Triplet CFTR modulators: future prospects for treatment of cystic fibrosis

Abstract

Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a chloride channel responsible for ion flow across epithelial surfaces of lung, sinuses, pancreas, intestine, and liver. Researchers have grouped CFTR genetic mutations into various protein defects: reduced protein synthesis (class 1 mutations), abnormal protein folding and maturation (class 2 mutation), and abnormal gating (class 3 mutation). These mutations usually present as severe forms of CF due to complete absence of CFTR at cell surfaces. Milder forms (eg, protein maturation and conductance defects, classes 4–6) present as less severe forms of CF related to the presence of CFTR at the cell surface. Differences in severity are directly due to CFTR function which is based on the severity of CFTR mutation. This knowledge has proven useful for designing therapy for individual mutations and mutation classes. The discovery and US Food and Drug Administration approval of Kalydeco® (ivacaftor) in early 2011 marked the beginning of a new era of therapies that are focused on improving defective CFTR protein function. However, due to its specificity for the G551D mutation, ivacaftor only benefitŝ5% of CF patients. Approximately 50% of CF patients have two copies of the F508Del mutation, while other CF patients carry only one copy of this gene. More recently, Orkambi®, a two compound medication composed of lumacaftor and ivacaftor, has provided the foundation necessary to further build on molecular concepts of: correction of trafficking, potentiation, and amplification of defective CFTR. These new concepts will form the basis of future CF therapies and extend CFTR treatment to almost 50% of CF patients. Evolving knowledge of the molecular mechanisms responsible for defective CFTR has prompted new research focused on “repair” of each phase of CFTR expression and function, thus creating a new class of combination “CFTR correctors” referred to as “triplet CFTR compounds.” This article will review how patients can be selected and treated with these newer agents that are based on specific mutations. In the future, many CF practitioners have expectations that initiation of treatment for CF patients will occur simply by use of biomarkers of CFTR expression (eg, sweat chloride, nasal potential difference, rectal organoids) rather than testing for specific mutations. As continued research identifies biomarkers with greater specificity and which predict clinical response, therapies can potentially be tailored to individual responses.

GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN)

“…Several next-generation correctors are in development for use in triplet combination therapies for CF [ 22 ]. In a phase 3 trial in subjects with one F508del mutation and one minimal function [ 30 ].…”

“…There is an unmet need for treatment combinations with improved efficacy and safety profiles, and scientific rationale for using combinations of correctors with differing mechanisms or sites of action in novel doublet and triplet combinations, due to potential additive or synergistic effects [ 20 , 21 ]. At the time that this study was conducted, there were a number of novel correctors at various stages of development, including but not limited to C1-type correctors (GLPG/ABBV-2222, lumacaftor, and tezacaftor), C2-type correctors (VX-659 and VX-445), and third-generation correctors (PTI-801) [22][23][24].…”

Intestinal organoids for Cystic Fibrosis research

“…CF remains incurable up until today, but the development of CFTR modulators has increased the prospects that CF disease manifestation might be stalled or even prevented, in the near future [21] . Two phase 2 clinical trials have shown that the efficacy of the newest triple combination therapy exceeds the efficacy of the previous developed combinations, but is still only accessible for pa- tients with particular CFTR mutations [ 22 , 23 ].…”

Phase separation as a therapeutic target in tight junction-associated human diseases

“…The barrier function of TJs is regulated by different mechanisms in various tissues. Cystic fibrosis is induced by the dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP-activated chloride channel located in the apical membrane of the secretory epithelium of airways, the intestine, bile ducts, and the epididymis [ 33 , 34 ]. The PDZ domain of CFTR interacts with ZO-1 to regulate cell proliferation and differentiation via the ZO-1/ZONAB pathway.…”