Study of PBI-0451 in Healthy Subjects.

Pardes Biosciences, Inc.130 enrolled

Overview

This is a phase 1, placebo-controlled, blinded, randomized, dose escalation study of PBI-0451 in healthy subjects. PBI-0451 is a new chemical entity and inhibitor of the main protease of coronaviruses, including the SARS-CoV-2 that causes COVID-19 disease. The study is designed to evaluate the safety, tolerability and pharmacokinetics of PBI-0451 after single and multiple ascending doses and also to explore drug-drug interaction potential of PBI-0451.

Combined Three part, double blind, (sponsor open) study. Part 1: Single ascending dose study. Part 2: Multiple ascending dose study. Part 3: Drug-drug interaction study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

130

Conditions

Covid19

Interventions

PBI-0451 Dose 1DRUG

Dose level 1 of PBI-0451

PBI-0451 Dose 2DRUG

Dose level 2 of PBI-0451

PBI-0451 Dose 3DRUG

Dose level 3 of PBI-0451

PBI-0451 Dose 4

Eligibility

Sex: ALLMin age: 18 YearsMax age: 59 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Non-smoking, healthy male or female subjects aged 18-59 years. 2. Body Mass Index (BMI) of ≥ 19.0 and ≤ 30.0 kg/m2. 3. 12-Lead electrocardiogram (ECG) evaluation without clinically significant abnormalities. 4. Normal renal function, including having a creatinine clearance (CLcr) ≥90mL/min 5. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception. 6. Screening laboratory assessments must be without clinically significant abnormalities as assessed by the investigator. Exclusion Criteria: 1. Pregnant and lactating females 2. Have received any investigational drug (or vaccine) within the last 30 days prior to study dosing. 3. Have a positive test result for HIV or HBsAg. 4. Have poor venous access that limits phlebotomy 5. Have taken any prescription medications or over-the-counter medications, including herbal products and dietary supplements within 28 days prior to start of study. 6. Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to Screening or is expected to receive these agents during the study. 7. Have a history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. 8. Have a history of significant drug sensitivity, cardiac disease, syncope, palpitations, or unexplained dizziness, implanted defibrillator or pacemaker, liver disease, severe peptic ulcer disease, gastroesophageal reflux disease and a medical or surgical treatment that permanently altered gastric absorption. 9. Have received inactivated vaccinations within 4 weeks prior to randomization or receive live vaccinations within 4 weeks of Screening. 10. Received the COVID-19 vaccine either within 7 days or have not completed the series of required 2 doses. 11. Have a history of excessive alcohol use or other illicit drug use within 6 months of screening.

Locations (1)

Auckland City Hospital

Auckland, New Zealand

Outcomes

Primary Outcomes

Number of subjects with treatment emergent adverse events (TEAEs) in Single Ascending Dose (SAD) compared to placebo

An adverse event is any untoward medical occurrence in patient or clinical study participant temporarily associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) is defined as any untoward medical occurrence at any dose that results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; results in congenital anomaly/birth defect. AEs include both SAEs and AEs. TAEs are AEs that occur following the start of treatment or AEs increasing in severity during treatment.

Time frame: Day 1- Day 14 (From start of study medication till 14 days of last administration of study drug)

Number of subjects with clinically significant change from Baseline in vital signs in SAD

Vital signs include blood pressure, heart rate, respiratory rate, and temperature

Time frame: Day 1-Day 14 (From start of study medication till 14 days of last administration of study drug)

Number of patients with laboratory abnormalities in SAD

Hematology and serum chemistry

Time frame: Day 1-Day 14 (From start of study medication till 14 days of last administration of study drug)

Number of subjects with treatment emergent adverse events (TEAEs) in Multiple Ascending Dose (MAD) compared to placebo

Data from ClinicalTrials.gov

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Secondary Outcomes

To collect ECG data for PBI-0451 for the purpose of concentration-QT/QTc modeling

Criteria for clinically significant changes in ECG (12 lead) are defined as: a postdose QTc interval increase by =/\>30msec from the baseline and is \>450 msec; or an absolute QTc value is =/\> 500 msec for any scheduled ECG.

Time frame: Day 1, 4, 6 and 11

Plasma concentration of each dose of study drug to determine AUCinf in SAD

AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 to extrapolated infinite time.

Time frame: Day 1-Day 6

Plasma concentration of each dose of study drug to determine AUClast in SAD

AUClast is summarized by dosing regimen and determined by linear/log trapezoidal method.

Time frame: Day 1-Day 6

Plasma concentration of each dose of study drug to determine %AUCexp in SAD

%AUCexp is summarized by dosing regimen and expressed as area under the plasma concentration-time curve extrapolated from time (tau) to infinity as a percentage of total AUC

Time frame: Day 1-Day 6

Plasma concentration of each dose of study drug to determine CL/F in SAD

CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological process

Time frame: Day 1-Day 6

Plasma concentration of each dose of study drug to determine CLss/F in MAD

CLss/F is the total body clearance for extravascular administration divided by the fraction of dose absorbed

Time frame: Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine AUCtau in MAD

Area under the plasma concentration- Time profile from Time zero to end of dosing interval. AUCtau is summarized by dosing regimen and period.

Time frame: Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine Cmax in MAD

Observed Cmax is estimated based on the plasma concentrations.

Time frame: Day 4, Day 6, Day 8 (Pre dose to 24 hours)

Plasma concentration of each dose of study drug to determine Tmax in MAD

Tmax is summarized by dosing regimen

Time frame: Day 4, Day 6, Day 8 (Pre dose to 24 hours)

Plasma concentration of each dose of study drug to determine Tlast in MAD

Tlast is the time of last measurable concentration

Time frame: Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine Clast in MAD

Clast is the last measurable concentration (above the quantification limit)

Time frame: Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine Ctau in MAD

Ctau is the concentration at the end of dosing interval

Time frame: Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine λz in MAD

Individual estimate of terminal elimination rate constant, calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.

Time frame: Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine t1/2

t1/2 is summarized by dosing regimen . It is determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline is used in the regression.

Time frame: Day 1(0 hours- 24 hours post dose), Day 4, Day 6, Day 8

Plasma concentration of each dose of study drug to determine Vz/F

Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. VZ/F after oral dose is influenced by the fraction absorbed.

Time frame: Day 4, Day 6, Day 8