Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis

There is a significant clinical need for new treatment modalities for chronic sinus disease. Chronic rhinosinusitis (CRS) causes substantial morbidity and detracts from quality of life for 16% of the US population. The disease accrues an estimated aggregated cost of $8.6b annual in healthcare expenditures. Patients with CRS describe poorer scores for physical pain and social functioning on quality of life questionnaires than those suffering from chronic obstructive pulmonary disease (COPD), congestive heart failure, or angina. Conventional CRS treatments are comprised of antibiotics, steroids, and surgical intervention. These interventions have been limited by bacterial resistance incurred with antibiotic overuse and the deleterious side effects of steroids.

Normal sinonasal mucociliary function is a vitally important host defense mechanism that clears the upper airways of inhaled particles such as bacteria, dusts, and aerosols. Sinonasal respiratory epithelium is a highly-regulated inert barrier critical to the mucociliary apparatus. Maintenance of MCC is dependent on intact respiratory epithelium, proper ciliary beating, and the biological properties of the airway surface liquid (ASL). The ASL is dramatically affected by alterations of vectorial Cl- and bicarbonate (HCO3-) secretion through the CFTR as clearly exemplified by cystic fibrosis (CF) airway disease. These abnormalities of electrolyte transport manifest as thick mucus formation and stasis of secretions in multiple organ systems, including the respiratory, gastrointestinal, and reproductive tracts. In the sinuses, chronic stasis of mucus in combination with bacterial infections results in paranasal sinusitis. Cystic fibrosis (CF) is caused by mutations in the CFTR gene. The most common cause of CF is a deletion of phenylalanine at CFTR position 508 (F508del CFTR), which confers protein misfolding and degradation from the endoplasmic reticulum. The absence of CFTR at the plasma membrane results in defective ion transport and the clinical manifestations of CF. Other mutations, such as the class III mutation Gly551Asp (G551D), result in adequate levels of CFTR protein at the apical cell surface, but exhibit defective function. In addition, there is now increasing evidence that wild type CFTR processing, endocytic recycling, and function can also be markedly compromised by various environmental insults, including cigarette smoke exposure, high altitude/hypoxemia, inflammation, and infectious agents.

CFTR is a member of the ATP binding cassette protein family, and composed of two transmembrane domains (TMs), two nucleotide binding domains (NBDs), and a regulatory domain (R). Activation of CFTR is thought to be a two-step process that involves 1) phosphorylation of the R-domain, and 2) dimerization of the two NBDs, facilitating ATP binding and activation of the Cl- channel by inducing a conformational change in the TMs. One model suggests that ATP binding to the canonical catalytic site conferred at the dimerization interface of NBD1 and NBD2 promotes opening of the channel gate. New compounds such as ivacaftor, which modify channel gating of WT-CFTR, F508del-CFTR, G551D-CFTR and nonsense mutations after induction of translational readthrough (i.e. G542X-CFTR), provide critical tools for understanding molecular defects caused by a mutation, the molecular basis of gating, and mechanisms required for mutant protein repair. At the same time, these drugs can be utilized for examining the molecular basis of environmental perturbations that confer functional and/or quantitative changes in wild type CFTR, as well as new treatment platforms for ameliorating the impact of deleterious external influences on healthy airway epithelial cells.

Ivacaftor is an oral CFTR potentiator identified by screening over 228,000 small-molecules using high throughput analysis and a cell-based fluorescence membrane potential assay. The drug was licensed in 2012 both in the United States and Europe for patients with CF aged six years and over (now 2 years and over) who carry at least one copy of the G551D mutation. Ivacaftor is the first licensed CF medication that addresses the primary consequences of CFTR protein dysfunction, rather that the downstream sequelae of the disease. Studies in both recombinant cell lines and primary cultures of human bronchial epithelia have demonstrated that ivacaftor promotes Cl- transport by increasing CFTR channel open probability, and augments both ASL height and ciliary beat frequency (CBF). The efficacy and safety of ivacaftor in CF patients with at least one G551D mutation has been evaluated in two large, multicenter, randomized, double-blind, placebo-controlled trials. Results of these trials, and a longitudinal cohort of patients receiving the drug, unequivocally showed significant improvement in markers of CFTR function (sweat chloride and nasal potential difference (NPD) and clinical endpoints (lung function (FEV1), body mass index, hospitalization rate, and Pseudomonas burden). Given that one of the primary endpoints showing improvement in the clinical testing was NPD, the expectation would be that patients should experience benefit in upper airway disease burden. While clinical outcomes regarding CRS are not published, at least one case report has shown "medical reversal" of CRS in a patient receiving the drug with marked improvement in symptoms as well as CT scan before and after starting therapy. Because MCC is critical to CRS pathogenesis, it is reasonable to presume that ivacaftor will improve clinical endpoints in non-CF CRS in the setting of acquired CFTR dysfunction. Since ivacaftor also ameliorates clinical disease of patients with non-G551D gating mutations, the drug does not confer activity to one specific mutation and thus should be effective potentiating ion transport regardless of external influences that impact function of the CFTR.

Conventional CRS interventions have been limited by bacterial resistance incurred with antibiotic overuse and the deleterious side effects of steroids. Ivacaftor is a CFTR potentiator that has been approved by the FDA for treatment of CF individuals with at least one copy of the G551D mutation. Enhancing Cl- secretion in sinus epithelia by CFTR potentiators represents a new and leading edge approach to treatment that has been shown to activate MCC in human subjects, but has not been investigated previously in non-CF CRS. Ivacaftor represents one of many drugs that enhance Cl- transport and could provide significant therapeutic advantages in this regard.