Trial of Verapamil in Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) impacts more than 30 million Americans resulting in $6.9 to $9.9
billion in annual healthcare expenditures and $12.8 billion in productivity costs. The
prevalence of Chronic Rhinosinusitis with Nasal Polyps(CRSwNP) in Europe has been estimated
to be 2-4.3% and is thought to be similar in the United States. Corticosteroids remain the
mainstay of treatment although novel therapies are being developed based on an evolving
understanding of the inflammatory pathways involved in disease pathogenesis. CRSwNP is
characterized by the presence of edematous polypoid mucosa and predominantly eosinophilic
inflammation. Recent evidence has focused on the sinonasal epithelial cell as a primary
driver of the local dysregulated immune response through secretion of type 2 helper
T-cell(Th2) promoting cytokines. While these studies suggest that epithelial cells are
capable of orchestrating a local immune response, the mechanisms responsible for regulating
cytokine secretion are poorly understood and may be influenced by the efflux function of
epithelial P-glycoprotein(P-gp).

P-gp is a 170 kiloDalton membrane protein which belongs to sub-family B of the adenosine
triphosphate(ATP)-binding cassette(ABC) transporter superfamily. P-gp utilizes ATP hydrolysis
to transport a wide range of substrates across the plasma membrane. P-gp mediated transport
has been observed in the regulation of cytokine secretion in both human T-cells as well as
sinonasal epithelial cells implicating a potential immunomodulatory role. Studies by our
group have demonstrated that P-gp is overexpressed in the mucosa of patients with Th2 skewed
CRS endotypes including CRSwNP and is capable of regulating the secretion of Th2 polarizing
cytokines. Together, these findings suggest that P-gp participates in the non-canonical
regulation of cytokine secretion within CRSwNP and may thereby represent a druggable target.

Verapamil Hydrochloride(HCl) was one of the first inhibitors of P-gp to be identified in 1982
and also functions as a calcium channel blocker(CCB). Verapamil has since been categorized as
a first generation P-gp inhibitor as more potent and selective 2nd and 3rd generation
molecules were subsequently developed for use as chemotherapy sensitizers. Several studies,
including those by our group, have reported that Verapamil is capable of modulating
inflammatory responses in human T-cells, animal models of asthma, and nasal polyps. Using an
organotypic explant model, we have previously shown that Verapamil has similar effects to
dexamethasone in its ability to abrogate Interleukin(IL)-5, IL-6, and Thymic Stromal
Lymphopoietin secretion. While Verapamil is cardioactive, it is considered the first-line
prophylactic drug for cluster headache and is usually well tolerated by otherwise healthy
patients.

In light of our prior studies demonstrating the immunomodulatory role of P-gp in promoting
Th2 skewing cytokine secretion in CRSwNP, we hypothesized that low dose Verapamil HCl
monotherapy would be safe and effective in the treatment of CRSwNP.

Inclusion Criteria:

1. Patients presenting to the Massachusetts Eye and Ear Sinus Center

2. Age 18-80 yrs old

3. Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012
consensus criteria

Exclusion Criteria:

1. Patients with the following comorbidities:

- GI Hypomotility

- Heart Failure

- Liver Failure

- Kidney Disease

- Muscular Dystrophy

- Pregnant or Nursing Females

- Steroid Dependency

2. Patients taking the following medications:

- Aspirin

- Beta-blockers

- Cimetidine(Tagamet)

- Clarithromycin(Biaxin)

- Cyclosporin

- Digoxin

- Disopyramide(Norpace)

- Diuretics

- Erythromycin

- Flecainide

- HIV Protease Inhibitors(Indinavir, Nelfinavir, Ritonavir)

- Quinidine

- Lithium

- Pioglitazone

- Rifampin

- St Johns Wort

3. Patients with cardiac or conduction abnormality picked up by screening EKG