State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators and Triple-Combination Therapy

Abstract

Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the CFTR gene in 1989, more than 2000 mutations have been identified so far and about 240 can cause CF. Until recently, the treatment for CF was aimed to prevent and manage the manifestations of CFTR dysfunction, primarily recurrent pulmonary infections and pancreatic exocrine failure. Over the past few decades, the therapeutic approach to CF has been revolutionized by the development of a new class of small molecules called CFTR modulators that target specific defects caused by mutations in the CFTR gene. CFTR modulators have been shown to change profoundly the clinical course of the CF, leading to meaningful improvements in the lives of a large proportion of people of CF heterozygous for F508del, especially if started in young children. Further studies are needed to extend the use of triple CFTR modulation therapy also for young children in order to prevent the irreversible effects of the disease and for patients with very rare mutations with a personalized approach to treatment.

Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770

“…More recently, several studies using high-throughput screens of small-molecule libraries have led to the identification of selective CFTR modulator compounds capable of directly targeting the molecular defects on mutant CFTR proteins ( Lopes-Pacheco et al, 2021 ). Several of these modulator drugs are now approved for clinical use in individuals with specific CF genotypes ( Meoli et al, 2021 ). Such is the case of Orkambi ® , approved by Federal Drug Administration (FDA) and European Medical Agency (EMA) in 2015 for adult CF patients and in 2018 for CF children aged 2 years and older, who are homozygous for the F508del-CFTR mutation ( Boyle et al, 2014 ).…”

“…Part of this improvement resulted from HGF preventing VX-770 from destabilizing VX-809-rescued F508del-CFTR at the PM, increasing the levels of rescued maturated channel (the higher molecular weight, fully glycosylated CFTR band C in immunoblots) ( Moniz et al, 2013 ; Matos et al, 2018 ). More recently, a second corrector/potentiator therapy was approved for clinical use by FDA and EMA, with the commercial designations of Symdeko ® and Symkevi ® , respectively ( Meoli et al, 2021 ). These drugs are a combination of VX-770 with Tezacaftor (VX-661), a second-generation corrector developed based on VX-809 structure but exhibiting better pharmacokinetic properties and fewer AEs reported in clinical trials ( Donaldson et al, 2018 ; Meoli et al, 2021 ).…”

“…More recently, a second corrector/potentiator therapy was approved for clinical use by FDA and EMA, with the commercial designations of Symdeko ® and Symkevi ® , respectively ( Meoli et al, 2021 ). These drugs are a combination of VX-770 with Tezacaftor (VX-661), a second-generation corrector developed based on VX-809 structure but exhibiting better pharmacokinetic properties and fewer AEs reported in clinical trials ( Donaldson et al, 2018 ; Meoli et al, 2021 ). The VX-661+VX-770 combination demonstrated comparable therapeutic efficacy to VX-809 + VX770 in F508del-homozygous patients ( Taylor-Cousar et al, 2017 ) but produced improved outcomes in certain CF individuals heterozygous for F508del, in comparison to treatment with VX-770 alone ( Rowe et al, 2017 ).…”

“…The VX-661+VX-770 combination demonstrated comparable therapeutic efficacy to VX-809 + VX770 in F508del-homozygous patients ( Taylor-Cousar et al, 2017 ) but produced improved outcomes in certain CF individuals heterozygous for F508del, in comparison to treatment with VX-770 alone ( Rowe et al, 2017 ). At present this combination is indicated in the United States and Europe for CF individuals aged 6 years and older, homozygous for the F508del mutation or heterozygous for the F508del mutation with one of several residual function mutations ( Meoli et al, 2021 ). Another combination drug, named Trikafta™, that combines an additional corrector, VX-445 (elexacaftor), with VX-661 and VX-770, has shown improved responses in patients with the mutation F508del in at least one allele, and has been recently approved by the FDA for the treatment of CF patients aged 6 years or older ( Meoli et al, 2021 ).…”

“…At present this combination is indicated in the United States and Europe for CF individuals aged 6 years and older, homozygous for the F508del mutation or heterozygous for the F508del mutation with one of several residual function mutations ( Meoli et al, 2021 ). Another combination drug, named Trikafta™, that combines an additional corrector, VX-445 (elexacaftor), with VX-661 and VX-770, has shown improved responses in patients with the mutation F508del in at least one allele, and has been recently approved by the FDA for the treatment of CF patients aged 6 years or older ( Meoli et al, 2021 ). We, therefore, found it important to clarify whether the prolonged exposure to the core VX-661+VX-770 combination common to all these drugs had similar epithelial dedifferentiation effects to those found for the VX-809+VX-770 combination.…”