the gate-like protein stay open once it’s there.
Orkambi
The combination of lumacaftor and ivacaftor is sold under the brand name Orkambi. It’s approved in the U.S. to treat CF patients ages 1 and older who carry two copies of the F508del mutation.
Symdeko
Symdeko contains the combination of tezacaftor and ivacaftor. It is approved in the U.S. for patients ages 6 and older who have two copies of F508del or one of more than 150 mutations that are responsive to the therapy.
Trikafta
Trikafta is a triple-combination therapy that contains tezacaftor and ivacaftor (the corrector and potentiator in Symdeko), as well as a third cystic fibrosis medication called elexacaftor that’s been reported to act as both a potentiator and a corrector. The same triple-combination combination is marketed under the name Kaftrio in Europe.
Trikafta is approved in more than 30 countries worldwide. In the U.S., it’s indicated for use in CF patients ages 2 and older who have at least one copy of the F508del mutation, or another mutation that responds to the medicine based on experimental data.
Potential side effects
While specific safety profiles vary from therapy to therapy, all four approved CFTR modulators can potentially cause some side effects. These may include:
- cold-like symptoms such as runny nose, congestion, and sore throat
- digestive complaints like nausea, diarrhea, and abdominal pain
- headache
- elevated levels of liver enzymes (indicating liver damage)
- cataracts, or clouding of the eye lens.
Other side effects are associated with specific modulator therapies.
- Orkambi may cause shortness of breath, called dyspnea, and fatigue.
- Kalydeco and Symdeko may cause dizziness.
- Orkambi and Trikafta may cause high levels of creatine phosphokinase (a marker of muscle damage).
- Orkambi, Trikafta, and Kalydeco may cause infections like flu or upper respiratory infections.
- Orkambi, Trikafta, and Kalydeco may cause rash.
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FAQs about CFTR modulators
CFTR modulators are not considered a cure for cystic fibrosis (CF), though the medications can help to ease CF symptoms and slow disease progression in people with specific disease-causing mutations. While CFTR modulators can increase the functionality of mutated CFTR protein, they don’t completely normalize the protein’s activity, so patients may still experience some symptoms and progression even with modulator treatment.
Cystic fibrosis (CF) is caused by mutations that impair the functionality of the CFTR protein. CFTR modulators are medications that can bind to specific mutated versions of this protein, increasing its function. By boosting the function of the CFTR protein, CFTR modulators can help to ease symptoms of CF and slow disease progression in patients with amenable mutations.
All four CFTR modulators now available — Kalydeco, Orkambi, Symdeko, and Trikafta — are taken by mouth, twice daily, with varying dosages depending on the patient’s age and weight. Depending on the cystic fibrosis medication and formulation, these therapies may be available in the form of granules or tablets. Each dose of modulator therapy should be taken along with a fat-containing food (e.g., eggs, meat, nuts, or whole-milk dairy products), and foods containing grapefruit should be avoided.
CFTR modulators may cause side effects that include cold-like symptoms (runny nose, congestion, etc.) and gastrointestinal effects — nausea, diarrhea, and abdominal pain — as well as headache, dizziness, rash, infections, cataracts, and liver damage. The specific side effect profile varies depending on the particular cystic fibrosis medication; patients are advised to consult with their healthcare providers about any effects they experience after starting on CFTR modulator therapy.
The CFTR protein normally functions like a gate at the surface of a cell, helping to regulate the flow of chloride in and out of the cell. CFTR potentiators are a type of modulator therapy that have the effect of propping open the gate-like protein at the cell surface. CFTR correctors are a distinct type of therapy that helps stabilize the CFTR protein so it can get to the cell surface without being degraded.
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