A Study Evaluating the Safety, Pharmacokinetics, and Antiviral Efficacy of SB 9200 in Subjects Infected With Chronic HBV

Hepatitis B, Hepatitis, Viral

Chronic Hepatitis, HBV, Double blind

This is a Phase 2, open-label,randomized, multiple dose, varied administration regimen study with 2 parts (Parts A and B) in Subjects Infected with Chronic Hepatitis B Virus

This is a Phase 2, open-label, randomized, multiple dose, varied administration regimen study with 2 parts (Parts A and B). Part A will utilize an ascending dose cohort design with sequential cohorts. Each cohort will be evaluated by the DSMB for safety. Additional cohorts may be added by the DSMB to determine doses of SB 9200 that exhibit significant antiviral response and safety. Approximately 80 subjects will be assigned sequentially to 1 of the following dosing cohorts (20 subjects per cohort) and randomized in a 4:1 ratio (active:placebo) within each cohort. Randomization will be stratified so that no more than 2 HBeAg positive subjects will be assigned to receive placebo. * SB 9200 25 mg or matching placebo administered qd * SB 9200 50 mg or matching placebo administered qd * SB 9200 100 mg or matching placebo administered qd * SB 9200 200 mg or matching placebo administered qd After informed consent is obtained, subjects will enter a Screening period, which will last up to 28 days. Once all eligibility criteria are confirmed and the subject is randomized, subjects will receive the IP or placebo as a 2-week supply of capsules/tablets. All randomized subjects will receive the IP or matching placebo for a total of 12 weeks. All subjects will then receive tenofovir 300 mg qd for an additional 12 weeks of treatment. Subjects will start the treatment period on Day 1. The PK samples will be collected on Day 1 at predose, 30 minutes, 1, 2, 4, 6, and 24 hours (predose the following day). At Week 6, the same sampling times will be used to collect PK samples from the subjects to collect steady state PK data. Subjects will return biweekly for the entire 12-week IP treatment period, except when beginning IP administration when subjects will be seen weekly, for safety assessments including physical examination and laboratory sample analysis of chemistry, hematology, and urine. Sample collection for efficacy (HBV DNA, HBsAg, HBeAg, hepatitis B envelope antibody \[HBeAb\], HBV RNA, and HBV resistance) will be collected as indicated in the Schedule of Events. A sample for genotyping will be collected at Day 1. Samples for Locarnini biomarkers and other biomarkers will also occur at Day 1; Weeks 2, 4, 8, 12, and 14; and at the End of Study Visit. Samples for cytokine levels will be collected at Day 1, Week 6, and Week 12. At Week 12, the end of IP administration, all subjects will return to the clinic and be administered IP and 300 mg tenofovir. Samples will be collected to explore the potential of a drug-drug interaction between SB 9200 and tenofovir. All subjects will have a predose PK sample then take the last dose of IP/placebo together with their first dose of tenofovir. The PK samples will then be collected for SB 9200 and tenofovir at 30 minutes,and 1, 2, 4, 6, and 24 hours. Thereafter, the subjects will receive only tenofovir 300 mg qd for an additional 12 weeks as 4-week supplies. All subjects will return to the clinic at Weeks 13, 14, 16, 20, and 24. Subjects will have safety assessments including symptom-directed physical examinations and safety hematology, biochemistry, and virological studies performed at these visits. At Week 24, all subjects will have completed the study Part A (or Part B, as applicable). Part B will be an open-label, randomized, combination therapy design consisting of multiple cohorts. The study is designed to evaluate the safety, tolerability, and antiviral response in subjects treated for 12 weeks with a dose of SB 9200 selected from Part A that exhibits significant antiviral response and safety when administered in combination with tenofovir 300 mg qd (Cohort 1) or with tenofovir 300 mg qd monotherapy alone (Cohort 2). All subjects will then continue in the study for an additional 12 weeks with tenofovir alone. Randomization between the 2 initial cohorts will be conducted using a 3:1 ratio resulting in 30 subjects being allocated to SB 9200 in combination with tenofovir (Cohort 1) and 10 subjects being allocated to tenofovir monotherapy (Cohort 2). No cohort can enroll more than 60% of either hepatitis e antigen negative or hepatitis e antigen positive subjects. Part B will utilize an adaptive design. The first 2 cohorts of Part B may start concurrently to Part A at any time after a dose has been selected from Part A. SB 9200 doses for which all subjects have not completed the initial 12 weeks monotherapy of SB 9200 from Part A and demonstrated safety of IP will not be selected to be administered in combination with tenofovir during Part B. The first 2 cohorts will randomize concurrently using a 3:1 ratio. * Cohort 1: 30 subjects will receive SB 9200 selected dose #1 from Part A administered in combination with tenofovir 300 mg qd. * Cohort 2: 10 subjects will receive tenofovir 300 mg qd monotherapy. Based on the results of Part A completed and ongoing cohorts and Part B first cohort, up to 2 additional cohorts for which the dose of SB 9200 will be either escalated or de-escalated may be opened to enrollment: * Cohort 3: 30 subjects will receive SB 9200 selected dose #2 from Part A administered in combination with tenofovir 300 mg qd. * Cohort 4: 30 subjects will receive SB 9200 selected dose #3 from Part A administered in combination with tenofovir 300 mg qd. Subjects will be enrolled into the Screening period, which will last up to 28 days. Once all eligibility criteria are confirmed, subjects will receive the IP as a 2-week supply of capsules/tablets and tenofovir as a 4-week supply. Subjects will be required to take the IP per protocol for 12 weeks. Subjects will return biweekly for the entire 12-week IP treatment period, except when beginning IP administration when subjects will be seen weekly, for safety assessments including physical examination and laboratory sample analysis of chemistry, hematology, and urine. Samples for Locarnini biomarkers will also occur at Day 1; Weeks 2, 4, 6, 12, and 14; and at the End of Study Visit. Sample collection for cytokine levels and other biomarkers of immune response and plasma samples will also occur at predose on Day 1 and at Weeks 6,12 and 24. The PK samples will be collected on Day 1 at predose, 30 minutes, and 1, 2, 4, 6, and 24 hours (predose the following day). At Week 12, the same sampling times will be used to collect PK samples from the subjects to collect steady state PK data. Sample collection for population PK analysis will also be collected before IP administration at Weeks 4 and 8. Urinary PK will be collected on Day 1 and Week 12 predose, 6 hours, and 24 hours (predose the following day). At Week 12, all subjects will be administered tenofovir 300 mg qd for an additional 12 weeks as 4-week supplies. All subjects will return to the clinic at Weeks 13, 14, 16, 20, and 24. Subjects will have safety assessments including symptom-directed physical examinations and safety hematology, biochemistry, and virological studies performed at these visits. Safety reporting for each subject in each cohort will continue after the subject first consents to participate in the study through the 24 week duration of the study or through the Extension Period until 30 days after the last dose is administered. At Week 24, all subjects will have completed the study Part A (or Part B, as applicable). Extension Period: Any subject who completes Part A or Part B may be eligible to take part in a 12-month Extension Period. Before any study-related procedures are performed, the subjects will have all study procedures explained to them, including information regarding the nature of the study, and subjects must sign an informed consent/assent form. During the Extension Period, subjects will receive tenofovir and return for visits every 3 months with laboratory tests of liver function and virological efficacy including HBsAg, HBeAg, HBeAb, and HBV DNA. No further study-related testing will be performed. Subjects who undergo full termination from the study during Part A or Part B will not be eligible to enroll into the extension study. Safety reporting for each subject in each cohort will continue after the subject first consents to participate in the study through the 24-week duration of the study or through the Extension Period until 30 days after the last dose is administered.

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