Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis

A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of PTI-808 in Healthy Adult Subjects and in Adults With Cystic Fibrosis

Part 1 of this trial will enroll healthy volunteers into a single ascending dose (SAD), multiple ascending dose (MAD), and Food Effect (FE) treatment groups.

The SAD treatment group is comprised of at least 3 ascending dose level cohorts where healthy adult subjects will be randomized to receive a single dose of either PTI-808 or placebo and will be followed for 7 days post dose. A safety review committee (SRC) will convene after the completion of each cohort to evaluate safety and pharmacokinetic (PK) data.

Following the conclusion of the respective SAD level dose groups and after sufficient review of study data and approval by the SRC, a second set of healthy adult subjects will participate in an assigned MAD treatment group. The MAD treatment group is comprised of 3 ascending dose level cohorts where subjects will be randomized to receive either PTI-808 or placebo daily for 7 days and will be followed for 7 days after receiving the last dose.

Also following the conclusion of the respective SAD level dose groups, healthy adult subjects will participate in the FE treatment group.

Part 2 of this will enroll healthy volunteers to assess the safety, tolerability, and PK of PTI 808 co administered with PTI 801 and PTI 428 to HVs with daily dosing for 7 consecutive days.

Part 3 will enroll adult subjects with cystic fibrosis (CF) into a MAD treatment group consisting of 2 cohorts. Subjects will receive PTI-808 co-administered with PTI-801 and PTI-428. PTI-808 will be administered daily for 7 consecutive days followed by PTI-808 + PTI-801 + PTI-428 administered daily for 14 consecutive days.

Part 4 will enroll adult subjects with cystic fibrosis (CF) into 28-day cohorts. Subjects will receive PTI-808 co-administered with PTI-801 with or without PTI-428 versus matching placebo.

Part 1 of this trial will enroll healthy volunteers into a single ascending dose (SAD), multiple ascending dose (MAD), and Food Effect (FE) treatment groups.

The SAD treatment group is comprised of at least 3 ascending dose level cohorts where healthy adult subjects will be randomized to receive a single dose of either PTI-808 or placebo and will be followed for 7 days post dose.

The MAD treatment group is comprised of 3 ascending dose level cohorts where subjects will be randomized to receive either PTI-808 or placebo daily for 7 days and will be followed for 7 days after receiving the last dose.

Following the conclusion of the respective SAD level dose groups the food effect portion of the study will be initiated and subjects will be randomized to receive an initial single dose of PTI-808 either after an overnight fast of at least 10 hours (fasted group) or after an overnight fast of at least 10 hours followed the consumption of a high fat high calorie meal (fed group). After a 10 day washout period, subjects will cross over to the opposite group and receive a second dose of PTI-808. Subjects will be followed for up to 7 days following dosing.

Part 2 of this will enroll healthy volunteers to assess the safety, tolerability, and PK of PTI 808 co administered with PTI 801 and PTI 428 to HVs with daily dosing for 7 consecutive days.

Part 3 - Part 3 will enroll adult subjects with CF to assess the safety, tolerability, and PK of multiple ascending doses of PTI-808 co-administered with PTI-801 and PTI-428. Subjects will receive 7 days of PTI-808 or placebo followed by 14 days of PTI-808 or placebo co-administered with PTI-801+PTI-428 or matching placebos.

Part 4 - Part 4 will assess the safety, tolerability, PK, and the effects of PTI-808 co-administered with PTI-801 with or without PTI-428 over a 28-day treatment period in CF subjects who are either homozygous for the F508del CFTR genotype or are heterozygous for the F508del CFTR genotype. Subjects will be randomized to receive treatment with PTI-808 co-administered with PTI-801 with or without PTI-428 versus matching placebo.

Part 1 and Part 2 Inclusion Criteria:

1. Adults aged 18 to 55 years old, inclusive, at the time of informed consent
2. Body mass index ≥18 and <30 kg/m2
3. Subject must be a non-smoker and non-tobacco user for a minimum of 30 days prior to screening and for the duration of the study.
4. Subject understands the full nature and purpose of the study, including possible risks and side effects, and is willing and able to comply with all compulsory study procedures and provides informed consent/permission prior to any study procedures being performed.
5. Females of childbearing potential and males capable of fathering a child must meet the contraception requirements

Part 1 & Part 2 Exclusion Criteria:

1. History or current evidence of any clinically significant cardiac, endocrinologic, hematologic, hepatobiliary, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or other major disease, as determined by the investigator
2. Prolonged QT interval with Fridericia's correction >450 msec at screening
3. Abnormal liver function as defined by aspartate transaminase (AST), alanine transaminase (ALT), or bilirubin >1.5× the upper limit of the normal range
4. Abnormal renal function at screening defined as creatinine clearance <90 mL/min using the Cockroft-Gault equation
5. Clinically significant screening results that would exclude subject from the study (e.g., medical histories, PE, ECGs, vital signs, and laboratory profiles) as deemed by the investigator
6. Participation in another clinical study or treatment with an investigational agent within 30 days or five half-lives, whichever is longer, prior to Study Day 1
7. History of cancer within the past 5 years (excluding non-melanoma skin cancer)
8. History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
9. Positive urine screen for prohibited drugs (cocaine, cannabinoids, nicotine [urine cotinine is the detection mechanism for nicotine], opiates, barbiturates, amphetamines, and benzodiazepines) or positive alcohol test at screening
10. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (HCVAb)
11. Clinically significant infection within 3 months of screening as determined by the investigator
12. Known or suspected hypersensitivity or idiosyncratic reaction to study medication or any components thereof
13. Has donated blood within 3 months of screening or plans to donate blood within 3 months of study completion
14. Pregnant or nursing women
15. Any conditions that, in the opinion of the investigator, would make the subject unsuitable for enrollment or could interfere with the subject's participation in or completion of the study
16. Use of prohibited medications within 14 days prior to dosing of study drug

Part 3 CF Inclusion Criteria:

1. Confirmed diagnosis of CF with the F508del/F508del genotype
2. Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive
3. Non-smoker and non-tobacco user for a minimum of 30 days prior to screening

Part 3 CF Exclusion Criteria:

1. Participation in another clinical trial or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Study Day 1
2. History of cancer within the past 5 years (excluding cervical cancer in situ with curative therapy for at least one year prior to screening and non-melanoma skin cancer)
3. History of organ transplantation
4. Hospitalization, sinopulmonary infection, CF exacerbation, or other clinically significant infection or illness (as determined by the investigator) requiring an increase or addition of medication, such as antibiotics or corticosteroids, within 14 days of Day 1
5. Initiation of any new chronic therapy (e.g., ibuprofen, hypertonic saline, azithromycin, Pulmozyme®, Cayston®, TOBI®)) or any change in chronic therapy (excluding pancreatic enzyme replacement therapy) within 28 days prior to Day 1
6. History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
7. Pregnant or nursing women
8. Currently taking or has taken a CFTR modulator within 30 days prior to initial dose of study drugs

Part 4 CF Inclusion Criteria:

1. Confirmed diagnosis of CF with either the F508del CFTR homozygous genotype on record or for heterozygote subjects, only one copy of the F508del CFTR mutation on record
2. Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive
3. Non-smoker and non-tobacco user for a minimum of 30 days prior to screening

Part 4 CF Exclusion Criteria:

1. Participation in another clinical trial or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Study Day 1
2. History of cancer within the past 5 years (excluding cervical cancer in situ with curative therapy for at least one year prior to screening and non-melanoma skin cancer)
3. History of organ transplantation
4. Hospitalization, sinopulmonary infection, CF exacerbation, or other clinically significant infection or illness (as determined by the investigator) requiring an increase or addition of medication, such as antibiotics or corticosteroids, within 28 days of Day 1
5. Initiation of any new chronic therapy (e.g., ibuprofen, hypertonic saline, azithromycin, Pulmozyme®, Cayston®, TOBI®)) or any change in chronic therapy (excluding pancreatic enzyme replacement therapy) within 28 days of Day 1
6. History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
7. Pregnant or nursing women
8. Currently taking or has taken a CFTR modulator within 14 days prior to the screening visit