VIR-2218 and Peginterferon Alfa-2a for Chronic Hepatitis B

Study Description: Up to 50 untreated, adult, male and female subjects with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) with low level viremia and antigenemia (hepatitis B surface antigen (HBsAg)) without cirrhosis will be screened in order to enroll 10 subjects in an open-label, phase 2a, single site (NIH Clinical Center), single arm, proof-of-concept study of a siRNA (VIR-2218) administered as a lead-in followed by combination with peginterferon alfa-2a. The primary endpoint of the study is log decline in quantitative HBsAg (qHBsAg) level. Secondary objectives include safety, functional cure defined as undetectable HBsAg (\<low limit of detection (LLOD) 0.085 IU/ml) and sustained suppression of HBV DNA \[\<lower limit of quantification (LLOQ\]) \<10 IU/ml)\] 24 weeks after discontinuation of all treatment (study week 60), antiviral activity, and to understand immunological changes following reduction/removal of HBsAg and to evaluate novel markers to monitor treatment response. A tertiary objective will be to assess the durability of the primary endpoint at week 120 (84 weeks after stopping treatment). After screening, eligible subjects will undergo a baseline liver biopsy followed by subcutaneous (SC) administration of VIR-2218 every 4 weeks followed by a repeat liver biopsy at week 12. Thereafter, peginterferon alfa-2a 180 ug mcg SC weekly will be initiated in combination with VIR-2218 for 12 weeks followed by peginterferon alfa-2a alone weekly for another 12 weeks. Total treatment duration will be 36 weeks (6 doses of VIR-2218 and 24 doses of peginterferon alfa-2a). Fine needle aspirates of the liver and blood for peripheral blood mononuclear cells (PBMCs) will be collected throughout the study to assess intrahepatic and peripheral immune parameters, respectively. Objectives: Primary Objective 1\. To evaluate the effect of administration of VIR-2218 in combination with peginterferon alfa-2a on qHBsAg levels Secondary Objectives 1. To evaluate the safety and tolerability of VIR-2218 in combination with peginterferon alfa-2a in non-cirrhotic adults with chronic HBV infection 2. To evaluate functional cure following administration of VIR-2218 in combination with peginterferon alfa-2a 3. To evaluate the antiviral activity of VIR-2218 in combination with peginterferon alfa-2a in non-cirrhotic adults with chronic hepatitis B virus (HBV) infection. 4. To evaluate the effects of VIR-2218 in combination with peginterferon alfa-2a on peripheral and intrahepatic immune responses in non-cirrhotic adults with chronic HBV infection 5. To evaluate for the development of antiviral resistance during administration of VIR-2218 in combination with peginterferon alfa-2a Exploratory Objectives 1. To evaluate other markers of HBV infection 2. To evaluate potential biomarkers for host responses to infection and/or to therapy 3. To compare intrahepatic and peripheral immune response obtained by fine needle aspiration (FNA) and PBMC, respectively 4. To assess the durability of the primary endpoint at week 120 (84 weeks after all treatment is discontinued) Endpoints: Primary Endpoint 1\. Decline in log IU/mL quantitative HBsAg level 24 weeks after discontinuation of all treatment (study week 60) Secondary Endpoints 1. Safety 2. Functional cure which is defined as undetectable HBsAg (\<0.085 IU/ml) AND sustained suppression of HBV DNA \[\< LLOQ\], \<10 IU/ml)\] for more than 6 months after discontinuation of all treatment 3. HBV DNA \<10 IU/ml at end of treatment and 6 months off treatment. The response will be reported as HBV DNA \<LLOQ target detected (TD) or target not detected (TND) 4. Changes in innate and adaptive host immune responses to HBV during and after treatment. * Greater natural killer (NK) cell response to the first peginterferon injection (measured as increase in TNFrelated apoptosis-inducing ligand (TRAIL)-expressing natural killer (NK) cell within the first 6 hours after peginterferon injection) in patients in this study compared to historic control * Preferential improvement of HBsAg-specific T cell responses (measured as increase in the frequency of interferon gamma (IFN-g) producing T cells from baseline to week 12, from baseline to week 36 and from baseline to week 84) as compared to HBV core and polymerasespecific T cell responses in the same patients. Tertiary Endpoints 1. HBV RNA, hepatitis B core-related antigen (HBcrAg), HBV DNA by digital droplet polymerase chain reaction (ddPCR) 2. qHBsAg using an ultrasensitive assay with a LLOQ of 0.005 IU/mL 3. Analysis of stool samples for microbiota (16s rRNA gene sequencing), Fibroscan. 4. Exploratory analysis of additional immunological parameters in serum, blood and liver and/or use of additional analysis techniques to further our understanding of changes in immune function during/after treatment. 5. To assess the durability of the primary endpoint at week 120 (84 weeks after all treatment is discontinued)