GSK antisense agent for hepatitis B shows promise

Keith Alcorn
Published:
29 August 2020

An antisense agent, GSK-3228836, significantly reduced hepatitis B surface antigen levels in previously untreated people with chronic hepatitis B after three injections, an early phase trial reported this week at the Digital International Liver Congress.

GSK-3228836 (formerly known as ISIS-505358) (proposed name bepirovirsen), is an antisense oligonucleotide, a chain of nucleic acid designed to cut hepatitis B RNA, preventing the transcription of viral proteins.

The drug was developed by the biotechnology company Ionis and has been licensed to GlaxoSmithKline (GSK) for development, along with a second antisense oligonucleotide, GSK3389404. GSK aims to develop a functional cure – long-term virus suppression after a fixed course of treatment – using a combination of agents.

GSK-3228836 was selected for development based on evidence from pre-clinical studies that showed dose-dependent reductions in hepatitis B surface antigen. The phase 2a study presented this week evaluated the antiviral activity and safety of GSK-3228836 dosed over a 4-week period followed by 6 months of nucleoside/nucleotide analogue (NRTI) treatment with tenofovir or entecavir.

The study recruited 18 NRTI-naïve and 6 NRTI-experienced people with chronic hepatitis B in Hong Kong and South Korea, with hepatitis B surface antigen levels above 50 IU/ml at screening. The study excluded people with cirrhosis or co-infection with hepatitis C, hepatitis D or HIV.

Dr Man-Fun Yueng of Queen Mary Hospital, University of Hong Kong, reported on treatment responses in the 300mg arm of the study (previous results of the phase 2a dose-ranging study were presented at the AASLD Liver Meeting in November 2019).

GSK-3228836 was administered by subcutaneous injection in six doses at days 1, 4, 8, 11, 15 and 22.

The NRTI-naive group had a mean age of 42, two-thirds were women and the mean hepatitis B surface antigen was 3.9 log10 IU/ml. Half were HBeAg positive. Twelve were assigned to active treatment and six to placebo. Three out of 12 had hepatitis B surface antigen reductions > 3 log10 IU/ml. Two were below the lower limit of quantification (LLOQ) (0.05 IU/ml) by day 29. The mean reduction in HBsAg was – 1.55 log10 IU/ml at day 29 compared to no change in the placebo group (p = 0.001).

The NRTI-experienced group had a mean age of 48 years, four out of five were male, the mean hepatitis B surface antigen level was 2.8 log10 IU/ml and all were HBeAg negative. Four were assigned to active treatment and two placebo. Three out of four who remained on study treatment had hepatitis B surface antigen reductions > 3 log10 IU/ml and two were below the lower limit of quantification (LLOQ) (0.05 IU/ml) by day 36. The mean reduction in HBsAg was – 2.51 log10 IU/ml at day 29 (non-significant compared to the placebo group, p = 0.454).

Three participants in the NRTI-experienced group had ALT flares that began during the GSK-3228836 treatment phase. In two cases the ALT increase was 3 x upper limit of normal (ULN) and commenced around day 20 of treatment. In the third case, ALT increased to 5 times ULN from day 20. All cases were asymptomatic and coincided with a reduction in HBsAg, and ALT returned to the normal range by day 120.

ALT flares occurred in both participants in the treatment-naïve group who had hepatitis B surface antigen clearance (< LLOQ), also self-limiting and asymptomatic.

In both study groups, ALT flares were associated with greater hepatitis B surface antigen reduction.

Study treatment was well tolerated. Injection site reactions lasting at least two days were observed in three of 12 treatment-naïve participants and reactions lasting at least four days in two of five NRTI-experienced participants.

GSK-3228836 is moving forward in a phase 2b study evaluating the effects of 12 or 24 weekly injections of two doses in NRTI-naïve and -experienced participants.

Reference

Yuen MF et al. Hepatitis B virus (HBV) surface antigen (HBsAg) inhibition with ISIS 505358 in chronic hepatitis B (CHB) patients on stable nucleos(t)ide analogue (NA) regimen and inNA -naive CHB patients: phase 2a, randomized, double-blind, placebo-controlled study. Journal of Hepatology, supplement 1 [International Liver Congress], AS067, S49, 2020.