Figure 7. Improvements in cystic fibrosis survival according with the advances CF care. 8

Cystic fibrosis affects about 1 in 2500 live births. 15

In 2013, CF-related hospital costs alone were estimated to exceed $1.1 billion. 19

Treatments for cystic fibrosis are known as CFTR modulator therapies, which are designed to correct the malfunctioning of the CFTR protein made by the CFTR gene. 1 There are two main types of modulators:

Potentiators: Potentiators bind to the CFTR protein in the plasma membrane and increase the probability of the channel’s opening and ion conductance. 22
Correctors: Correctors assist the CFTR protein in forming the right 3-D conformation, which improves the processing and trafficking of CFTR, thus increasing cell-surface expression. 1, 11

There are four FDA approved drugs available on the market that involve a combination of potentiators and correctors. The drug that we will be looking at is TRIKAFTA®, which is a combination of a dual-function modulator Elexacaftor (VX-445), a folding corrector Tezacaftor (VX-661), and a channel potentiator Ivacaftor (VX-770). 1, 7, 11 There are several clinical studies that demonstrated TRIKAFTA® is a highly effective treatment for CF, specifically for those individuals with at least one F508del mutation or at least one other mutation in the cystic fibrosis (CF) gene. 21 Also, as of recently, in April 2023, TRIKAFTA® is approved for ages 2-5, whereas previously it was approved for ages 6+. This is another breakthrough of treatment option because approximately additional 2,250 children in the U.S. will be eligible for TRIKAFTA® that can help prevent lung damage and the onset of complications. 3

Figure 8. Phase 3 trial with 403 participants who were 12+ years-old that were randomly assigned to TRIKAFTA® or placebo. 21

Figure 9. Network meta-analysis Results for ppFEV1 comparing CF modulator therapy to placebo. 19

As seen in Figure 8, the phase 3 trial demonstrated that those who received TRIKAFTA® had a 14.3% improvement in the lung function compared to the placebo group. 21 In addition to lung function, TRIKAFTA® improves other CF-related symptoms such as body mass index (BMI), pulmonary exacerbations, respiratory symptoms, and sweat chloride. Within 24 weeks of the trial, 63% of the people taking TRIKAFTA® significantly decreased in pulmonary exacerbation, significant BMI increase of 1 kg/m2, and a significant decrease of 41.2 mmol/L compared to the placebo group. 21 In a study for ivacaftor-only therapy trial, their study has also shown a significantly decreased in pulmonary exacerbation, increase in BMI, and an increase in respiratory symptoms. However, their study has shown no significant difference in sweat chloride. 9 The Ivacaftor-only drug does not demonstrate ineffectiveness, but rather the medication is an important clinical tool for other specific CFTR mutations such as the G551D mutation . 17 The specificity of the mutation in the CFTR allows for the physicians to determine which treatment option is best for the patient.

Effectiveness of triple combination therapy drug:

Triple combination therapy drugs outperformed all the currently available medications in terms of improving pulmonary function, reducing exacerbations, and enhancing the quality of life of CF patients. 4
TRIKAFTA® has significantly higher efficacy and safety in treating CF than the placebo for individuals with at least one F508del mutation. 20
As seen in Figure 9, TRIKAFTA® has the highest ppFEV for CF individuals with homozygous F508del mutation.
A head-to-head trial between TRIKAFTA® and Symdeka® shows 10.0 points higher ppFEV1 at 4 weeks. 19, 21

Figures 10 (left) and 11 (right). The binding of TRIKAFTA® to the F508del CFTR protein with the green molecule representing Tezacaftor, pink molecule representing Ivacaftor, and blue molecule representing Elexacaftor. 16 Fig. 11 shows the binding of TRIKAFTA® to mutated CFTR in the top-bottom view.

Tezacaftor 14, 16

Tezacaftor (VX-661)

Type 1 correctors such as Tezacaftor (VX-661), aim to repair the F508 deletion, by adjusting the position of the CFTR protein on the cell surface to the correct position, thus permitting adequate ion channel formation and increased water and salt movement through the cell membrane. 18 Specifically, Tezacaftor stabilizes the misfolded CFTR protein and increases trafficking of the protein through the golgi complex to the plasma membrane. Tezacaftor binds to an internal hydrophobic cavity in TMD1 (inside the membrane) and links together four alpha helices that are thermodynamically unstable. 7 The polar region of Tezacaftor forms a hydrogen bond with R74 and interacts with a few residues in TMD1. 5 TM helices 1, 2, 3, and 6, that form the binding site for Tezacaftor are predicted to be unstable, thus type 1 correctors like Tezacaftor help to stabilize TMD1 by filling the cavity and structurally linking the four unstable helices. 7 When used in Trikafta, Tezacaftor is the first to bind to the CFTR protein to stabilize the N-terminal of TMD1. 7

Elexacaftor 12, 16

Elexacaftor (VX-445)

Type 3 correctors such as Elexacaftor (VX-445) binds to the CFTR protein within the membrane, “extending from the center of the lipid bilayer to the edge of the inner leaflet” to stabilize NBD1. 7 Unlike type 1 correctors, the binding pocket of elexacaftor is much shallower. Elexacaftor primarily interacts with TM helix 11 (TMD1) through van der Waals interactions and also comes into contact with TM helices 2 and 10. TM helices 10 and 11 are the “domain swapped” helices of TMD2 that extend into the cytosol and interact with NBD1. This interface is important for protein assembly and for “transmitting conformational changes of the NBDs to the TMDs to control ion permeation”. 7 Elexacaftor binding to TM10 and TM11 allows for communication of ATP-binding effects in the NBDs to open the channel because this binding site stabilizes the conformation fragility of the F508del CFTR. 15 Also, recent studies have shown that Elexacaftor and Ivacaftor appeared to be multiplicatively synergistic due to the close proximity of the drugs binding to the CFTR. In a study done by Karol Fiedorczuk and Jue Chen, Elexacaftor-bound F508 “closely resemble[d] the full-length CFTR in the phosphorylated, ATP bound conformation.” 7 However, the nucleotide-binding domains were different. Elexacaftor “ ‘cracked-open’ ” the NBD dimer, which allowed for the degenerated site to be solvent accessible. 7 As a result, ATP was able to bind exclusively with the NBD1 face of the composite site. In TRIKAFTA®, Elexacaftor and Tezacaftor fully restore the F508 mutation “to an NBD-dimerized conformation with ATP fully bound to both the consensus and degenerate sites”. 7 In TRIKAFTA®, Elexacaftor is the second to bind to the CFTR protein when TMDs assemble to form a protease-resistant form. When the CFTR protein reaches the plasma membrane, Elexacaftor strengthens allosteric communication between ATP-bound dimers and the channel gate, which increases ion conductance. 7

Ivacaftor 13, 16

Ivacaftor (VX-770)

Ivacaftor (VX-770) is a potentiator that amends the channel gating defect in the F508 deletion mutation by binding to the defective CFTR protein at the cell surface and opening the chloride channel to allow the chloride anion to flow through. Ivacaftor “binds to a cleft formed by TM helices 4, 5, and 8 [TMD2], approximately halfway through the lipid bilayer, coincident with the TM8 hinge region involved in gating”. 7 Ivacaftor binds to the CFTR protein, inside the membrane through hydrogen bonds, which helps to stabilize polar groups in the low dielectric environments of the membrane. Ivacaftor is the last to bind to the CFTR protein when used in TRIKAFTA®. Once it binds, it enhances channel activity, which stabilizes the open configuration of the channel pore. 7 Ivacaftor is 99% plasma protein bound, which would allow the “gates” of the CFTR to stay open longer to allow more chlorides flow out of the epithelial cells. 2, 10

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