On August 28, GSK announced at the 2020 Digital International Liver Congress (Digital ILC 2020) that its antisense oligonucleotide drug GSK’836 (GSK3228836) achieved positive results in a Phase IIa study involving patients with chronic hepatitis B. Compared with placebo, four weeks of treatment with GSK’836 significantly reduced hepatitis B surface antigen (HBsAg) levels and hepatitis B virus DNA viral load.
This Phase IIa study enrolled 31 patients who were either stable on nucleos(t)ide analogue (NA) therapy or NA-naïve, to evaluate the efficacy of subcutaneous GSK’836 at two dose levels (150 mg and 300 mg) over a 4-week treatment period. Following the last subcutaneous dose, all patients continued standard nucleos(t)ide antiviral therapy (tenofovir or entecavir) for 6 months to assess whether HBsAg levels could be sustained at reduced levels. The primary endpoints included safety and tolerability, while the primary efficacy endpoints comprised changes from baseline in serum HBsAg levels and HBV DNA viral load at Week 4. Additional endpoints included other antiviral and pharmacokinetic parameters.
Data from the 300 mg dose group showed a decline in HBsAg levels in both patients receiving nucleos(t)ide analogue therapy (HBeAg-positive) and those not receiving such therapy (including both HBeAg-positive and HBeAg-negative patients). By Day 29, a total of six patients exhibited a reduction in HBsAg levels of more than 3 log10 IU/mL, with four of these patients achieving HBsAg levels below the lower limit of detection (0.05 IU/mL), which is considered undetectable and may be defined as “functional cure.” Additionally, two patients who achieved “functional cure” maintained undetectable HBsAg levels for an extended period: one patient receiving nucleos(t)ide analogue therapy (from Day 36 to Day 113) and one patient not receiving such therapy (from Day 23 to Day 126). The primary efficacy endpoint data at Week 4 include:
In terms of safety, mild-to-moderate injection site reactions, including erythema, pain, pruritus, swelling, and/or bruising, were observed in 5 out of 17 patients. A sharp increase in ALT levels was observed upon HBsAg clearance, which may reflect the elimination of infected hepatocytes. The elevated ALT levels were asymptomatic and self-resolving. The safety and tolerability profile was acceptable, supporting the administration of a longer treatment duration.
GSK’836 was jointly discovered by GSK and Ionis Pharmaceuticals. In August 2019, GSK entered into multiple licensing collaborations with Ionis for antisense oligonucleotide-based anti-HBV projects, of which GSK’836 is one asset. GSK currently holds full development, regulatory, and commercial rights to GSK’836. Based on these data, GSK decided to continue advancing the Phase IIb studies codenamed B-Clear, B-Fine, and B-Together at multiple sites across Europe, Africa, North America, and Asia by the end of 2020.
Hepatitis B affects approximately 260 million people worldwide, causing 900,000 deaths annually due to liver failure and hepatocellular carcinoma, making it one of the major global public health burdens. Current nucleos(t)ide analogue therapies for hepatitis B can suppress the hepatitis B virus (HBV) but cannot completely eradicate it from the body. This is primarily because, upon entering the host, HBV integrates its genome into the host hepatocyte nucleus, forming covalently closed circular DNA (cccDNA), which then utilizes the host machinery to synthesize mRNA and produce proteins required for viral particle assembly. Existing drugs can only reduce levels of hepatitis B surface antigen (HBsAg) and viral DNA, making it difficult to thoroughly eliminate cccDNA. Furthermore, viral rebound is common after discontinuation of therapy. Therefore, there is an urgent need to develop new therapies capable of achieving a functional cure (undetectable HBsAg levels) and a complete cure (eradication of cccDNA) for hepatitis B.
GSK’836 is an antisense oligonucleotide that specifically recognizes mRNA encoding viral antigens (pathogenic proteins) in HBV-infected hepatocytes. By recruiting the liver’s endogenous enzymatic machinery to inactivate viral mRNA, it suppresses levels of the hepatitis B surface antigen (HBsAg), thereby aiming to achieve a functional cure for chronic hepatitis B.
However, antisense oligonucleotide drugs still only act on viral mRNA to block viral DNA replication at an earlier stage, making it difficult to completely eliminate cccDNA. To achieve the goal of a "complete cure," new drugs with novel mechanisms of action need to be developed. Inhibitors of inhibitor of apoptosis proteins (IAPs) represent a completely new antiviral mechanism; their target is not the hepatitis B virus itself but rather the host cells. By inducing apoptosis in hepatocytes infected with hepatitis B virus, these inhibitors offer the potential to completely clear cccDNA and are thus one of the promising therapies for achieving a complete cure for hepatitis B.
On August 27, Ascentage Pharma also presented clinical data on its IAP inhibitor APG-1387 at the Digital ILC 2020 conference. The preclinical findings reported in this oral presentation demonstrated that, compared with the control group, 4–20 weeks of treatment with APG-1387 in three different chronic hepatitis B mouse models completely cleared serum HBsAg, HBeAg, and hepatitis B virus (HBV) DNA, as well as hepatic HBcAg and HBV replication intermediates from infected liver tissue, without rebound after cessation of therapy. Further investigations revealed that HBV clearance was likely associated with upregulated frequency and function of intrahepatic HBV-specific CD4+ and CD8+ T cells. Moreover, TNFα knockout or deficiency in CD4+ or CD8+ T cells completely abrogated the HBV-clearing effects of APG-1387. In addition, gene enrichment analysis of hepatic RNA-seq data indicated that APG-1387 administration induced upregulation of immune-related gene expression in the liver, with a profile similar to the differential gene expression pattern observed in the liver of an acute HBV-infected chimpanzee model.
The above results indicate that APG-1387 can clear HBV infection in various chronic mouse models through unique apoptosis-inducing and immunomodulatory mechanisms. The application of IAP inhibitors is expected to become a novel immunotherapeutic strategy for promoting functional cure of HBV.