A Study of Safety and Efficacy of ATI-2173 in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection and in Subjects With Hepatitis D Virus Coinfection

A Phase 2A Randomized, Double-blinded, Placebo-controlled, Multicenter, Dose Ranging Study of Safety and Efficacy of ATI-2173 in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection and in Subjects With Hepatitis D Virus Coinfection

This is a randomized, double-blinded, placebo-controlled, multi center, dose ranging study of safety and efficacy in both volunteers with chronic hepatitis B virus infection and in volunteers with hepatitis D virus coinfection. Volunteers will be administered multiple oral doses of ATI-2173 and assessed for safety and efficacy 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 one of the following criteria:

   1. Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include:

      • Abstinence from heterosexual intercourse from the first study drug administration through to at least 6 months after the last dose of the study drug or until completion of the study, whichever is longer
      • 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 6 months 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
      • Male partner vasectomized at least 6 months prior to the first study drug administration OR

   2. Male partner has had a vasectomy less than 6 months prior to dosing, and the female subject agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 6 months 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 (ie, has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (ie, at least 1 year without menses without an alternative medical condition prior to the first study drug administration and follicle-stimulating hormone [FSH] levels within the normal ranges for postmenopausal state of the clinical site at screening)

4. If male, meets one of the following criteria:

   1. Is able to procreate and agrees to use one 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. Only for Cohort D: male subjects able to procreate must agree to use an accepted contraceptive regimen and not to donate sperm from the first study drug administration to at least 6 months after the last drug administration. An acceptable method of contraception includes one 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 (ie, has undergone a vasectomy at least 6 months prior to the first study drug administration)

5. Male or female aged at least 18 years but not older than 70 years

6. Body mass index (BMI) within 18.0 kg/m2 to 35.0 kg/m2, inclusively

7. 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 [refer to APPENDIX 7 for conversions of nicotine usage]. An ex-smoker is defined as someone who completely stopped using nicotine products for at least 6 months prior to the first study drug administration)

8. Serum HBsAg positive at screening and at least 6 months prior to screening

9. For Cohorts A, B and E only, serum HBeAg positive and HBV DNA ≥ 20,000 IU/mL, or serum HBeAg negative and HBV DNA ≥ 2,000 IU/mL at screening

10. ALT and AST < 5 times the upper limit of normal (ULN) at screening and on the day prior to the first study drug administration (Day -1)

    SUBJECTS COINFECTED WITH CHRONIC HBV AND HDV ONLY:

11. HDV RNA in serum ≥ 500 IU/mL at screening and evidence of HDV infection (HDVAb or HDV RNA) at least 6 months prior to screening

    SUBJECTS IN COHORT D ONLY:

12. Serum HBsAg levels ≥ 100 IU/mL at screening

Exclusion Criteria:

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, tenofovir disoproxil fumarate or any related products (including excipients of ATI-2173, tenofovir disoproxil fumarate, and the placebo) 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 any clinically significant disease, as captured in the medical history or evidence of findings on the physical examination, vital sign assessment and/or ECG assessment, and that would otherwise exclude subject from eligibility in the context of all other listed inclusion and exclusion criteria, as determined by an Investigator

7. Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment

8. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration

9. Any history of tuberculosis

10. Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoids is acceptable)

11. Significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)

12. Use of amiodarone in the 28 days prior to the first study drug administration

13. Presence or history of clinically significant gastrointestinal or kidney disease, or surgery that may affect drug bioavailability

14. Cirrhosis of the liver as determined by one of the following:

    • A score greater than F2 (or greater than F3 for HBV/HDV coinfected subjects) 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 (or greater than F3 for HBV/HDV coinfected subjects) on liver biopsy within 12 months prior to screening or at the time of screening

15. History of or known presence of hepatocellular carcinoma

16. Acute infection or any other clinically significant illness within 14 days of Day 1 of the study

17. History of organ transplantation

18. Presence of uncontrolled hypertension

19. Positive screening results to HIV Ag/Ab combo or hepatitis C virus tests

20. Any other clinically significant abnormalities in laboratory test results at screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data

21. Inclusion in another cohort for this clinical study

22. Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration

23. Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration

24. Donation of 500 mL or more of blood in the 56 days prior to the first study drug administration

25. Previous approved or investigational treatment for HBV or HDV, including nucleoside therapy, other than treatment by tenofovir or interferon alpha. Prior treatment with tenofovir or interferon alpha must have been discontinued at least 6 months prior to Screening.

    SUBJECTS WITH CHRONIC HBV (COHORTS A, B, AND D):

26. Positive screening results to HDV tests

    SUBJECTS IN COHORT D ONLY:

27. History of significant hypersensitivity to excipients of AB-729, any siRNAs, or antisense oligonucleotides (ASOs)