Study Assessing PTI-428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis
Study Assessing PTI-428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis
This trial will consist of three arms: Part A, Part B, and Part C. Part A has two groups. The
 first group will enroll adult subjects with cystic fibrosis (CF) into a single ascending dose
 (SAD) treatment group. The second group will enroll adult subjects with CF, including those
 on background treatment with ORKAMBI® and those not on a cystic fibrosis transmembrane
 conductance regulator (CFTR) modulator, into a multiple ascending dose (MAD) treatment group.
 Part B will enroll adult subjects with CF currently on stable ORKAMBI® background therapy for
 a minimum of 3 months into a Phase II treatment group consisting of two cohorts. Part C will
 enroll adult subjects with CF, including those on background treatment with KALYDECO® and
 those not on a CFTR modulator, into a Phase II treatment group consisting of three cohorts.
 Approximately 136 subjects will be enrolled.
PART A The SAD treatment group is comprised of 3 cohorts where subjects will be randomized to
 either PTI-428 or placebo. Following the conclusion of at least 3 SAD treatment groups, a set
 of adult subjects diagnosed with CF will participate in an assigned MAD treatment group. The
 MAD treatment group is comprised of 3 cohorts. MAD Cohort 1 will enroll adult subjects with
 CF currently on stable ORKAMBI® background therapy for a minimum of 3 months at the time of
 randomization. MAD Cohorts 2 and 3 will enroll adult subjects with CF who are not currently
 on any background therapies. Subjects in all MAD cohorts will be randomized to either PTI-428
 or placebo. Each dose will be administered once daily (QD) for a total of 7 Days.

 PART B Following the conclusion of MAD Cohort 1, a set of adult subjects diagnosed with CF
 currently on stable ORKAMBI® background therapy for a minimum of 3 months will participate in
 Part B. The Part B Phase II treatment group is comprised of 2 cohorts where subjects will be
 randomized to either PTI-428 or placebo. Each dose will be administered QD for a total of 28
 days.

 PART C Following the conclusion of Part B Phase II, a set of adult subjects diagnosed with CF
 will participate in Part C. The Part C Phase II treatment group is comprised of 3 cohorts.
 Part C Cohort 1 will enroll adult subjects with CF who are eligible to take, but not
 currently taking, ORKAMBI® in accordance with the approved label. Part C Cohort 2 will enroll
 adult subjects with CF currently on stable KALYDECO® background therapy for a minimum of 3
 months at the time of randomization. Part C Cohort 3 will enroll adult subjects with CF who
 are not currently on any background therapies and are pancreatic sufficient. Each PTI-428 or
 placebo dose will be administered QD for a total of 28 days.
Inclusion Criteria:

 -  Confirmed diagnosis of CF.

 -  Forced expiratory volume in 1 second (FEV1) 40-90% predicted.

 -  Non-smoker and non-tobacco user for a minimum of 30 days prior to screening and for
 the duration of the study.

 Exclusion Criteria:

 -  Participation in another clinical trial or treatment with an investigational agent
 within 30 days or 5 half-lives, whichever is longer, prior to Study Day 1.

 -  History of cancer within the past five years (excluding cervical CIS with curative
 therapy for at least one year prior to screening and non-melanoma skin cancer).

 -  History of organ transplantation.

 -  Any sinopulmonary infection or CF exacerbation requiring a change or addition of
 medication (including antibiotics) within 1 month of Study Day 1 or any other
 clinically significant infection as determined by the investigator within 1 month of
 Day 1.

 -  History of alcohol or drug abuse or dependence within 12 months of screening as
 determined by the Investigator.

 -  Male and female of child-bearing potential, unless they are using highly effective
 methods of contraception during participation in the clinical study and for 4 weeks
 after termination from study.

 -  Pregnant or nursing women.