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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: ATI-2173
* Drug: ATI-2173 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects: 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 1 of the following criteria: 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 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 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) If male, meets 1 of the following criteria: 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 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) 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) 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 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): Male or female, aged at least 18 years but not older than 55 years Body mass index (BMI) within 18.0 kg/m2 to 32.0 kg/m2, inclusive HBV-infected subjects (Phase 1b): Male or female, aged at least 18 years but not older than 65 years BMI within 18.0 kg/m2 to 35.0 kg/m2, inclusive 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 prior to the first study drug administration Exclusion Criteria: All subjects: 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 or any related products (including excipients of the formulations) 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 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 Inclusion in a previous cohort for this clinical study Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoid is acceptable) 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 Healthy subjects (Phase 1a): 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) Any clinically significant illness in the 28 days prior to the first study drug administration Presence or history of clinically significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus tests 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): 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 Medical history or known presence of hepatocellular carcinoma Previous treatment for hepatitis B virus, including nucleoside therapy Acute infection or any other clinically significant illness within 14 days of randomization History of organ transplantation Uncontrolled hypertension Positive screening results to HIV Ag/Ab combo, hepatitis C virus or hepatitis D virus tests

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATI-2173<br> | Drug: ATI-2173<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>|
| Placebo Comparator: ATI-2173 Placebo<br> | Drug: ATI-2173 Placebo<br>* ATI-2173 Placebo is used as an inactive comparator to ATI-2173. It will be dosed as a capsule by mouth.<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 one treatment emergent serious AE (SAE). |  | Through study completion, an average of 1 year | 
| Percentage of subjects who experienced a treatment-emergent dose limiting toxicity (DLT) |  | 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 |  | Through study completion, an average of 1 year | 
| Percentage of subjects who discontinued study drug due to a TEAE |  | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) of ATI-2173 and clevudine in Single Dose Healthy Volunteers |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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. | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | Screening, Day -1, 1, 3, 7, 10, 14, 21, 28, 34, 37, 41, and 55 |