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

Study Overview
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Brief Summary
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This is a randomized, double-blinded, placebo-controlled, multi center, dose ranging study of safety and efficacy in volunteers with chronic hepatitis B virus infection. Volunteers will be administered multiple oral doses of ATI-2173 vebicorvir in combination with tenofovir disoproxil fumarate 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.

Official Title
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A Phase 2a Randomized, Double-blinded, Placebo-controlled, Multi Center, Dose Ranging Study of the Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection

Conditions
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Chronic Hepatitis b

Intervention / Treatment
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* Drug: ATI-2173 25mg
* Drug: Vebicorvir 300mg
* Drug: Viread 300Mg Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form (ICF) Stated willingness to comply with all study procedures and availability for the duration of the study If female, meets one of the following criteria: 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 non-hormonal intrauterine device, 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 Use of a double-barrier method Male partner vasectomized at least 6 months prior to the first study drug administration Or 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). If the subject engages in sexual relations, a barrier method (male or female condom) should be used to prevent the spread of HBV. If male, meets one of the following criteria: a) 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. 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 c) Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at least 6 months prior to the first study drug administration). If the subject engages in sexual relations, a barrier method (male or female condom) should be used to prevent the spread of HBV. Male or female aged at least 18 years but not older than 70 years Body mass index (BMI) within 18.0 kg/m2 to 35.0 kg/m2, inclusively 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) Serum HBsAg positive at screening and at least 6 months prior to screening. Serum HBeAg positive and HBV DNA ≥ 20,000 IU/mL, or serum HBeAg negative and HBV DNA ≥ 2,000 IU/mL at screening 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) Exclusion Criteria: Female who is lactating at screening Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration 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 History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease Presence of clinically significant muscle disorders, myopathies or other forms of liver disease 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 Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration Any history of tuberculosis Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoids is acceptable) Significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) Use of amiodarone in the 28 days prior to the first study drug administration Presence or history of clinically significant gastrointestinal or kidney disease, or surgery that may affect drug bioavailability 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 History of or known presence of hepatocellular carcinoma Acute infection or any other clinically significant illness within 14 days of Day 1 of the study History of organ transplantation Presence of uncontrolled hypertension Positive screening results to HIV Ag/Ab combo or hepatitis C virus tests 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 Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration Donation of 500 mL or more of blood in the 56 days prior to the first study drug administration Previous approved or investigational treatment for HBV, 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. Positive screening results to hepatitis D virus (HDV) tests History of significant hypersensitivity to excipients of vebicorvir or its placebo Current or prior use of prohibited concomitant medications as defined in Section 4.5.1. Participation in the ANTT201 study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATI-2173 25mg, Vebicorvir 300mg and Tenofovir 300mg<br>Subjects randomized to active arm will receive active 25mg ATI-2173 + active Vebicorvir 300mg + active Tenofovir 300mg | Drug: ATI-2173 25mg<br>* ATI-2173 is a liver-targeted phosphoramidate prodrug of clevudine designed to enhance anti-HBV activity while decreasing systemic exposure to clevudine. It will be dosed as a capsule by mouth.<br>Drug: Vebicorvir 300mg<br>* Vebicorvir (formerly ABI-H0731) is an orally administered, potent and selective small molecule inhibitor of the HBV core protein<br>Drug: Viread 300Mg Tablet<br>* Viread is a nucleotide analogue reverse transcriptase inhibitor used for chronic hepatitis B virus.<br>|
| Active Comparator: Tenofovir Disoproxil Fumarate<br>Subjects randomized to placebo arm will receive placebo 25mg ATI-2173 + placebo Vebicorvir 300mg + active Tenofovir 300mg | Drug: Viread 300Mg Tablet<br>* Viread is a nucleotide analogue reverse transcriptase inhibitor used for chronic hepatitis B virus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of subjects who experienced at least 1 treatment-emergent adverse event (TEAE) |  | Through study completion, an average of 1 year | 
| The percentage of subjects who experienced at least 1 treatment-emergent serious adverse event (TE SAE) |  | Through study completion, an average of 1 year | 
| The percentage of subjects who experienced a treatment-emergent dose-limiting toxicity (TE DLT) |  | Through study completion, an average of 1 year | 
| The percentage of subjects who experienced at least 1 treatment-emergent Division of AIDS (DAIDS) Grade 1, 2, 3, 4, or 5 laboratory abnormality |  | Through study completion, an average of 1 year | 
| The percentage of subjects who discontinued the study drug due to a TEAE |  | Through study completion, an average of 1 year | 
| Alanine aminotransferase and aspartate aminotransferase levels versus time |  | Through study completion, an average of 1 year | 
| Time to HBV viral load relapse in HBV-infected subjects as measured by HBV DNA viral load in IU/mL |  | Through study completion, an average of 1 year, which is 6 months after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline-adjusted maximal reduction in HBV DNA viral load (Emax,HBV) through 6 months after end of treatment following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects |  | Through study completion, an average of 1 year, which is 6 months after end of treatment | 
| TEmax,HBV through 6 months after end of treatment following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects |  | Through study completion, an average of 1 year, which is 6 months after end of treatment | 
| AUEC(HBV) through 6 months after end of treatment following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects |  | Through study completion, an average of 1 year, which is 6 months after end of treatment | 
| Proportion of subjects with HBV DNA sustained viral response as measured by HBV DNA viral load at 6 months after end of treatment |  | Through study completion, an average of 1 year, which is 6 months after end of treatment | 
| Cmax of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| Tmax of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| Ctrough of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| Ctau of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| AUC0-24 of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| AUCtau of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| t1/2 of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| RAC(Cmax) of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| RAC(AUC) of ATI-2173, clevudine and M1 in plasma |  | Through study completion, an average of 1 year | 
| Proportion of subjects with HBV SVR12, SVR18, and SVR24months |  | Through study completion, an average of 1 year, or through 24 months if applicable | 
| Proportion of subjects with on-treatment ALT flares |  | Through Day 90 | 
| Proportion of subjects with off-treatment ALT flares |  | From Day 90 through end of study, about 6 months | 
| Rate of HBV viral load return to baseline off-treatment |  | From Day 90 through end of study, about 6 months | 
| Relationship between HBV RNA and HBV Sustained Viral Response at 6 months |  | Through study completion, an average of 1 year, which is 6 months after treatment | 
| Change from baseline value in HBV RNA at end of treatment and Sustained Viral Response at 6 months |  | Through study completion, an average of 1 year, 6 months after treatment | 
| Change from baseline in HBsAg over time and Sustained Viral Response at 6 months |  | Through study completion, an average of 1 year, 6 months after treatment | 
| Change from baseline value in HBcrAg at end of treatment and Sustained Viral Response at 6 months |  | Through study completion, an average of 1 year, 6 months after treatment | 
| Relationship between HBV DNA Sustained Viral Response and HBsAg |  | Through study completion, an average of 1 year | 
| Reduction from baseline in HBsAg following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects |  | Through study completion, an average of 1 year | 
| Reduction from baseline in HBV RNA following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects |  | Through study completion, an average of 1 year | 
| Reduction from baseline in HBcrAg following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects |  | Through study completion, an average of 1 year | 
| Cmax of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| Tmax of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| Ctrough of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| Ctau of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| AUC0-24 of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| t1/2 of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| RAC(Cmax) of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| RAC(AUC) of tenofovir in plasma |  | Through study completion, an average of 1 year | 
| Cmax of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| Tmax of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| Ctrough of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| Ctau of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| AUC0-24 of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| t1/2 of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| RAC(Cmax) of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| RAC(AUC) of vebicorvir in plasma |  | Through study completion, an average of 1 year | 
| Correlation between individual tie to viral load relapse and Day 90 clevudine, vebicorvir, and tenofovir Cmin and AUC |  | Through study completion, an average of 1 year | 
| Correlation between SVR6 and Day 90 clevudine, vebicorvir, and tenofovir Cmin and AUC |  | Through study completion, an average of 1 year |