Study of N91115 in Patients With Cystic Fibrosis Homozygous F508del-CFTR Mutation
Study of N91115 in Patients With Cystic Fibrosis Homozygous F508del-CFTR Mutation
This Phase 1b study in F508del-CFTR homozygous CF patients is being conducted to assess the
 safety of N91115 as the sole cystic fibrosis transmembrane conductance regulator (CFTR)
 modulator at doses near the expected therapeutic exposure level in preparation for Phase 2
 studies of N91115 added to the CFTR modulator combination lumacaftor/ivacaftor when launched.
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