HEPATITIS B CHRONIC, Hepatitis B Chronic Infection
Conditions
Keywords
hepatitis B, Bepirovirsen, Liver Biopsy
Brief summary
Bepirovirsen Liver Biopsy study is a single centre open label phase II study to examine the antiviral and immunological effects of bepirovirsen in CHB patients both treated and untreated with HBsAg\<1000 IU/ml
Detailed description
HYPOTHESIS AND OBJECTIVES Bepirovirsen, an ASO, has shown 19% Functional Cure rates in a phase 3 clinical trial but its intrahepatic mechanism of action is unclear, possibly through immune mechanisms since animal studies show a significant proportion of Bepirovirsen accumulates in non-parenchymal cells of the liver. Investigating the immunological and virological intrahepatic microenvironment before and during Bepirovirsen therapy will lead to insights into the mechanism of HBsAg loss, and differentiate sustained responders from transient responders. Study Aims 1. Determine the functional cure rate in Chronic Hepatitis B (CHB) patients with qHBsAg ≤1000 IU/ml treated with Bepirovirsen weekly for 24 weeks at the end of the study at 72 weeks and 60 weeks for patients on NA therapy and not on NA therapy respectively 2. Determine the immunological and virological effects of Bepirovirsen in the intrahepatic microenvironment using paired liver biopsies Primary Objective 1. Proportion of patients with functional cure in CHB patients who have qHBsAg ≤1000 IU/ml treated with Bepirovirsen Secondary Objectives 1\. Determine intrahepatic immune cell types and pathways activated by Bepirovirsen
Interventions
DRUGBepirovirsen
Weekly Bepirovirsen treatment for 24 weeks, with loading doses
PROCEDURELiver biopsy
Liver biopsy as previously described
PROCEDUREOptional Liver biopsy
An optional Liver biopsy as previously described
Sponsors
National University Health System, Singapore
A*Star
National University of Singapore
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. At least 21 years of age at the time of signing the informed consent. 2. Documented to be HBsAg positive for ≥ 6 months prior to Screening. 3. Currently receiving stable NA therapy (defined as no changes to their NA regimen from at least 6 months prior to Screening and with no planned changes to the stable regimen over the duration of the study), or not receiving any Hepatitis B treatment for at least 6 months, or Hepatitis B treatment naïve. 4. qHBsAg ≤1000 IU/ml 5. Alanine aminotransferase (ALT) ≤2x ULN 6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: * Is a woman of non-childbearing potential * Is a woman of childbearing potential and using a contraceptive method 7. Capable of giving signed informed consent
Exclusion criteria
1. qHBsAg \> 1000 IU/ml 2. Do not consent to participate in the Bepirovirsen Liver Biopsy study 3. Clinically significant abnormalities or clinically significant physical examination findings (e.g. major surgery within 3 months of screening) 4. Past history of or current co-infection with Hepatitis C infection, Human immunodeficiency virus (HIV) or Hepatitis D virus 5. History of or liver cirrhosis as determined by: 1. Fibroscan \> 12kPa 2. Participant's historic record of either/both liver biopsy or liver stiffness measurements in their medical records where their results are Liver biopsy Metavir Score is F4, they will be excluded from the study(If the participant has inconsistent clinical picture of cirrhosis, confirm and discuss eligibility with an investigator) 6. Diagnosed with hepatocellular carcinoma as evidenced by Alpha-fetoprotein concentration ≥200 ng/mL or if the screening alpha fetoprotein concentration is ≥50 ng/mL and \<200 ng/mL, the absence of liver mass must be documented by imaging within 6 months of or at screening. Cases should be discussed with an investigator. 7. History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer). Participants under evaluation for possible malignancy are not eligible. 8. History of vasculitis or presence of symptoms and signs of potential vasculitis, current or history of an autoimmune condition or history/presence of other diseases that may be associated with vasculitis condition 9. History of extrahepatic disorders possibly related to HBV immune conditions 10. Current/History of alcohol or drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance 11. Currently taking, or took within 3 months of screening, any immunosuppressing drugs, other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use. 12. Participants requiring anti-coagulation therapies or anti-platelet agents unless treatment can safely be discontinued throughout duration of Bepirovirsen treatment, by the discretion of the investigator. Occasional use is permitted. 13. The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown). 14. Prior treatment with any oligonucleotide or siRNA within 12 months prior to the first dosing day 15. Prior treatment with Bepirovirsen within 6 months 16. Fridericia's QT correction formula (QTcF) ≥450 msec (if single ECG at screening shows QTcF ≤450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion). 17. Laboratory results as follows: 1. Serum albumin ≤3.5 g/dL 2. Glomerular filtration rate (GFR) ≤60 mL/min/1.73m2 as calculated by the CKD-EPI formula 3. INR \>1.25 4. Platelet count \<140 x 109/L 5. Total bilirubin \>1.25x ULN (For participants with benign unconjugated hyperbilirubinemia with total bilirubin \>1.25x ULN, discussion for inclusion to the study is required with the investigator) 6. Urine albumin to creatinine ratio (uACR) \>0.3 mg/mg (or \>300 mg/g). (In the event of an uACR above this threshold, eligibility may be confirmed by a second measurement. In cases where results are shown as unable to perform (UTP), please check the individual labs and confirm that the participant has urine albumin and/or urine creatinine within normal levels. The investigator should confirm that the participant does not have a history of medical conditions or other risk factors that may affect renal function) 18. History of/sensitivity to Bepirovirsen or components thereof or a history of drug or other allergy that, in the opinion of the investigator, contraindicates their participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional cure rate after 24 weeks of weekly Bepirovirsen therapy at the end of the study at 72 weeks and 60 weeks for participants on NA therapy and not on NA therapy respectively. | 72 weeks | Functional cure defined as HBsAg\<0.05 IU/ml and HBV DNA \<LLOQ 24 weeks off all therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in intrahepatic virology | Up to week 72 | The changes of liver HBsAg, HBcAg, HBV RNA, integration HBV DNA and covalently closed circular DNA (cccDNA) compared to baseline; |
| Changes in Intrahepatic immunology | Up to week 72 | The changes in the liver immune cells compared to baseline |
| Changes in blood biomarkers | Up to week 72 | The changes of serum HBsAg, HBsAb, HBV DNA, HBV RNA, HBcrAg, HBsAg isoforrms, ultrasensitive HBsAg compared to baseline; changes in immune cell phenotypes, blood cytokines compared to baseline |
| Safety measurements including adverse events (AEs) and serious adverse events (SAEs) | Up to week 72 | Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAE) and clinically significant adverse events of interest |
Countries
Singapore
Contacts
CONTACTSeng Gee Prof Lim, Professor
PRINCIPAL_INVESTIGATORSeng Gee Prof Lim, Professor
Division of Gastroenterology & Hepatology, National University Hospital (NUH)
Outcome results
None listed