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

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

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.

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