A Phase 1 Double-Blinded Study for Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of ATI-2173 in Healthy Subjects and Subjects With Chronic Hepatitis B Virus Infection

Antios Therapeutics, Inc88 enrolled

Overview

This is a double-blinded, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics, and antiviral activity in both healthy volunteers and volunteers with chronic hepatitis B virus infection. Healthy volunteers will be administered either a single oral dose or multiple oral doses of ATI-2173 and assessed for safety and tolerability including blood tests to show how the body metabolizes and eliminates the investigational drug. Volunteers with a diagnosis of chronic hepatitis B virus infection will be administered multiple oral doses of ATI-2173 and assessed for safety and tolerability including blood tests to show how the body metabolizes and eliminates the investigational drug as well as how the drug effects the virus infection.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Hepatitis B, Chronic

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: All subjects: 1. Provision of signed and dated informed consent form (ICF) 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. If female, meets 1 of the following criteria: 1. Is of childbearing potential and agrees to use an accepted contraceptive method. Acceptable method of contraception include: * Abstinence from heterosexual intercourse from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer * Male partner vasectomized at least 6 months prior to the first study drug administration * Use a systemic contraceptive or an intrauterine device (with or without hormones), from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer, with a male condom or a diaphragm/cervical cap plus spermicide, from the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer Or 2. Male partner has had a vasectomy less than 6 months prior to dosing, and agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer Or 3. Is of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (i.e. at least 1 year without menses without an alternative medical condition prior to the first study drug administration and follicle-stimulating hormone levels ≥ 40 mIU/mL at screening) 4. If male, meets 1 of the following criteria: 1. Is able to procreate and agrees to use 1 of the accepted contraceptive regimens and not to donate sperm from the first study drug administration to at least 90 days after the last drug administration. An acceptable method of contraception includes 1 of the following: * Abstinence from heterosexual intercourse * Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository) or 2. Is unable to procreate; defined as surgically sterile (i.e. has undergone a vasectomy at least 180 days prior to the first study drug administration) 5. Light-, non- or ex-smoker (A light-smoker is defined as someone using 10.0 nicotine units or less per day for at least 90 days prior to the first study drug administration. An ex smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration) 6. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by an investigator 7. Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an investigator Healthy subjects (Phase 1a): 8. Male or female, aged at least 18 years but not older than 55 years 9. Body mass index (BMI) within 18.0 kg/m2 to 32.0 kg/m2, inclusive HBV-infected subjects (Phase 1b): 10. Male or female, aged at least 18 years but not older than 65 years 11. BMI within 18.0 kg/m2 to 35.0 kg/m2, inclusive 12. Serum HBsAg positive at screening and at least 6 months prior to screening 13. Serum HBeAg positive and HBV DNA ≥ 20,000 IU/mL, or serum HBeAg negative and HBV DNA ≥ 2,000 IU /mL at screening 14. ALT and AST \<5 times the upper limit of normal (ULN) at screening and prior to the first study drug administration Exclusion Criteria: All subjects: 1. Female who is lactating at screening 2. Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration 3. History of significant hypersensitivity to clevudine or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs 4. History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease 5. Presence of clinically significant muscle disorders, myopathies or other forms of liver disease 6. Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment 7. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration 8. Any history of tuberculosis 9. Inclusion in a previous cohort for this clinical study 10. Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration 11. Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoid is acceptable) 12. Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration 13. Donation of 500 mL or more of blood in the 56 days prior to the first study drug administration Healthy subjects (Phase 1a): 14. Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 15. Any clinically significant illness in the 28 days prior to the first study drug administration 16. Presence or history of clinically significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability 17. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus tests 18. Use of any prescription drugs including amiodarone (with the exception of hormone replacement therapy) in the 28 days prior to the first study drug administration, that in the opinion of an investigator would put into question the status of the participant as healthy HBV-infected subjects (Phase 1b): 19. Significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 20. Use of amiodarone in the 28 days prior to the first study drug administration 21. Presence or history of clinically significant gastrointestinal or kidney disease, or surgery that may affect drug bioavailability 22. Cirrhosis of the liver as determined by one of the following: * A score greater than F2 for liver fibrosis by FibroScan or FibroSure test within 6 months prior to screening or at the time of screening OR * A score greater than F2 on liver biopsy within 12 months prior to screening or at the time of screening 23. Medical history or known presence of hepatocellular carcinoma 24. Previous treatment for hepatitis B virus, including nucleoside therapy 25. Acute infection or any other clinically significant illness within 14 days of randomization 26. History of organ transplantation 27. Uncontrolled hypertension 28. Positive screening results to HIV Ag/Ab combo, hepatitis C virus or hepatitis D virus tests

Locations (3)

Altasciences

Montreal, Quebec, Canada

Republican Clinical Hospital "Timofei Mosneaga" Arensia EM Unit

Chisinau, Republic of Moldova, Moldova

Medical Center of Limited Liability Company "Harmoniya krasy" Department of Clinical Trials

Kyiv, Ukraine

Outcomes

Primary Outcomes

The percentage of subjects who experienced at least 1 treatment-emergent adverse event (TEAE)

Time frame: Through study completion, an average of 1 year

The percentage of subjects who experienced at least one treatment emergent serious AE (SAE).

Time frame: Through study completion, an average of 1 year

Percentage of subjects who experienced a treatment-emergent dose limiting toxicity (DLT)

Time frame: Through study completion, an average of 1 year

Percentage of subjects who experienced at least one treatment emergent Grade 1, 2, 3, 4 or 5 laboratory abnormality

Time frame: Through study completion, an average of 1 year

Percentage of subjects who discontinued study drug due to a TEAE

Time frame: Through study completion, an average of 1 year

Secondary Outcomes

Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Food effect on Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Time of maximum observed plasma concentration (Tmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Food Effect on Time of maximum observed plasma concentration (Tmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Time of maximum observed plasma concentration (Tmax) of ATI-2173 and clevudine in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Time of maximum observed plasma concentration (Tmax) of ATI-2173 and clevudine in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Area under plasma concentration time curve (AUC) of ATI-2173 and clevudine in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Food Effect on Area under the concentration time curve (AUC0-t) from time 0 (dose administration) to the time of last quantifiable concentration (TLQC) of ATI-2173 and clevudine

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Food Effect on Area under the concentration time curve (AUC0-inf) extrapolated to infinity, calculated as AUC0-t + CLQC/λZ, where CLQC is the measured concentration at time TLQC in ATI-2173 and clevudine

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Area under the concentration time curve from time 0 (dose administration) to 24 hours (AUC0-24) in ATI-2173 and clevudine in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Area under the concentration time curve from time 0 (dose administration) to 24 hours (AUC0-24) in ATI-2173 and clevudine in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Terminal elimination half-life (t1/2) of ATI-2173 in plasma in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, and 120 hours

Terminal elimination half-life (t1/2) of ATI-2173 in plasma in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Terminal elimination half-life (t1/2) of ATI-2173 in plasma in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Trough Peak plasma concentration (Ctrough) of ATI-2173 and clevudine in Multiple Dose Healthy Volunteers

Time frame: Pre-dose on days 3, 5, 7, 10, and 13.

Trough Peak plasma concentration (Ctrough) of ATI-2173 and clevudine in Multiple Dose HBV Infected Patients

Time frame: Pre-dose on days 3, 5, 7, 10, 14 and 21

Minimum observed plasma concentration (Cmin) of ATI-2173 and clevudine in a dosing interval in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Minimum observed plasma concentration (Cmin) of ATI-2173 and clevudine in a dosing interval in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Cumulative amount of drug excreted in urine over all time intervals (Ae) in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96, and 96-120 hours

Cumulative amount of drug excreted in urine over all time intervals (Ae) in Multiple Dose Healthy Volunteers

Time frame: Pre-dose on Day 1, post-dose on Days 1 & 14 at 0-4, 4-8, 8-12, 12-24 hours

Cumulative amount of drug excreted in urine over all time intervals (Ae) in Multiple Dose HBV Infected Patients

Time frame: Pre-dose on Day 1, post-dose on Days 1 & 28 at 0-4, 4-8 and 8-24 hours

Apparent metabolic clearance (mCLr) of clevudine in urine in Single Dose Healthy Volunteers

Time frame: Pre-dose, post-dose at 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96, and 96-120 hours

Apparent metabolic clearance (mCLr) of clevudine in urine in Multiple Dose Healthy Volunteers

Time frame: Pre-dose on Day 1, post-dose on Days 1 & 14 at 0-4, 4-8, 8-12, 12-24 hours

Apparent metabolic clearance (mCLr) of clevudine in urine in Multiple Dose HBV Infected Patients

Time frame: Pre-dose on Day 1, post-dose on Days 1 & 28 at 0-4, 4-8 and 8-24 hours

Accumulation ratio of ATI-2173 and clevudine in plasma (RAC) evaluated by comparing Day 14 (Ph1a) Cmax to Day 1 Cmax in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Accumulation ratio of ATI-2173 and clevudine in plasma (RAC) evaluated by comparing Day 28 (Ph1b) Cmax to Day 1 Cmax in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Accumulation ratio of ATI-2173 and clevudine in plasma (RAC) evaluated by comparing Day 14 (Ph1a) AUCtau to Day 1 AUC0-24 in Multiple Dose Healthy Volunteers

Time frame: Day 1 & Day 14: Pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Day 14 only: post-dose at 48, 72, 144, 216, and 312 hours

Accumulation ratio of ATI-2173 and clevudine in plasma (RAC) evaluated by comparing Day 28 (Ph1b) AUCtau to Day 1 AUC0-24 in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Resistance Mutations in Multiple Dose HBV Infected Patients

To assess the emergence of resistance mutations in HBV-infected subjects. The frequency of targeted mutations may be calculated in each subject.

Time frame: Day -1, Day 1, Day 7, Day 14, Day 21, Day 28, Day 31, Day 37, Day 55, Day 111, Day 195

Maximum observed HBV DNA change (reduction) from baseline through Day 28 (Emax) in Multiple Dose HBV Infected Patients

Time frame: Screening, Day -1, 7, 14, 21, 28

Maximum observed HBV DNA change (reduction) from baseline through end of study (Emax) in Multiple Dose HBV Infected Patients

Time frame: Screening, Day -1, 7, 14, 21, 28, 31, 37, 55, 111, and 195

Time (day) of maximum observed effect through Day 28 (TEmax) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours

Time (day) of maximum observed effect through end of study (TEmax) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours

Area under the effect concentration time curve from time 0 (first dose administration) to Day 28 that is above baseline (AUEC) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours

Area under the effect concentration time curve from time 0 (first dose administration) to end of study (24 weeks post last dose) that is above baseline (AUEC) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Area under the effect concentration time curve from time 0 (first dose administration) to Day 28 that is below baseline (AUEC) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours

Area under the effect concentration time curve from time 0 (first dose administration) to end of study (24 weeks post last dose) that is below baseline (AUEC) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

Area under the effect concentration time curve from time 0 (first dose administration) to Day 28 (AUEC) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours

Area under the effect concentration time curve from time 0 (first dose administration) to end of study (24 weeks post last dose) (AUEC) in Multiple Dose HBV Infected Patients

Time frame: Day 1: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; Day 28: pre-dose, post-dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 144, 216 and 312 hours

ALT/AST Concentration versus Time in Multiple Dose HBV Infected Patients

Time frame: Screening, Day -1, 1, 3, 7, 10, 14, 21, 28, 34, 37, 41, and 55