Safety, Tolerability, Pharmacokinetics, and Preliminary Pharmacodynamics of QBW251 in Healthy Subjects and Cystic Fibrosis Patients

Key inclusion criteria (Parts 1 and 2)

- Healthy female (of non-childbearing potential) and male subjects of 18 to 55 years of
age (inclusive)

- Body mass index (BMI) must be within the range of 15 to 30 kg/m2

- Oxygen saturation (O2) at screening must be ≥ 96% on room air.

Key exclusion criteria (Parts 1 and 2)

- Use of any prescription drugs or herbal supplements within four (4) weeks prior to
dosing or within 5 half-lives of the drug, whichever is longer

- Over-the-counter (OTC) medication (including vitamins, dietary supplements) within two
(2) weeks prior to dosing

- Use of other investigational drugs at the time of enrollment, or within 30 days or 5
half-lives of enrollment, whichever is longer

- Unwilling to avoid direct sun exposure by covering exposed skin, using topical sun
block and wearing sunglasses from the first dose of study drug to the end of
participation in the study

- Pregnant or nursing (lactating) women.

Key inclusion criteria (Parts 3 and 4):

- Male and female patients of 18 to 65 years of age (inclusive) with a confirmed
diagnosis of cystic fibrosis as per the Cystic Fibrosis Foundation (CFF) consensus
guidelines

- Heterozygous with one allele represented as any CFTR mutation and the other allele
must represent a class III, IV, V, VI CFTR mutation (Note: since the CFTR mutation,
F508del, can be considered either a class II or III mutation, heterozygous CF patients
that have one allele that contains F508del, must have the other allele contain a class
III (i.e., not F508del), IV, V, or VI mutation). Patients with F508del/F508del
mutation should only be included in Part 3 Cohort 3.

- Body mass index (BMI) must be within the range of 15-35 kg/m2

- FEV1 at Screening must be 40 to 100% predicted (inclusive) by NHANES/Hankinson
standards

- Oxygen saturation (O2) at screening must be > 90% on room air.

Key exclusion criteria (Parts 3 and 4)

- Use of herbal supplements within four (4) weeks prior to dosing or within 5 half-lives
of the supplement, whichever is longer

- Use of other investigational drugs at the time of enrollment, or within 30 days or 5
half-lives of enrollment, whichever is longer

- Unwilling to avoid direct sun exposure by covering exposed skin, using topical sun
block and wearing sunglasses from the first dose of study drug to the end of
participation in the study

- Pregnant or nursing (lactating) women

- Women of child-bearing potential, UNLESS they are using highly effective contraception

- Any changes in concomitant medications for 14 days prior to screening

- History or clinical evidence of pancreatic injury or pancreatitis; clinical evidence
of liver disease or liver injury as indicated by clinically significant abnormal liver
function tests as judged by the investigator such as SGOT, SGPT, GGT, alkaline
phosphatase, or serum bilirubin

- History or presence of impaired renal function as indicated by abnormal creatinine or
BUN values or abnormal urinary constituents (e.g., albuminuria)

- History of Burkholderia cepacia respiratory tract infection (must have at least two
negative cultures and no positive cultures in the past 18 months prior to screening to
be eligible for enrollment)

- Sexually active males unless they use a condom during intercourse while taking drug
and for condom is required to be used also by vasectomized men in order to prevent
delivery of drug via seminal fluid.

- Patient is currently receiving (or has received within 4 weeks of baseline visit)
VX-770/Ivacaftor.

- History of lung transplant