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.

Inclusion Criteria:

- 18 years of age

- Patient has provided informed consent

- Diagnosis of CRS made by one of the investigators

- Standard of care CT scan with definitive demonstration of isolated or diffuse mucosal
thickening, bone changes, and air fluid levels, obtained within 30 days of treatment

- Positive culture of at least one gram negative bacteria (e.g. Pseudomonas, E. coli,
Steenotrophomonas) within 30 days prior to testing

- Previous surgery with (at least) exposed maxillary and ethmoid sinuses

- Ability to perform EDSPD testing such that nasal cavity space and sinus openings are
sufficient for catheter placement

- Negative pregnancy test for females of childbearing potential within 72 hours of
testing and start of study treatment

Exclusion Criteria:

- < 18 years of age

- Acute illness other than sinusitis within 2 weeks before start of study treatment
that, in the opinion of the investigator, would preclude participation

- Currently taking medications that are moderate or strong CP3A inhibitors

- History of asthma attack requiring emergency room visit or treatment with oral
steroids within 2 months prior to study treatment

- History of solid organ or hematological transplantation

- History of known immunodeficiency, autoimmune or granulomatous disorder

- Serum creatinine > 1.5x upper normal limit

- Abnormal liver function, as defined by serum AST > 2x upper normal limit, serum ALT >
2x upper normal limit, Alkaline phosphatase > 2x upper normal limit, Total bilirubin >
2x upper normal limit

- Women who are pregnant or breastfeeding