Single Ascending Dose Study of PBI-4547 in Healthy Subjects

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

Detailed Description
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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.

Official Title
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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

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: PBI-4547
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Dose 1 of PBI-4547 or Placebo<br>Dose 1 of PBI-4547 or matching Placebo tablets by mouth | Drug: PBI-4547<br>* PBI-4547 tablet<br>Other: Placebo<br>* Placebo tablet<br>|
| Experimental: Cohort 2, Dose 2 of PBI-4547 or Placebo<br>Dose 2 of PBI-4547 or matching Placebo tablets by mouth | Drug: PBI-4547<br>* PBI-4547 tablet<br>Other: Placebo<br>* Placebo tablet<br>|
| Experimental: Cohort 3, Dose 3 of PBI-4547 or Placebo<br>Dose 3 of PBI-4547 or matching Placebo tablets by mouth | Drug: PBI-4547<br>* PBI-4547 tablet<br>Other: Placebo<br>* Placebo tablet<br>|
| Experimental: Cohort 4, Dose 4 of PBI-4547 or Placebo<br>Dose 4 of PBI-4547 or matching Placebo tablets by mouth | Drug: PBI-4547<br>* PBI-4547 tablet<br>Other: Placebo<br>* Placebo tablet<br>|
| Experimental: Cohort 5, Dose 5 of PBI-4547 or Placebo<br>Dose 5 of PBI-4547 or matching Placebo tablets by mouth | Drug: PBI-4547<br>* PBI-4547 tablet<br>Other: Placebo<br>* Placebo tablet<br>|

What is the study measuring?
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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 |