Losartan and Inflammation in Cystic Fibrosis

The propose of this study to conduct a proof of concept clinical trial to test if
administration of losartan augments CFTR function in vivo in patients who are on Orkambi™.
The goal of this pilot clinical trial is to examine the ability of losartan on CFTR (primary
hypothesis) and possibly BK rescue/augmentation (secondary hypothesis) in patients homozygous
for F508del on Orkambi™ therapy. The additional benefit for Large, Ca 2+ - and
voltage-activated K + channels (BK) channels could be important, but is harder to measure in
vivo. Towards this end, however, the study will assess calcium-activated chloride channel
(CaCC)/BK activity together as the response to adenosine triphosphate (ATP) during nasal
potential difference (NPD) measurements, even though this is not an accurate reflection of
either channel on its own.

Note that ATP-induced changes in NPD in CF patients are higher than in normal subjects
because in vitro data show that this response is increased in the absence of BK activity.
Thus, the expectation here is that the rescue of BK activity with losartan will DECREASE NPD
(ΔNPD) responses to ATP.

Primary hypothesis: Losartan at 100 mg for 12 weeks will improve CFTR conductance as measured
by NPD in patients on Orkambi therapy. It is expected that compared to placebo, ΔNPD in
response to 0 Cl-/isoproterenol will change by more than -4 millivolt (mV) using the most
polarized nostril each time.

Secondary hypotheses: Losartan 100 mg for 12 weeks will improve BK and CaCC activity as
assessed by a decrease of changes in NPD to ATP exposure. Furthermore, losartan will reduce
nasal cytokine levels and systemic inflammatory markers.

Study plan: Briefly, 36 patients with CF, > 12 years of age, who are homozygous for F508del
and have been on treatment with Orkambi™ for at least 3 months will be recruited for this
trial. This trial will be randomized 1:1 with placebo (n=18 for each group). After signing
informed consent at the screening visit, subjects will perform spirometry, determine sweat
chloride, take blood, and test for pregnancy where applicable. Eligible patients will
complete visits as outlined below. Quality of life will be assessed by CF quality of life
questionnaire - revised (CFQ-R), 12). NPD will use standard protocols and so will nasal cell
harvest (see below for assessments). Cytokines will be measured from nasal fluid recovered by
Leukosorb filter paper (13). There will be two visits for these different nasal assessments
to assure that nasal cell fluid and cell collection will not influence NPD and vice versa.
After assessing baselines, a daily dose of 50 mg losartan or placebo will be started. A
safety visit will occur after 7 days of treatment (± 2 days) and the losartan dose (or
placebo) increased to 100 mg daily (higher dose is likely needed to get anti-inflammatory
effect in airways if present). Since this trial assesses anti-inflammatory effects of
losartan (and lack of placebo), the total duration will be 14 weeks to achieve 12 weeks of
treatment with the higher dose of losartan (or placebo).

Inclusion Criteria:

- CF patients homozygous for F508del and on current treatment with Orkambi™ for at least
3 months

- Age >12 years

- Forced expiratory volume at one second (FEV1) >/= 40% of predicted

Exclusion Criteria:

- Female patients not willing to adhere to strict birth control (combination of two
methods)

- Pregnancy

- History of intolerance to angiotensin receptor blockers (ARBs)

- Treatment with angiotensin converting enzyme (ACE) inhibitor

- NPD response to zero chloride (0Cl)/isoproterenol of > - 6.6 mV at screening (evidence
of detectable CFTR activity at baseline)

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

- Oral corticosteroid use within 6 weeks

- Exacerbation requiring treatment within 6 weeks

- Active treatment for mycobacterial infections

- Significant hypoxemia (oxygen saturation <90% 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 (ABPA).

- Subjects with prior thoracic surgery