CFTR Modulator Therapies

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

What Are They and How Do They Work?

CFTR (cystic fibrosis transmembrane conductance regulator) 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 three CFTR modulators for people with certain CFTR mutations: ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi ®), and tezacaftor/ivacaftor (SymdekoTM).

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 -- hair-like cilia move mucus and germs out of the airways -- and what happens when the protein doesn't work.

In people with certain mutations, CFTR modulators help the defective protein move to the cell's surface and function properly once it is there. For some, the problem is only at the cell's surface, where the defective protein disrupts the flow of water and chloride. For example, in people with gating mutations, the “gate” to the chloride channel at the cell surface is locked.

Ivacaftor, a CFTR modulator, helps people with CF who have gating mutations. Ivacaftor 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 water at the surface of the cell. The following video shows how this happens in people who have the G551D gating mutation.

Lumacaftor/ivacaftor is a combination therapy that works in people with two copies of the F508del mutation. Lumacaftor is a modulator known as a corrector. It helps the 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. But, 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.

Tezacaftor/ivacaftor is another treatment option for people with two copies of the F508del mutation who were unable to take lumacaftor/ivacaftor. Tezacaftor, another corrector, acts in the same way that lumacaftor does, but the tezacaftor/lumacaftor combination does not seem to cause the chest tightness or drug interactions caused by lumacaftor/ivacaftor. In addition, tezacaftor/lumacaftor is approved for people with a single copy of one of 26 specified mutations.

Who Can Take Them?

The following therapies are approved for specific mutations, listed below:

Ivacaftor

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

The lumacaftor/ivacaftor combination therapy is prescribed for people ages 6 and older who have two copies of the F508del mutation, which is the most common CF mutation. 

Protein Processing Mutation
F508del

Tezacaftor/Ivacaftor

Tezacaftor/ivacaftor is approved for people with CF ages 12 and older who have two copies of the F508del mutation. It was also approved for people with CF who have a single copy of one of 26 specified mutations.

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   

Because these medications are for people with specific CF mutations, they will not work if you do not have one or more of these mutations. The first step in knowing if either ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor will work for you is to know what your CF mutations are. If you do not know your mutation, you can take a genetic test to learn which mutation or mutations you have. The CF Foundation's Mutation Analysis Program offers free genetic testing for people with CF. If you are interested in enrolling, ask your CF care team.

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

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.

The following are general dosing recommendations:

For ivacaftor, the general dosing for adults and children ages 6 and older is to take one 150 mg tablet by mouth every 12 hours with foods that contain fat, such as eggs, avocados, nuts, butter, and peanut butter. Children ages 2 to 5 should take a certain amount of the medication based on their weight. Typically, for children this young, the medication comes in a packet, which can be mixed into soft food or liquid and taken with foods that contain fat.

For lumacaftor/ivacaftor, the general dosing for people ages 6 and older is to take two tablets every 12 hours with foods that contain fat.

For tezacaftor/ivacaftor, people ages 12 and older take one tablet of tezacaftor/ivacaftor with foods that contain fat in the morning and one tablet of ivacaftor with foods that contain fat in the evening, about 12 hours later.

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.

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

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.

Common side effects of ivacaftor include:

  • Headache
  • Upper respiratory tract infection (common cold, including sore throat, nasal or sinus congestion, and runny nose)
  • Stomach pain
  • Rash
  • Nausea
  • Dizziness

Common side effects of lumacaftor/ivacaftor include:

  • Shortness of breath and/or chest tightness
  • Upper respiratory tract infection (common cold, including sore throat, nasal or sinus congestion, and runny nose)
  • Nausea
  • Diarrhea
  • Rash
  • Fatigue
  • Flu or flu-like symptoms
  • Increase in muscle enzyme levels
  • Irregular, missed, or abnormal menstrual periods, including increased bleeding

Common side effects of tezacaftor/ivacaftor include:

  • Headache
  • Nausea
  • Sinus congestion
  • Dizziness

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