Effect of Losartan in Cystic Fibrosis (CF)-NIH Grant #133240

CF is the most common inherited disease causing a shortened life span, affecting ~30,000
people in the United States with annual health care costs of at least $1.8 billion. The
median age of predicted survival of these patients has improved and is now almost 40 years in
the US. Over the last two decades, investigators have identified ~2,000 mutations in the CF
transmembrane conductance regulator (CFTR) gene. These mutations are imperfectly classified
into 5 groups, and small molecules are being developed that rescue group-specific CFTR
mutants. These agents have produced remarkable improvements in some patients. The CFTR
potentiator ivacaftor (Kalydeco™), approved by the FDA mainly for class III mutations
especially G551D, improves ion transport (large decrease in sweat chloride), clinical outcome
(increased FEV1 and weight, decreased exacerbations), and quality of life. Furthermore, the
FDA recently approved Orkambi™ (a corrector and potentiator: lumacaftor plus ivacaftor)
because it reduced exacerbation rates by up to 39% in patients homozygous for F508del.

It has been demonstrated in vitro that improvements in airway surface liquid (ASL) volume are
highly predictive of changes seen in clinical studies and track with tracheal mucus
velocities measured in sheep in vivo using the CFTR potentiator ivacaftor, inhaled hypertonic
saline and other interventions (preliminary data). ASL volume is regulated by ion fluxes
through ENaC, CFTR, CaCC, and BK channels, and TGF-β1-mediated inflammation in CF cells
decreases activities of CaCC (8) and BK. These findings suggest that effective and safe
anti-inflammatory therapy has the potential to improve mucociliary dysfunction in CF
patients, even in the absence of small molecule therapy. Currently used anti-inflammatory
therapies such as high-dose ibuprofen and steroids produce unwanted side effects that negate
their effectiveness. Other medications showed severe side effects in clinical trials.
However, experiments proposed in this application will test the hypothesis that losartan
provides a safe and effective anti-inflammatory therapy needed to improve outcomes in CF
patients.

Briefly, 16 patients with CF, >18 years of age, who are not on CFTR augmentation therapy will
be recruited for this trial (4 per year). After signing informed consent at the screening
visit, spirometry will be performed, take blood for safety and inflammatory markers, and test
for pregnancy where applicable. Since losartan has teratogenic effects, strict birth control
in female participants will be enforced. Eligible patients will complete visits as following:

Quality of life will be assessed by CF quality of life questionnaire - revised (CFQ-R).
Cytokines will be measured from nasal fluid collected by Leukosorb filter paper. After
assessing baselines, a daily dose of 50 mg losartan will be started, followed by a safety
visit 7 days after treatment start (± 2 days). Then, the losartan dose will be increased to
100 mg daily until week 14. Since this trial assesses anti-inflammatory effects of 100 mg
losartan, the total duration will be 14 weeks to achieve >12 weeks of treatment with
losartan.

Inclusion Criteria:

- CF patients with any known mutation combination not on CFTR augmentation therapy

- ≥18 years of age

- Severity of the Disease: Suitable patients will have mild to moderate lung disease, as
defined by:

- Pulmonary Function: Each patient must have an FEV1 ≥40% of predicted at the
screening visit.

- Hemoglobin saturation: Patients must have an oxygen saturation of >92% on room
air as determined by pulse oximetry at the screening visit.

- Produces sputum regularly (daily basis, at minimum)

- FEV1 40-80%

- Able to sign Informed consent

Exclusion Criteria:

- When enrolling female patients

- Not willing to adhere to strict birth control (combination of two methods)

- If female, patient must be non-pregnant and non-lactating, and those of childbearing
potential must be using an acceptable method of birth control (i.e., an Intrauterine
Contraceptive Device with a failure rate of <1%, hormonal contraceptives or a barrier
method). If a female patient is abstinent, she must agree to use one of the acceptable
methods if she becomes sexually active.

- Unstable lung disease: As defined by a change in medical regimen during the preceding
2 weeks or an FEV1 ≥15% below value within 3 months

- Received an investigational drug or therapy during the preceding 30 days

- Active or former smokers with less than 1 year since quitting, or >10 pack-year
smoking history

- Unable to adequately complete study measures, including spirometry and travel to
University of North Carolina (UNC)

- Intolerance to angiotensin receptor blockers (ARB)

- Treatment with angiotensin converting enzyme (ACE) inhibitor

- Regular use of NSAIDs or potassium supplementation, treatment with aliskiren, on
anticoagulation

- Oral corticosteroid use within 6 weeks

- Exacerbation requiring treatment within 6 weeks

- Treatment of mycobacterial infections

- Significant hypoxemia (oxygen saturation <92% on room air and rest or use of
continuous oxygen treatment), chronic respiratory failure by history (pCO2 > 45 mmHg),
clinical evidence of cor pulmonale

- Untreated arterial hypertension (systolic blood pressure >140 mm Hg, diastolic blood
pressure > 90 mmHg)

- Blood pressure less than 90 mm Hg systolic while standing

- Cardiac, renal (creatinine 1.5 times normal limit), hepatic (LFTs > 3x normal upper
limit), neurological, psychiatric, endocrine or neoplastic diseases that are judged to
interfere with participation in study

- Known renal artery stenosis

- Concomitant airway disorders other than CF, such as allergic bronchopulmonary
aspergillosis or asthma

- Subjects with prior thoracic surgery

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with trial participation or may
interfere with the interpretation of trial results and, in the judgment of the PI,
would make the subject inappropriate for enrollment.

- Patients using intermittent inhaled or oral antibiotics will be allowed to participate
in this trial. Patients on chronic, cycling antibiotics will be required to have
completed at least 2 full cycles of the prescribed antibiotic prior to enrollment and
should be studied during the same phase of treatment (on or off) during each study
period.

- Have had radiation exposure within the past year that would cause them to exceed
Federal Regulations by participating in this study.