CFTR Modulator Therapies

What Are They?

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. Because different mutations cause different defects in the protein, the medications that have been developed so far are effective only in people with specific mutations. There are four CFTR modulators for people with certain CFTR mutations:  

  • Kalydeco® (ivacaftor)
  • Orkambi® (lumacaftor/ivacaftor)
  • Symdeko® (tezacaftor/ivacaftor)
  • Trikafta® (elexacaftor/tezacaftor/ivacaftor)

More potential CFTR modulators are in development to address the underlying cause of the disease in people with other CF mutations.

The CFTR protein regulates the proper flow of water and chloride in and out of cells lining the lungs and other organs. In people with CF, mutations in the CFTR gene result in either a defective protein being produced or no protein at all. This leads to the buildup of thick, sticky mucus, which can lead to infections in the lungs and damage to the pancreas. It can also lead to problems in other parts of the body.

The following video shows what it looks like when the CFTR protein functions normally in the lungs and what happens when the protein doesn't work.

 
CFTR modulators have been approved by the U.S. Food and Drug Administration (FDA) for people with the specific CF mutations. The first step in knowing whether you can take these drugs is to know your CF mutations. If you do not know your mutations, specialized genetic tests are available to identify your mutations. The Cystic Fibrosis Foundation's Mutation Analysis Program offers free genetic testing for people with CF who have unknown mutations. If you are interested in enrolling, ask your CF care team.

Trikafta

The newest CFTR modulator Trikafta (elexacaftor/tezacaftor/ivacaftor) is known as the triple combination or triple combo. It combines the next-generation corrector elexacaftor with tezacaftor/ivacaftor. Like lumacaftor and tezacaftor, elexacaftor also helps the F508del-CFTR protein form the right shape so that it can traffic to the cell surface. Because elexacaftor corrects an additional flaw in the formation of the F508del-CFTR protein, including it with tezacaftor/ivacaftor helps the CFTR protein perform better than other modulators for an even greater number of people with CF. The triple combo has been approved for people with CF ages 6 and older who have at least one copy of the F508del mutation or at least one copy of 177 specified mutations  (Esta lista de mutaciones también está disponible en español).

Kalydeco

In people with CF who have gating mutations, the “gate” to the chloride channel at the cell surface is locked. Kalydeco (Ivacaftor), a CFTR modulator known as a potentiator, binds to the defective protein at the cell surface and opens the chloride channel (holds the gate open) so that chloride can flow through, regulating the amount of fluids at the surface of the cell. The following video shows how this happens in people who have the G551D gating mutation.

Ivacaftor is approved for people with CF ages 4 months and older who have one of 97 specified mutations.

Orkambi

Orkambi (lumacaftor/ivacaftor) is a combination therapy that is FDA-approved for people with two copies of the F508del mutation. Lumacaftor is a modulator known as a corrector. It helps the F508del-CFTR protein form the right shape, traffic to the cell surface, and stay there longer. But, even with lumacaftor, only about a third of the CFTR protein reaches the cell surface, and those proteins do not open enough to allow chloride to pass through the cell membrane. If a corrector is used in combination with a potentiator -- such as ivacaftor -- to hold the gate on the CFTR protein open, enough chloride can then flow to reduce the symptoms of CF.

Orkambi is prescribed for people ages 2 and older who have two copies of the F508del mutation, which is the most common CF mutation. To learn about one person's experience on Orkambi, read, "Orkambi: A Life Sentence."

Protein Processing Mutations
F508del + F508del

 

Symdeko

Symdeko is made up of tezacaftor and ivacaftor. Tezacaftor, another corrector, acts in the same way that lumacaftor does in Orkambi: It helps the CFTR protein form the right shape, traffic to the cell surface, and stay there longer. The difference between the correctors is that the tezacaftor/ivacaftor combination has been shown to have fewer side effects -- such as chest tightness -- and drug interactions than lumacaftor/ivacaftor. In addition to providing another treatment option for people ages 6 and older with two copies of the F508del mutation, Symdeko is also approved for people ages 6 and older with a single copy of one of 154 specified mutations.

To read about the experience of two adults with CF on Symdeko, read, “Life on Symdeko Three Months Later” and “How CFTR Modulators Changed My Reality.”

How Do I Take Them?

Your CF care team or pharmacist will give you specific instructions for taking CFTR modulators as part of your daily care plan. Instructions for taking CFTR modulators may be different for you than they are for others. Your specific dosage may depend on other medications you're already on, your health needs, and personal circumstances.

What Should I Expect After Taking Them?

The effects of CFTR modulators only last for as long as the medication is in your system. Therefore, you need to take the medication every 12 hours, or as your care team prescribes.

“After 33 years of living with cystic fibrosis, I thought I knew my body pretty well. Since I started on Symdeko®, I have noticed that my body is different, and I need to re-learn how to interpret my symptoms.” -- Aimee Lecointre, adult with CF, from the CF Community Blog

You may experience side effects when you take any medication. When discussing any new medications or changes in dosages for medications you are already taking, be sure to ask your care team about:

  • Any potential side effects.
  • Which side effects might be more serious than others.
  • How long they might last.
  • When to talk to your care team if side effects don't go away or if they interfere with your quality of life.
  • Any potential drug interactions.

Let your care team know if you feel any side effect that bothers you or makes it hard for you to continue taking this medication as prescribed. Your care team can work with you to help you manage side effects or to adjust your treatment plan.

You can learn more about CFTR modulators at DailyMed, which is a service from the National Library of Medicine that provides information about drugs, including dosages and possible side effects.

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Reference to any specific product, process, or service does not necessarily constitute or imply its endorsement, recommendation, or favoring by the Cystic Fibrosis Foundation. The appearance of external hyperlinks does not constitute endorsement by the Cystic Fibrosis Foundation of the linked websites, or information, products, or services contained therein.

Information contained on this site does not cover all possible uses, actions, precautions, side effects, or interactions. This site is not intended as a substitute for treatment advice from a medical professional. Consult your doctor before making any changes to your treatment.

FDA-approved drug information is available at dailymed.nlm.nih.gov/dailymed.

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