IONIS-HBVRx Advanced Drug Monograph

IONIS-HBVRx Report

Name: IONIS-HBVRx Name (English): IONIS-HBVRx DrugBank ID: DB16202 CAS Number: 1403787-62-1 Type: Biotech Background: IONIS-HBVRx, also known as bepirovirsen (GSK3228836), is an investigational antisense oligonucleotide (ASO) being developed for the treatment of chronic hepatitis B (CHB). It was discovered and jointly developed by Ionis Pharmaceuticals and GSK. GSK licensed the program from Ionis in August 2019. IONIS-HBVRx is currently under investigation in several clinical trials, including a long-term follow-up study NCT04544956 (B-Sure) to assess the durability of efficacy in participants who previously received bepirovirsen and achieved a complete or partial response in parent studies like B-Clear (NCT04449029), B-Together (NCT04676724), and B-Fine (NCT04544956).

Mechanism of Action: Bepirovirsen is a 20-mer antisense oligonucleotide that targets all hepatitis B virus (HBV) RNA, including messenger RNA (mRNA) and pregenomic RNA (pgRNA). By binding to these RNA molecules, it promotes their degradation through an RNase H1 mechanism, thus inhibiting the synthesis of viral proteins, including hepatitis B surface antigen (HBsAg), and reducing HBV DNA levels. Additionally, bepirovirsen has been shown to stimulate toll-like receptor 8 (TLR8), which may contribute to the clearance of the virus by the immune system. This triple action – reducing viral replication, suppressing HBsAg, and stimulating the immune system – distinguishes bepirovirsen from current treatments that primarily focus on viral DNA suppression.

Clinical Trial NCT04544956: This study, titled "A Mechanistic Study of GSK3228836 With Fine Needle Aspiration (FNA) in Participants With Chronic Hepatitis B" (also known as B-Fine), was one of the parent studies for the long-term follow-up study NCT05358132 (B-Sure). While details specific to the mechanistic aspects investigated in NCT04544956 are not readily available, its inclusion as a parent study indicates it contributed to the data on bepirovirsen's efficacy and safety that are now being evaluated for long-term durability in B-Sure.

Clinical Trial Results: Phase 2b study (B-Clear) results, published in the New England Journal of Medicine, demonstrated that bepirovirsen treatment led to sustained clearance of HBsAg and HBV DNA for 24 weeks after the end of treatment in some patients with CHB, both those on and not on nucleoside/nucleotide analogue (NA) therapy. Higher sustained response rates were observed in patients with low baseline HBsAg levels. An interim analysis of the B-Clear study also showed that a significant proportion of patients achieved virologic response (HBsAg and HBV DNA below the lower limit of quantification) at the end of the 24-week treatment period.

Safety Profile: In clinical trials, bepirovirsen has generally shown a favorable safety profile. Most adverse events reported were mild to moderate, with injection site reactions being the most common. Transient and self-resolving alanine aminotransferase (ALT) flares were also observed in some patients.

Current Status: Following positive Phase 2b results, bepirovirsen (GSK3228836) is currently being evaluated in Phase 3 clinical trials (B-Well program) as a monotherapy and in combination with NAs for the treatment of CHB. GSK is also exploring sequential treatment regimens with other therapeutic modalities to potentially increase functional cure rates in a broader patient population. The FDA has granted Fast Track designation for bepirovirsen for the treatment of CHB.