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Trikafta (Triple Combination Therapy: Elexacaftor/Tezacaftor/Ivacaftor) Is Only Effective in CF Patients With f508del Gene Mutation

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Trikafta is a combination of three drugs that target the defective CFTR protein. It helps the protein made by the CFTR gene mutation function more effectively. Currently available therapies that target the defective protein are treatment options for some patients with cystic fibrosis, but many patients have mutations that are ineligible for treatment. Trikafta is the first approved treatment that is effective for cystic fibrosis patients 12 years and older with at least one F508del mutation, which affects 90% of the population with cystic fibrosis or roughly 27,000 people in the United States.

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Elexacaftor + tezacaftor + ivacaftor (Trikafta™) is a combination therapy combining three CFTR modulators. Elexacaftor and tezacaftor are CFTR correctors, a type of modulator designed to fix the defective CFTR protein so that it can move to the proper place on the cell surface. Ivacaftor is a potentiator. Once CFTR protein reaches the cell surface, potentiators help facilitate the opening of the chloride channel to allow chloride and sodium (salt) to move in and out of the cell. Trikafta™ is approved for people with CF ages 12 years and older who have at least one copy of the F508del mutation. Two phase 3 studies to test the safety and effectiveness of Trikafta™ in people with CF 12 years and older have been completed. People with two copies of the F508del mutation had a 10 percent increase in lung function compared to treatment with the modulator tezacaftor/ivacaftor (Symdeko®), and people with one copy of F508del had more than a 14 percent increase in lung function compared to placebo. In people with one copy of the F508del mutation, Trikafta™ was also associated with significant improvements in sweat chloride, pulmonary exacerbations and quality of life. A study of Trikafta™ in children with CF ages 6-11 years old is currently underway.

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CFTR modulators have been developed to improve mutant CFTR folding and trafficking (“correctors”) or to potentiate channel opening at the PM (“potentiators”). Until recently, only three CFTR modulators were market approved for mono or combination therapy: potentiator ivacaftor (VX-770) and correctors lumacaftor (VX-809) and its derived molecule tezacaftor (VX-661). Together, they offer a treatment to approximately half of the CF patient population, with moderate to impressive clinical benefit, depending on the mutation present. With the recent FDA approval of Trikafta™, a triple combination therapy consisting of two distinct CFTR correctors, tezacaftor and elexacaftor (VX-445), and potentiator ivacaftor, 82 to 90% of CF patients will soon qualify for a CFTR-targeting therapy. Trikafta™ was shown to significantly improve lung function and overall clinical benefit in patients carrying one or two F508del alleles [Heijerman HGM, McKone EF]

This leaves 10% of CF patients without causal treatment. These are patients with two minimal function alleles, such as nonsense mutations, insertion and deletion mutations, canonical splicing mutations, and processing mutations other than F508del. Due to their low prevalence, these rare mutations have not been thoroughly characterized. Many mutations, however, cause multiple defects [Veit G, Avramescu RG, Chiang AN].

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To sum up, these approaches are complemented by high-resolution single-channel recording, which provides unique insights into CFTR behaviour, illuminating the action of CF mutations and CFTR modulators. Finally, just as combinations of CFTR correctors have proved decisive in restoring the plasma membrane expression and stability of mutant CFTR, the identification of potent efficacious potentiator combinations heralds a strategy to restore wild-type levels of activity to CF mutants

Translation of these potentiator combinations to the clinic should now be a priority.

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De Boeck K., Amaral M.D. Progress in therapies for cystic fibrosis. Lancet Respir. Med. 2016;4:662–674.

Veit G., Avramescu R.G., Chiang A.N., Houck S.A., Cai Z., Peters K.W., Hong J.S., Pollard H.B., Guggino W.B., Balch W.E., et al. From CFTR biology toward combinatorial pharmacotherapy: Expanded classification of cystic fibrosis mutations. Mol. Biol. Cell. 2016;

Heijerman H.G.M., McKone E.F., Downey D.G., Van Braeckel E., Rowe S.M., Tullis E., Mall M.A., Welter J.J., Ramsey B.W., McKee C.M., et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial. Lancet. 2019;394:1940–1948.

Middleton P.G., Mall M.A., Drevinek P., Lands L.C., McKone E.F., Polineni D., Ramsey B.W., Taylor-Cousar J.L., Tullis E., Vermeulen F., et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N. Engl. J. Med. 2019;

HIGHLIGHTS OF PRESCRIBING INFORMATION—KALYDECO® (Ivacaftor) Tablets, for Oral Use. [(accessed on 27 February 2020)];2017

Randell S.H., Fulcher M.L., O’Neal W., Olsen J.C. Primary epithelial cell models for cystic fibrosis research. Methods Mol. Biol. 2011

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