GSK has an ambitious mission: to eradicate hepatitis B and achieve a functional cure for this disease. Steve Hood, Senior Director of Oligonucleotide ADME Strategy at GSK, has dedicated the last 10 years of his career to achieving this goal. Globally, around 250 million people are believed to have hepatitis B, although only 22 million of them are diagnosed. Unfortunately, of the 22 million patients only around 8% are receiving treatment.
The current standard treatment is nucleoside analogues which knock down but do not remove the virus from the body. Back in 2015, GSK began to develop two molecules, 836 and 404 (GalNAc version). Hood looked for efficacy in in vitro and in vivo HPV models. The study showed that the GalNAc adapted 404 was ten times more effective than 836.
Building on this success, the team investigated the molecules’ performance in phase II A clinical trials. The GalNAc version (404) showed promising results, but the non-GalNAc version (836) unexpectedly showed significantly more knockdown of the S antigen, a major biomarker for hepatitis B. They were initially puzzled by the 836’s performance. 836 was selected for phase II B studies.
However, the FDA raised concerns about drug-drug interactions (DDIs) and requested in-depth drug-drug interaction studies for oligonucleotides leading to additional data generation and modelling to ensure safety. This slowed progress slightly for the team, but Hood and his team still managed to progress to phase III in 2022.
Hood also highlighted the complexities of drug distribution within the liver, highlighting the differences between hepatocytes and non-hepatocytes in mouse models. They found that non-GalNAc oligos predominantly accumulated in non-hepatocytes, while GalNAc oligos targeted hepatocytes more effectively. Most of the drug remained in endosomes and lysosomes, with only a small fraction (1-2%) released into the cytoplasm where it could potentially cause DDI.
To more accurately mimic the liver’s structure, Hood and his colleagues developed a “pomegranate model”. This model accounted for the flow between different compartments, such as lysosomes and endosomes in hepatocytes and non-hepatocytes. This helped the team understand the intracellular rates and the impact of different compartments on drug efficacy and safety.
Unlike macrophages, hepatocytes show a distinct difference between GalNAc and non-GalNAc tests. The simultaneous label-free auto-fluorescent multiharmonic microscope (SLAM) enabled Hood to identify oligo uptake and the metabolic status of cells.