GSK Reports Phase 2B Results on Bepirovirsen for Chronic Hepatitis B Treatment

According to the World Health Organization (WHO), there are an estimated 296 million people worldwide who have chronic hepatitis B (CHB). This disease can lead to liver complications including cirrhosis and liver cancer, which results in nearly 900,000 deaths per year.

Currently, viral suppression is the goal for clinical outcomes. However, viral replicative activity may return if treatment is stopped, so ongoing, lifelong therapy is required to prevent viral rebound. Right now only a limited number of patients currently treated for CHB achieve reduced levels of hepatitis B surface antigen (HBsAg) loss, which is considered the hallmark for achieving a functional cure.

GSK’s investigational therapy bepirovirsen (GSK3228836) recently reported results from its phase 2B clinical trial which demonstrated it reduced HBsAg levels and hepatitis B virus (HBV) DNA after 24 weeks of treatment in people with CHB.

“Specifically, the reduction in hepatitis B surface antigen and HBV DNA to below the lower limit of quantification has the potential to be clinically meaningful and lead to functional cure. This could help people living with CHB and healthcare providers manage the long-term consequences of CHB which include the social burden as well as the risk of developing life-threatening liver complications,” Professor Man-Fung Yuen, MD, PhD, principal Investigator and chief of Division of Gastroenterology and Hepatology, Queen Mary Hospital, The University of Hong Kong, said.

Therapy’s Mechanism of Action

According to GSK, bepirovirsen is a antisense oligonucleotide (ASO) designed to specifically recognise the RNA that the hepatitis B virus uses to replicate itself in the infected liver cells (hepatocytes) and make the viral antigens, which facilitate chronicity of the disease by helping to avoid clearance by the immune system. The ASO recruits the liver’s own enzymes to eliminate the RNA by digesting it to an inactive form.

The subsequent reduction in the levels of the RNA results in a decrease in both the virus and the production of viral antigen (HBsAg) by the hepatocytes, which can be measured by a drop in the HBV DNA and antigen levels in the circulating blood. Bepirovirsen has an additional property of stimulating immune responses via Toll-like receptor 8 (TLR8) which may help the immune system to achieve durable clearance of the virus from circulating blood.

Bepirovirsen was discovered by, and jointly developed, with Ionis Pharmaceuticals.

Data from GSK

The B-Clear phase 2b study is investigating the efficacy and safety of 12 or 24 weeks treatment with bepirovirsen in people with CHB on stable NA treatment or not on NA treatment at study start. The primary endpoints are the proportion of patients achieving HBsAg levels below the Lower Limit of Quantification (LLOQ), and HBV DNA levels below LLOQ sustained for 24 weeks without rescue medication after end of treatment with bepirovirsen.

The study consists of 2 parallel cohorts, one for patients receiving NA treatment and the other for patients who were not on NA. Patients from each arm were randomised to 1 of 4 treatment arms within each cohort, with treatment administered weekly with or without loading doses (LD) on days 4 and 11:

• Bepirovirsen 300 mg with LD for 24 weeks;
• Bepirovirsen 300 mg with LD for 12 weeks then 150 mg for 12 weeks;
• Bepirovirsen 300 mg with LD for 12 weeks then placebo for 12 weeks;
• Placebo with LD for 12 weeks then bepirovirsen 300 mg without LD for 12 weeks.

In both cohorts, virologic responses were observed at the end of treatment:

• For those patients receiving NA treatment (n=227), 24 weeks treatment of 300 mg bepirovirsen resulted in HBsAg < LLOQ and HBV DNA < LLOQ in 28% of patients at end of treatment.
• For patients not on NA (n=230), 24 weeks treatment of 300 mg bepirovirsen resulted in HBsAg < LLOQ and HBV DNA < LLOQ in 29% of patients at end of treatment.

The durability of these responses is being assessed.

“These encouraging data support further investigation of bepirovirsen, both as monotherapy and in combination, as a potentially transformative new treatment option for patients with chronic hepatitis B,” GSK Senior Vice President, Development, Chris Corsico, said.