Safety and Pharmacokinetic Study of ARTS-011 in Chinese Healthy Volunteers

Allorion Therapeutics Inc76 enrolled

Overview

This single- and multiple-ascending dose study is a Phase 1, first in human study of ARTS-011. The goal of the study is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of ARTS-011 after single and multiple oral doses of ARTS-011 in Chinese healthy volunteers.

ARTS-011 is an oral potent Tyrosine kinase 2 (TYK2) inhibitor with a good selectivity profile over other human kinase. TYK2 is required for signal transduction and cellular functions downstream of interferons (IFN), IL-23, and IL-12 which are involved in the initiation and pathogenesis of psoriatic diseases. ARTS-011 is being developed for treatment of moderate-severe psoriasis and other autoimmune diseases.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Chinese Healthy Volunteer

Interventions

ARTS-011DRUG

Single ascending dose (SAD): 3mg, 10mg, 20mg, 40mg, and 60mg. Multiple ascending dose (MAD): 10mg QD, 20mg QD, and 40mg QD X 7 days. Food effect study: single dose of ARTS-011 under the fasting and high-fat meal.

PlaceboDRUG

Multiple ascending dose (MAD): 10mg QD, 20mg QD, and 40mg QD X 7 days. Multiple ascending dose (MAD): 10mg QD, 20mg QD, and 40mg QD X 7 days.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy female and male subjects between the ages of 18 and 55 years. * Body Mass Index (BMI) of 19.0 to 28.0 kg/m2; and a total body weight male ≥50.0 kg, female ≥45.0 kg. * Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. * Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. * No evidence or history of clinically significant abnormalities of , vital signs (body temperature, pulse and blood pressure), laboratory tests (blood hematology and biochemistry, urine and coagulation function), 12-lead ECG and other examinations. * Subjects has no fertility and sperm donation, egg donation plan and takes highly effective contraception during correctly for the duration of the active treatment period and for at least 90 days after the last dose of investigational drugs. Exclusion Criteria: * Evidence or history of clinically significant hematological, renal, endocrine pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). * Any condition possibly affecting drug absorption (eg, gastrectomy). * A positive urine drug screen. * History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males (1 drink = 150 mL) of wine or 360 mL of beer or 45 mL of hard liquor within 3 months of screening. * History of tobacco/nicotine containing products in excess of \>5 cigarettes/day within 3 months of screening. * Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of investigational product, whichever is longer. * 12-lead ECG demonstrating QTc \>450, or a QRS interval \>120 msec at Screening. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTc (or QRS) values should be used to determine the subject's eligibility. * Screening laboratory abnormalities as defined by the protocol. * Unwilling or unable to comply with the Lifestyle Guidelines as defined by the protocol. * Subjected is not appropriate to be enrolled in the study per investigator's assessment.

Locations (1)

Beijing Friendship Hospital, Capital Medical University

Beijing, Beijing Municipality, China

Outcomes

Primary Outcomes

Incidence of Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Discontinuation Due to AEs

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; Initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug up to the end of study that are absent before treatment or that worsened relative to pretreatment state.

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 14, Food Effect Cohort: Baseline up to Day 15

Number of Adverse Events (AEs) according to severity

AEs are classified according to the severity in 3 categories: 1. mild - AEs does not interfere with participant's usual function 2. moderate - AEs interferes to some extent with participant's usual function 3. severe - AEs interferes significantly with participant's usual function

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 14, Food Effect Cohort: Baseline up to Day 15

Number of participants with change from baseline in vital signs (blood pressure, pulse rate, oral temperature)

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 14, Food Effect Cohort: Baseline up to Day 15

Number of participants with change from baseline in 12-Lead Parameters (PR Interval, QRS Complex, QT Interval, QTC Interval)

Electrocardiogram (ECG)

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 14, Food Effect Cohort: Baseline up to Day 15

Number of participants with change from baseline physical examination

Physical examinations included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems.

Data from ClinicalTrials.gov

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Secondary Outcomes

Maximum Observed Plasma Concentration (Cmax) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 1 and Day 7

Time to Reach Maximum Observed Plasma Concentration (Tmax) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 1 and Day 7

Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Dose normalized (dn) Cmax is calculated by dividing Cmax by the exact dose of ARTS-011 (in mg) administered to a participant.

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 1 and Day 7

Area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 1 and Day 7

Plasma Decay Half-Life (t1/2) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 1 and Day 7

Apparent Volume of Distribution (Vz/F) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Volume of distribution 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 7

Apparent Clearance (CL/F) of ARTS-011 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) if data permit

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Clearance obtained after oral dose is influenced by the fraction of the dose absorbed. CL/F =Dose of ARTS-011/AUCinf.

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1; MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 7

Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of ARTS-011 in Single Ascending Dose (SAD)

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1

Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of ARTS-011 in Multiple Ascending Dose (MAD)

Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours for MAD once daily.

Time frame: MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 7

Dose Normalized Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf[dn]) of ARTS-011 in Single Ascending Dose (SAD)

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUCinf(dn) was calculated by dividing AUCinf by the exact dose of ARTS-011 (in mg) administered to a participant.

Time frame: SAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1

Dose Normalized Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau[dn]) of ARTS-011 in Multiple Ascending Dose (MAD)

Area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours for MAD once daily. AUCtau(dn) is calculated by dividing AUCtau by the exact dose of of ARTS-011 (in mg) administered to a participant.

Time frame: MAD: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose on Day 7

Maximum Observed Plasma Concentration (Cmax) of ARTS-011 in Food Effect Cohort