Last updated March 23, 2022, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD
Cystic fibrosis (CF) is a genetic condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These mutations result in faulty production or lower levels of the CFTR protein. Normally, the CFTR protein sits on the cell surface and acts as a gated passageway for transporting salt and water molecules across cell membranes.
Depending on the specific mutation in the CFTR gene, the encoded CFTR protein can be affected in different ways. CFTR modulators are a class of medication that can work to increase the CFTR protein’s functionality with specific CF-causing mutations. Several CFTR modulators are widely approved to treat amenable mutations and new modulator therapies are in development.
The CFTR protein normally functions like a channel with a “gate” that can open or close to control the movement of water and salts through the channel. Certain CF-causing mutations in the CFTR gene, such as the G551D mutation, impair the protein’s gating activity. In such cases, the protein is made and transported to the cell surface, but the “gate” gets “stuck” closed, preventing water and salt molecules from moving through the channel.
Potentiators are a type of CFTR modulator that effectively work to “prop open” the gate, thus allowing water and salts to flow more smoothly through the channel.
Kalydeco (ivacaftor) is an oral CFTR potentiator developed by Vertex Pharmaceuticals. In the U.S. and in Europe, Kalydeco is approved to treat CF patients as young as 4 months who have one of 97 genetic mutations that are amenable to potentiator treatment. It is currently available in dozens of countries worldwide, though specific age ranges and mutations may vary by country.
Proteins like CFTR fold to form a three-dimensional structure, which is vital for their proper functioning. The protein needs to fold correctly in order to be transported to the cell surface. If it folds incorrectly, it’s not stable and gets degraded before it reaches the surface. The most common type of CF-causing CFTR mutation, F508del, affects the protein’s folding 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.
An ivacaftor/lumacaftor combination — developed by Vertex and marketed as Orkambi — is used to treat CF patients with two F508del CFTR mutations. Orkambi is approved in the U.S., Europe, Australia and Canada to treat CF patients as young as 2.
Another combination treatment, ivacaftor/tezacaftor, has also been developed by Vertex. Marketed as Symdeko in the U.S., it’s FDA-approved for CF patients ages 6 and up who have one of 154 mutations in the CFTR gene. The E.U. approved this combination in Europe under the brand name Symkevi. The therapy also is approved in Canada and Australia for patients ages 12 and older.
Vertex also markets a triple-combination therapy containing the potentiator ivacaftor and the corrector tezacaftor, as well as a third medication called elexacaftor that acts as both a potentiator and a corrector. The therapy is approved in the U.S., under the brand name Trikafta to treat children as young as 6 who have at least one F508del mutation or one of 177 other mutations. The triple-combo therapy is also approved in Europe, where it is marketed as Kaftrio. In Canada and Australia, Trikafta is approved to treat CF patients ages 12 and up.
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