Single Ascending Dose Study of PBI-4547 in Healthy Subjects

A Phase 1, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of PBI-4547 in Healthy Subjects

This study will evaluate the safety, tolerability, and pharmacokinetics (PK) of PBI-4547 in healthy adult participants.

Study Overview

• Status: Terminated
• Conditions: Healthy Subjects
• Intervention / Treatment: Other: Placebo; Drug: PBI-4547

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1P 0A2
    • Syneos Health
  • Quebec
    • Montréal, Quebec, Canada, H3X 2H9
      • Syneos Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: QUADRUPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1, Dose 1 of PBI-4547 or Placebo; Dose 1 of PBI-4547 or matching Placebo tablets by mouth	Other: Placebo; Placebo tablet; Drug: PBI-4547; PBI-4547 tablet
EXPERIMENTAL: Cohort 2, Dose 2 of PBI-4547 or Placebo; Dose 2 of PBI-4547 or matching Placebo tablets by mouth	Other: Placebo; Placebo tablet; Drug: PBI-4547; PBI-4547 tablet
EXPERIMENTAL: Cohort 3, Dose 3 of PBI-4547 or Placebo; Dose 3 of PBI-4547 or matching Placebo tablets by mouth	Other: Placebo; Placebo tablet; Drug: PBI-4547; PBI-4547 tablet
EXPERIMENTAL: Cohort 4, Dose 4 of PBI-4547 or Placebo; Dose 4 of PBI-4547 or matching Placebo tablets by mouth	Other: Placebo; Placebo tablet; Drug: PBI-4547; PBI-4547 tablet
EXPERIMENTAL: Cohort 5, Dose 5 of PBI-4547 or Placebo; Dose 5 of PBI-4547 or matching Placebo tablets by mouth	Other: Placebo; Placebo tablet; Drug: PBI-4547; PBI-4547 tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-emergent adverse events (TEAEs)	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.	5-6 days
Number of participants with clinically significant laboratory evaluation findings	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).	5-6 days
Number of participants with clinically significant electrocardiogram (ECG) Findings	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.	5-6 days
Number of participants with clinically significant vital sign findings	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).	5-6 days
Number of participants with physical examination findings	Brief physical examination will be conducted upon admission and at discharge. A complete physical examination will be conducted at screening and follow-up visit.	5-6 days

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Liminal BioSciences Ltd.
• Collaborators: Syneos Health
• Investigators: Study Director: John Moran, MD, Prometic Pharma SMT Ltd.; Principal Investigator: Richard Larouche, MD, Syneos Health

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 5, 2019
• Primary Completion (ACTUAL): October 8, 2019
• Study Completion (ACTUAL): October 8, 2019

Study Registration Dates

• First Submitted: August 22, 2019
• First Submitted That Met QC Criteria: August 22, 2019
• First Posted (ACTUAL): August 28, 2019

Study Record Updates

• Last Update Posted (ACTUAL): December 8, 2020
• Last Update Submitted That Met QC Criteria: December 7, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: PBI-4547-CT-9-01; 180271 (OTHER: Syneos Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No