Study of N91115 in Patients With Cystic Fibrosis Homozygous F508del-CFTR Mutation

Study procedures, frequency and timing are provided in the attached study schema. Adverse
events and concomitant medication will be monitored throughout the study from informed
consent signing until end of study participation. A Data Monitoring Committee (DMC) will
also review unblinded safety data on a monthly basis throughout the study. Limitations on
bronchodilators for pulmonary assessments prior to study drug dosing are described below
except in emergent situations.

- Short acting β-agonists and anticholinergics will be held for at least 4 hours

- Long acting β-agonists dosed twice daily will be held for at least 12 hours

- Long acting β-agonists dosed once daily and long acting anticholinergics will be held
for at least 24 hours

Screening (Day -28 to Day -3):

Patients will sign the informed consent and undergo procedures to determine eligibility
including pregnancy testing, demographic information, medical history, and genotype by
historical confirmation or blood sample confirmation (as applicable), height and weight,
12-Lead electrocardiogram (ECG), 48-hour Holter monitoring, chemistry, hematology, full
physical examination, sweat chloride, smoking and alcohol history, spirometry, sputum
microbiology, urinalysis and vital signs.

Day 1 Predose (Day -2 to -1) Patients will return to the clinic to reconfirm eligibility and
assess any changes in medical history and pregnancy status. An abbreviated physical
examination focusing on cardiovascular, pulmonary and gastrointestinal systems plus an
assessment of weight will be conducted. The following will be obtained: 12-lead ECG,
abbreviated physical exam, blood for DNA (optional), blood for leukocyte messenger
ribonucleic acid (mRNA), blood inflammatory biomarkers, cystic fibrosis
questionnaire-revised (CFQ-R), O2 Sat, patient global impression of change (PGIC), safety
labs, serum pharmacokinetics (PK), spirometry, sputum microbiology, sweat chloride (SC) (if
more than 2 weeks since the screening value was obtained), and vital signs. Sites may choose
to perform any of these assessments on Day -2, Day -1 or Day 1 predose except for serum PK
that starts Day 1 predose and vital signs that are done Day 1 predose.

Dosing and Food Intake:

Patients will take their dose of study drug every 12 hours at approximately the same time
each morning and night. There are no restrictions related to food intake.

Dosing Days 1 and 2:

On Day 1, patients will be observed for at least 4 hours following the first dose of study
drug. Patients return to the clinical site on Day 2 for a predose PK sample that is 24 hours
after their first dose. Patients will be observed for at least 2 hours after the second dose
on Day 2.

Days 3-28:

Patients self-administer study drug at approximately the same time each morning and evening
with the exception that the morning doses on clinic Days 7, 14, 21 and 28, which will be
administered and witnessed in the clinic.

Day 7 (Dosing in Clinic):

On Day 7, patients will return to the clinic to monitor any changes in health status and for
an abbreviated physical exam, 12-Lead ECG, O2 Sat, safety labs, PK, spirometry, study drug
compliance, SC and vital signs.

Day 14 (Dosing in Clinic):

On Day 14, patients will return to the clinic to monitor any changes in health status and
for an abbreviated physical exam, urine pregnancy, 12-lead ECG, blood inflammatory
biomarkers, CFQ-R, O2 Sat, safety labs, PK, spirometry, study drug compliance, SC and vital
signs.

Day 21 (Dosing in Clinic):

On Day 21, patients will return to the clinic to monitor any changes in health status and
for an abbreviated physical exam, 12-Lead ECG, O2 Sat, safety labs, PK, spirometry, study
drug compliance, SC and vital signs.

Day 28 (Dosing in Clinic):

On Day 28 patients will return to the clinic to monitor any changes in health status and for
an abbreviated physical exam, 12-Lead ECG, blood for DNA (optional), blood for leukocyte
mRNA, blood inflammatory biomarkers, CFQ-R, urine pregnancy, O2 Sat, PGIC, safety labs, PK,
spirometry, sputum microbiology, study drug compliance, SC, weight, and vital signs.

Day 42 (Final study day 2 weeks after last dose):

On Day 42 (± 2 days) study follow-up assessments include: abbreviated physical exam, blood
inflammatory biomarkers, O2 Sat, PGIC, spirometry, SC, weight, and vital signs.

Inclusion Criteria:

1. Male or female, age ≥ 18 years with confirmed diagnosis of CF, homozygous for the
F508del-CFTR mutation based on historical results generated by Ambry Genetics within
the past two years or if unavailable, confirmed by testing done within the past 28
days

2. Sweat chloride ≥ 60 (milliequivalents) mEq/L, by quantitative pilocarpine
iontophoresis test (QPIT) at screening

3. Weight ≥ 40 kg at screening

4. Forced expiratory volume (FEV1) ≥ 40% of predicted normal for age, gender, and height
(Hankinson standards) pre- or post-bronchodilator value, at screening

5. Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening

6. Hematology, clinical chemistry and urinalysis results with no clinically significant
abnormalities that would interfere with the study assessments at screening

Exclusion Criteria:

1. Any acute infection, including acute upper or lower respiratory infections and
pulmonary exacerbations that require treatment or hospitalization within 2 weeks of
Study Day 1

2. Any change in chronic therapies for CF lung disease (e.g., Ibuprofen, Pulmozyme®,
hypertonic saline, Azithromycin, Tobi®, Cayston®) within 4 weeks of Study Day 1

3. Blood hemoglobin < 10 g/dL at screening

4. Serum albumin < 2.5 g/dL at screening

5. Abnormal liver function defined as ≥ 3 x upper limit of normal (ULN) in 3 or more of
the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT),
g-glutamyl transferase (GGT), alkaline phosphatase (ALP), or total bilirubin at
screening

6. History of abnormal renal function (creatinine clearance < 50 mL/min using
Cockcroft-Gault equation) within a year of screening

7. History, including the screening assessment, of ventricular tachycardia or other
ventricular arrhythmias

8. History, including the screening assessment, of prolonged cardiac QT interval and/or
QTcF (QT with Fridericia's correction) interval (> 450 msec)

9. History of solid organ or hematological transplantation

10. History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in
the year prior to screening

11. Use of continuous (24 hr/day) or nocturnal supplemental oxygen