Mechanism of Action of Trikafta (Elexacaftor/Tezacaftor/Ivacaftor)
Trikafta works through a dual mechanism: elexacaftor and tezacaftor bind to different sites on the defective CFTR protein to correct its misfolding and trafficking to the cell surface, while ivacaftor increases the opening probability of the CFTR chloride channel once it reaches the cell membrane. 1, 2
The Three-Component Mechanism
Corrector Components: Elexacaftor and Tezacaftor
Elexacaftor and tezacaftor bind to distinct sites on mutant CFTR protein and have an additive effect in facilitating cellular processing and trafficking of select mutant forms (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone 1, 2
Elexacaftor functions as a type III corrector that targets the nucleotide binding domain 1 (NBD1) and works synergistically with tezacaftor (a type II corrector targeting NBD2) to restore F508del-CFTR processing 3
The combination of these two correctors addresses the fundamental defect in cystic fibrosis: the misfolding and premature degradation of CFTR protein in the endoplasmic reticulum that prevents it from reaching the cell surface 3, 4
Potentiator Component: Ivacaftor
Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface, increasing the time that CFTR channels remain in the activated state to enhance chloride ion movement across the cell membrane 1, 2
Ivacaftor functions as a CFTR potentiator that increases the opening probability of CFTR channels at the cell surface, enhancing ion flow through the channel 5
This gating function is critical because even when correctors successfully deliver CFTR to the membrane, the protein may not function properly without potentiation 5
The Synergistic Effect
The combined effect of elexacaftor, tezacaftor, and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR-mediated chloride transport in vitro and by sweat chloride reduction in patients with CF 1, 2
In human bronchial epithelial cells, the VX-661 plus VX-445 treatment restored F508del-CFTR chloride channel function in the presence of VX-770 to approximately 62% of wild-type CFTR in homozygous nasal epithelia 3
Structural studies demonstrate that elexacaftor partially rectifies interdomain assembly defects in Δ508 CFTR when used alone, but when combined with tezacaftor (a type I corrector), does so fully, illustrating the synergistic rescue mechanism 4
Clinical Implications of the Mechanism
The triple combination demonstrates substantial superiority over tezacaftor-ivacaftor alone in F508del homozygous patients, with a mean ppFEV1 improvement of 10.2 percentage points greater than tezacaftor-ivacaftor 6
Trikafta increases chloride transport in cells expressing various CFTR mutations, with a threshold of ≥10% of normal over baseline used to predict clinical benefit 1, 2
The mechanism extends beyond F508del mutations: substantial rescue of rare misprocessing mutations (S13F, R31C, G85E, E92K, V520F, M1101K, and N1303K) confined to different domains of CFTR has been observed, suggesting an allosteric correction mechanism 3
Important Mechanistic Caveat
Research suggests that ivacaftor may actually limit the correction efficacy when combined with elexacaftor/tezacaftor, as the basal F508del-CFTR current is significantly increased by elexacaftor/tezacaftor alone compared to the triple combination, though the triple combination remains clinically superior 7
When cells are treated with ivacaftor combined with correctors, the F508del-CFTR current becomes unresponsive to subsequently added ivacaftor, unlike other CFTR potentiators which can still increase corrected F508del-CFTR currents 7