Cystic fibrosis (CF) is a genetic condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These mutations result in the production of a faulty CFTR protein. Depending on the mutation, the encoded CFTR protein can be affected in different ways.
Types of CFTR modulators
CFTR modulators are a specialized group of CF therapies designed to address the underlying cause of CF according to the specific defect in the CFTR protein.
There are three main types of CFTR modulators:
A normal CFTR protein sits on the cell surface and acts as a gated passageway for the transport of chloride ions across cell membranes. In CF, certain mutations in the CFTR gene, such as the G551D mutation, impair the gating activity of the protein. In such cases, the CFTR protein is made and transported to the cell surface, but the gates do not open correctly to permit ion exchange. Potentiators mitigate this defect by opening the gates and keeping them open longer to facilitate the smooth flow of chloride ions.
Kalydeco (ivacaftor) is a CFTR potentiator developed by Vertex Pharmaceuticals. It is an oral medication approved by the U.S. Food and Drug Administration (FDA), the EU, and Health Canada for CF patients as young as 1 with at least one mutation (such as G551D) that impairs chloride ion flow. Kalydeco enhances the activity of the CFTR protein by keeping the opening of the CFTR gate longer at the cell surface, thereby boosting the flow of chloride ions to improve hydration and mucus clearance.
Proteins fold to form a three-dimensional structure, which is vital for their proper functioning. The CFTR protein needs to fold correctly in order to be transported to the cell surface where it performs its function. In CF, the most common type of CFTR mutation, F508del, is the one that affects its folding — the CFTR protein is produced, but it misfolds and does not reach the cell surface.
Correctors are CFTR modulators that assist the protein in folding correctly into its three-dimensional shape so that it can reach the cell surface to function properly.
Lumacaftor (VX-809) and tezacaftor (VX-661) are two therapies by Vertex Pharmaceuticals that function as correctors. They help the CFTR protein fold correctly and reach the cell surface, but fall short in alleviating CF symptoms by themselves. Therefore, they are not approved as a monotherapy for CF.
However, combining a potentiator with a corrector can improve CFTR activity and reduce CF symptoms.
An ivacaftor/lumacaftor combination — developed by Vertex and marketed as Orkambi — is a treatment for CF patients with two F508del CFTR mutations. Orkambi is approved in the U.S., Europe, 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., the treatment is FDA-approved for CF patients 12 and older. The E.U. approved this combination in Europe under the brand name Symkevi.
Proteostasis Therapeutics is also working on developing CFTR correctors. One example is PTI-801.
For a protein to be made based on the instructions in the gene, the cell machinery must be able to read the instructions correctly. Certain CFTR mutations, such as the A455E mutation, interfere with the cell’s ability to read the instructions correctly and results in very low amounts of CFTR protein being made. The mutation can also lead to the degradation of the CFTR protein, leaving limited quantities of it on the cell surface. In either case, levels of the CFTR protein are insufficient on the cell surface to sustain its activity.
Amplifiers are a type of CFTR modulator that enhances the production of CFTR protein by the cells. When used in combination with other modulators, amplifiers can make more CFTR available for the other modulators to act upon.
PTI-428 is an investigational first-generation CFTR amplifier by Proteostasis Therapeutics, which is being tested as a single and combination therapy for CF.
CFTR modulators are considered breakthrough therapies that target the underlying cause of CF rather than the symptoms alone. Pioneering treatments such as Kalydeco, Orkambi, and Symdeko are referred to as “first-generation modulators.”
Next-generation modulators are expected to be more effective and address the underlying cause of CF in greater detail. Triple combination therapies using CFTR modulators to improve different aspects of the faulty CFTR protein is an example of next-generation modulators. The additive effect of three medications is likely to benefit more CF patients with different mutations. Results from clinical trials on next-generation modulators for CF show promise.
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