Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy.

BACKGROUND & AIMS: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection. METHODS: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/ml reduction from baseline) rate, safety and pharmacokinetics. RESULTS: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours. CONCLUSIONS: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified. CLINICAL TRIAL NUMBER: NCT03020745. LAY SUMMARY: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.

HBV/A and HBV/C genotype predominance among patients with chronic hepatitis B virus infection in Cebu City, Philippines.

CONTEXT: Chronic Hepatitis B virus (HBV) infection causes significant morbidity and mortality with widespread global distribution. Different genotypes display variations in pathogenesis, disease behavior, and treatment response. HBV/B and HBV/C are prevalent in Asia, but minimal data come from the Philippines. OBJECTIVE: This study is aimed to determine the HBV genotypes of Filipino patients with Chronic HBV infection seen in Cebu City, Philippines and describe the age, sex, viral activity, alanine aminotransferase (ALT) levels and viral load patterns by genotype. STUDY DESIGN: Case series with prospective mode of data collection. STUDY SETTING: Gastroenterology specialty clinics, Cebu City, Philippines. STUDY POPULATION: Patients with Chronic HBV infection seen in 2008. MANEUVERS: Chronic HBV infection was defined as HBsAg(+) for >6 months with persistent/intermittent ALT/aspartate aminotransferase levels (AST) elevations. Hepatitis panel and biochemical tests determined disease activity. Ultrasound documented liver cirrhosis with corresponding hypoalbuminemia and prolonged Prothrombin time. Hepatitis C virus (HCV) co-infection was a reactive anti-HCV test. Hepatocellular carcinoma was diagnosed by ultrasound or computed tomography (CT) scan with alpha-feto protein (AFP) > 500 ng/L. COBAS Taqman HBV Test(®) determined HBV-DNA level. Polymerase chain reaction (PCR) genotyping was done using type-specific primers. RESULTS: This study analyzed data from 50 patients, where 74% were males, and median age was 31 years (IR 25-40 years.). Chronic active hepatitis was seen in 76.6%. Only 18% had ALT levels >2 × ULN. Viral loads >20,000 IU/L were reported in 71% of HBeAg(+) patients. Viral loads >2,000 IU/L were seen in 73% of HBeAg(-) patients. Predominant genotypes identified were HBV/A (28%) and HBV/C (26%). No significant correlation between genotype and age (p = 0.92) and ALT levels (p = 0.58) was determined. Consistently high-DNA titers were reported for 83% of HBV/C patients and for all patients with >1 HBV genotypes. Hepatocelullar carcinoma was noted for one patient with HBV/A. Two patients with liver cirrhosis had HBV/C. LIMITATION: Possible significant associations between genotype and some patient-related parameters could not be determined due to scarcity of subjects. CONCLUSION: HBV/A and HBV/C genotypes are equally predominant among Filipino patients with Chronic HBV infection seen in two specialty clinics in Cebu City, Philippines.

Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir.

UNLABELLED: This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-naïve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-naïve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated. CONCLUSION: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.