CFTR Modulator Therapies

Here's what you need to know about the four CFTR (cystic fibrosis transmembrane conductance regulator) modulators, ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi®), tezacaftor/ivacaftor (Symdeko®), and elexacaftor/tezacaftor/ivacaftor (Trikafta™).

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:  

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

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.

Elexacaftor/tezacaftor/ivacaftor

The newest CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) 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 12 and older who have at least one copy of the F508del mutation.

Protein Processing Mutations
F508del + F508del
F508del + any other mutation

Ivacaftor

In people with CF who have gating mutations, the “gate” to the chloride channel at the cell surface is locked. 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 6 months and older who have one of the following mutations:

Gating Mutations
G178R G1244E S549R
G551D  G1349D  S1251N
G551S S549N  S1255P 
Residual Function Mutations
A455E E193K  R117C 
A1067T F1052V  R347H 
D110E F1074L R352Q 
D110H G1069R R1070Q  
D579G K1060T R1070W 
D1152H  L206W  S945L
D1270N  P67L S977F
E56K R74W  
Splice Mutations
711+3A→G 3272-26A→G E831X
2789+5G→A 3849+10kbC→T  
Conduction Mutation
R117H

Lumacaftor/ivacaftor

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.

The lumacaftor/ivacaftor combination therapy 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

Tezacaftor/ivacaftor

Tezacaftor, another corrector, acts in the same way that lumacaftor does: 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, tezacaftor/ivacaftor is also approved for people ages 6 and older with a single copy of one of 26 specified mutations.

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

Protein Processing Mutations 
F508del + F508del
Residual Function Mutations
A455E E56K R74W 
A1067T E193K  R117C
D110E F1052V R347H
D110H F1074L R352Q 
D579G K1060T R1070W
D1152H  L206W S945L
D1270N  P67L S977F
Splice Mutations
711+3A→G 3272-26A→G  E831X
2789+5G→A  3849+10kbC→T   

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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