Single Ascending Dose Study of PBI-4547 in Healthy Subjects

This is a first-in-human, single-ascending dose study of PBI-4547 in healthy adult participants. PBI-4547 is a synthetic ligand of G protein-coupled receptor (GPR)40 and GPR84, which have been reported to play a role in fibrosis in various animal models as well as in tissue culture.

A total of 40 healthy adult participants will sequentially receive 1 of 5 doses of PBI-4547 (Dose1, 2, 3, 4 or 5) or matching placebo, with each cohort of 8 participants randomized in a 3:1 ratio to receive PBI-4547 or matching placebo.

A food-effect cohort will be added after review of the PK results of at least the first dose, and the following 2 doses, if needed. In this cohort participants will initially receive the study drug under fasting conditions (Period 1) followed by the same dose after the ingestion of a high-fat meal (Period 2) after a 14-day washout period.

• PBI-4547 (Drug): PBI-4547 tablet
• Placebo (Other): Placebo tablet

Primary outcomes

• Number of participants with treatment-emergent adverse events (TEAEs) [5-6 days]: TEAE is any untoward medical occurrence in a subject who has been administered a pharmaceutical product or not, which does not necessarily have a causal relationship with this treatment.
• Number of participants with clinically significant laboratory evaluation findings [5-6 days]: Laboratory tests for hematology, serum chemistry and urinalysis will be performed upon admission, at discharge, and at the follow-up visit (5 ± 1 day post-dose).
• Number of participants with clinically significant electrocardiogram (ECG) Findings [5-6 days]: Triplicate ECG will be performed upon admission, pre-dose, and approximately 1, 2, 8, and 24 hours post-dose, and at the follow-up visit (5 ± 1 day post-dose). Subjects will be continuously monitored using a Holter monitor from approximately 1 hour pre-dose until approximately 24 hours post-dose.
• Number of participants with clinically significant vital sign findings [5-6 days]: Vital signs include blood pressure, heart rate, respiratory rate, and oral body temperature will be measured upon admission, before discharge from the clinic and at the follow-up visit (5 ± 1 day post-dose).
• Number of participants with physical examination findings [5-6 days]: Brief physical examination will be conducted upon admission and at discharge. A complete physical examination will be conducted at screening and follow-up visit.

Secondary outcomes

• AUC0-t for PBI-4547 [48 hours]: Area under the concentration-time curve from time zero to the last non-zero concentration
• AUC0-inf for PBI-4547 [48 hours]: Area under the concentration-time curve from time zero to infinity (extrapolated)
• Cmax for PBI-4547 [48 hours]: Maximum observed concentration
• Residual area for PBI-4547 [48 hours]: Residual area calculated as 100*(1- AUC0-t / AUC0-inf)
• Tmax for PBI-4547 [48 hours]: Time of observed Cmax
• T1/2 el for PBI-4547 [48 hours]: Elimination half-life
• Kel for PBI-4547 [48 hours]: Elimination rate constant
• Rkel for PBI-4547 [48 hours]: Accumulation factor based on elimination rate constant
• MRT for PBI-4547 [48 hours]: Mean residence time
• Cl/F for PBI-4547 [48 hours]: Total body clearance, calculated as Dose/AUC0-inf;Cl/F normalized for subject body weight in kg will be calculated
• Vd/F for PBI-4547 [48 hours]: Apparent volume of distribution, calculated as Dose/(Kel x AUC0-inf). Vd/F normalized for subject body weight in kg will be calculated
• AUC0-t for PBI-4547 under fed condition [48 hours]: Area under the concentration-time curve from time zero to the last non-zero concentration after a high-fat diet
• AUC0-inf for PBI-4547 under fed condition [48 hours]: Area under the concentration-time curve from time zero to infinity (extrapolated) after a high-fat diet
• Cmax for PBI-4547 under fed condition [48 hours]: Maximum observed concentration after a high-fat diet
• Tmax for PBI-4547 under fed condition [48 hours]: Time of observed Cmax after a high-fat diet

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

* Healthy male participants or non-childbearing potential female participants, ≥18 and ≤55 years.
* Body mass index > 18.5 and < 30.0 kg/m\^2, and body weight ≥ 50.0 kg for male participants and ≥ 45.0 kg for female participants.
* Continuous non-smoker who has not used tobacco or nicotine-containing products for at least 3 months prior to screening.
* Male participants with a pregnant partner must agree to use a condom from the first dosing until at least 90 days after study drug administration.
* Male participants must be willing not to donate sperm until 90 days after study drug administration.

Exclusion Criteria:

* Any clinically significant abnormality or abnormal laboratory test results.
* An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m\^2.
* Positive urine drug screen and history of significant drug abuse.
* History of significant allergic reactions to any drug.
* Use of any drugs known to induce or inhibit hepatic drug metabolism.
* Positive pregnancy test or breast-feeding participant.
* Clinically significant abnormalities in ECG, blood pressure, and heart rate at screening.
* History of significant alcohol abuse or regular use of alcohol.
* Use of medication other than topical products without significant systemic absorption.
* Donation of plasma.

• Leduc M, Grouix B, Tremblay M, GervaisL, Sarra-Bournet F, Felton X, Simard J, Leblond FA, Laurin P and Gagnon L. PBI-4547 Improves Glucose Metabolism and Insulin Resistance, and Reduces Liver Damage in a High-Fat Diet Mouse Model of Obesity and Metabolic Syndrome. Diabetes 2018 Jul; 67(Supplement 1).
• Gagnon L, Laverdure A, Sarra-Bournet F, Cloutier M, Felton A, Treemblay M, Richard J, Gervais L, Laurin P, Leblond FA and Grouix B. PBI-4547 Reverses Diabetes and Metabolic Syndrome through Regulation of Lipid/Glucose Metabolism, ß-Oxidation and Fibrosis in Liver, and White Adipose Tissue in ob/ob Mice. Diabetes 2018 Jul; 67(Supplement 1).
• Sarra-Bournet F, Grouix B, Hince K, Felton A, Tremblay M, Abbott S, Duceppe JS, Zacharie B, Laurin P, Gagnon G. PBI-4547 decreases hepatic stellate cell activation via AMPK signaling pathway, and reduces fibrosis in carbon tetrachloride (CCL4)-induced hepatic fibrosis model. Journal of Hepatology 2018, 68:S365-S604.

• John Moran, MD, Study director, Prometic Pharma SMT Ltd.
• Richard Larouche, MD, Principal investigator, Syneos Health