Study to Evaluate the Safety, Tolerability, and Antiviral Activity of Selgantolimod (Formerly GS-9688) in Viremic Adult Participants With Chronic Hepatitis B (CHB) Who Are Not Currently on Treatment

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the safety and tolerability of multiple oral doses of selgantolimod and to evaluate the antiviral activity of selgantolimod in adult participants with chronic hepatitis B (CHB) who are viremic and not currently being treated.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety, Tolerability and Antiviral Activity of GS-9688 in Viremic Adult Subjects With Chronic Hepatitis B Who Are Not Currently on Treatment

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Placebo
* Drug: Selgantolimod
* Drug: TAF


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures. Adult male and non-pregnant, non-lactating females Documented evidence of chronic hepatitis B virus (HBV) infection with detectable hepatitis B surface antigen (HBsAg) levels at screening Screening HBV deoxyribonucleic acid (DNA) ≥ 2000 international units per milliliter (IU/mL). Screening electrocardiogram (ECG) without clinically significant abnormalities Key Exclusion Criteria: Extensive bridging fibrosis or cirrhosis Received a commercially available HBV OAV treatment(s) within the 3 months prior to screening. Received prolonged therapy with immunomodulators or biologics within 3 months of screening Individuals meeting any of the following laboratory parameters at screening: Alanine aminotransferase > 5 * upper limit of normal (ULN) International normalized ratio > ULN unless the individual is stable on an anticoagulant regimen Albumin < 3.5 g/dL Direct bilirubin >1.5x ULN Platelet Count < 100,000/µL Estimated creatinine clearance < 60 mL/min (using the Cockcroft-Gault method) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus or hepatitis D virus Prior history of hepatocellular carcinoma or screening alpha-fetoprotein ≥ 50 ng/mL without imaging Diagnosis of autoimmune disease, poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease, hemoglobinopathy, retinal disease, or are immunosuppressed. Chronic liver disease of a non-HBV etiology except for non-alcoholic fatty liver disease. Received solid organ or bone marrow transplant. Use of another investigational agent within 90 days of screening, unless allowed by the sponsor. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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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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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selgantolimod 3 mg + TAF<br>Participants with Hepatitis B e antigen (HBeAg)-positive CHB or HBeAg-negative CHB currently not on oral antiviral (OAV) treatment, will receive selgantolimod 3 mg (2 x 1.5 mg tablet) on the same day once weekly for 24 doses along with tenofovir alafenamide (TAF) 25 mg once daily for 24 weeks. After the 24th dose, selgantolimod will be discontinued, and participants will continue to receive TAF until Week 48/early discontinuation (ED). At Week 48, per Principal Investigator's (PI's) discretion, participants can continue in the Treatment Free Follow-Up (TFFU) phase for up to an additional 48 weeks. | Drug: Selgantolimod<br>* Tablet(s) administered orally every 7 days for 24 doses in fasted state<br>* Other names: GS-9688;Drug: TAF<br>* Tablet(s) administered orally once daily with food<br>* Other names: Vemlidy®;|
| Experimental: Selgantolimod 1.5 mg + TAF<br>Participants with HBeAg-positive CHB or HBeAg-negative CHB currently not on OAV treatment, will receive selgantolimod 1.5 mg (1 x 1.5 mg tablet) and placebo (1 tablet) on the same day once weekly for 24 doses along with TAF 25 mg once daily for 24 weeks. After the 24th dose, selgantolimod will be discontinued, and participants will continue to receive TAF until Week 48/ED. At Week 48, per PI's discretion, participants can continue in the TFFU phase for up to an additional 48 weeks. | Drug: Placebo<br>* Tablet(s) administered orally every 7 days for 24 doses in fasted state<br>Drug: Selgantolimod<br>* Tablet(s) administered orally every 7 days for 24 doses in fasted state<br>* Other names: GS-9688;Drug: TAF<br>* Tablet(s) administered orally once daily with food<br>* Other names: Vemlidy®;|
| Placebo Comparator: Placebo + TAF<br>Participants with HBeAg-positive CHB or HBeAg-negative CHB currently not on OAV treatment, will receive 2 tablets of placebo on the same day once weekly for 24 doses along with TAF 25 mg once daily for 24 weeks. After the 24th dose, placebo will be discontinued, and participants will continue to receive TAF until Week 48/ED. At Week 48, per PI's discretion, participants can continue in the TFFU phase for up to an additional 48 weeks. | Drug: Placebo<br>* Tablet(s) administered orally every 7 days for 24 doses in fasted state<br>Drug: TAF<br>* Tablet(s) administered orally once daily with food<br>* Other names: Vemlidy®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With ≥ 1 log10 IU/mL Decline in Serum Quantitative Hepatitis B Surface Antigen (qHBsAg) From Baseline at Week 24 |  | Baseline, Week 24 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE was any unfavorable and unintended sign, symptom, disease, and/or laboratory or physiological observation that may or may not be related to the investigational medicinal product. A TEAE was defined as any AE with an onset date on or after the first dose date and no later than 30 days after permanent discontinuation of selgantolimod/placebo; or any AE leading to premature discontinuation of study drugs. | First dose date up to Week 24 plus 30 days | 
| Percentage of Participants With Treatment-Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of the last dose of study drug plus 30 days for selgantolimod/placebo at Week 24. If the relevant baseline laboratory value was missing, any abnormality of at least Grade 1 observed within the time frame specified above was considered treatment emergent. Clinical laboratory results were graded according to Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities. | First dose date up to Week 24 plus 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With ≥ 1 log10 IU/mL Decline in Serum qHBsAg From Baseline at Week 4 |  | Baseline, Week 4 | 
| Percentage of Participants With ≥ 1 log10 IU/mL Decline in Serum qHBsAg From Baseline at Week 8 |  | Baseline, Week 8 | 
| Percentage of Participants With ≥ 1 log10 IU/mL Decline in Serum qHBsAg From Baseline at Week 12 |  | Baseline, Week 12 | 
| Percentage of Participants With ≥ 1 log10 IU/mL Decline in Serum qHBsAg From Baseline at Week 48 |  | Baseline, Week 48 | 
| Change From Baseline in Serum qHBsAg at Week 4 |  | Baseline, Week 4 | 
| Change From Baseline in Serum qHBsAg at Week 8 |  | Baseline, Week 8 | 
| Change From Baseline in Serum qHBsAg at Week 12 |  | Baseline, Week 12 | 
| Change From Baseline in Serum qHBsAg at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Serum qHBsAg at Week 48 |  | Baseline, Week 48 | 
| Percentage of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < Lower Limit of Quantification (LLOQ) at Week 12 | LLOQ was defined as 20 IU/mL. | Week 12 | 
| Percentage of Participants With HBV DNA < LLOQ at Week 24 | LLOQ was defined as 20 IU/mL. | Week 24 | 
| Percentage of Participants With HBV DNA < LLOQ at Week 48 | LLOQ was defined as 20 IU/mL. | Week 48 | 
| Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 12 | HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a postbaseline visit. | Week 12 | 
| Percentage of Participants With HBsAg Loss at Week 24 | HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a postbaseline visit. | Week 24 | 
| Percentage of Participants With HBsAg Loss at Week 48 | HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a postbaseline visit. | Week 48 | 
| Percentage of Participants With HBeAg Loss and Seroconversion at Week 12 | HBeAg loss was defined as qualitative HBeAg changing from positive at baseline to negative at a postbaseline visit. HBeAg seroconversion was defined as Hepatitis B e antibody (HBeAb) loss and anti-HBe change from negative/missing at baseline to positive at a postbaseline visit. | Week 12 | 
| Percentage of Participants With HBeAg Loss and Seroconversion at Week 24 | HBeAg loss was defined as qualitative HBeAg changing from positive at baseline to negative at a postbaseline visit. HBeAg seroconversion was defined as HBeAb loss and anti-HBe change from negative/missing at baseline to positive at a postbaseline visit. | Week 24 | 
| Percentage of Participants With HBeAg Loss and Seroconversion at Week 48 | HBeAg loss was defined as qualitative HBeAg changing from positive at baseline to negative at a postbaseline visit. HBeAg seroconversion was defined as HBeAb test changing from negative or missing at baseline to positive at a postbaseline visit. | Week 48 | 
| Percentage of Participants With Virologic Breakthrough From Baseline up to Week 24 | Virologic breakthrough was defined as confirmed HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL or confirmed HBV DNA ≥ 1 log10 IU/mL increase from nadir. | Baseline up to Week 24 | 
| Percentage of Participants With Virologic Breakthrough From Baseline up to Week 48 | Virologic breakthrough was defined as confirmed HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL or confirmed HBV DNA ≥ 1 log10 IU/mL increase from nadir. | Baseline up to Week 48 | 
| Percentage of Participants With Drug Resistance Mutations |  | Baseline up to Week 48 | 
| Pharmacokinetic (PK) Parameter: AUClast of Selgantolimod | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 | 
| PK Parameter: AUC0-24 of Selgantolimod | AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hours. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 | 
| PK Parameter: AUCinf of Selgantolimod | AUC0-inf is defined as the concentration of drug over time from time zero to infinity. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 | 
| PK Parameter: Cmax of Selgantolimod | Cmax is defined as the maximum concentration of drug. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 | 
| PK Parameter: Tmax of Selgantolimod | Tmax is defined as the time (observed time point) of Cmax. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 | 
| PK Parameter: CL/F of Selgantolimod | CL/F is defined as the apparent oral clearance following administration of the drug. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 | 
| PK Parameter: t1/2 of Selgantolimod | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose at Day 1 and Week 23 |