Benitec Biopharma, Ltd., announced that initial in vitro results demonstrated the efficacy of BB-HB-331, a ddRNAi-based therapeutic developed to treat and potentially cure hepatitis B with a single injection. These results were recently presented at the HEP DART 2015 Annual Conference and support progression of BB-HB-331 into in vivo testing.
DNA-directed RNA interference (ddRNAi) is Benitec’s unique RNAi platform for silencing unwanted genes. Benitec’s patents cover the use of RNAi resulting from the introduction of a DNA construct into a human cell nucleus in vivo, leading to an effective long-lasting genetic silencing. BB-HB-331 consists of a recombinant DNA expression construct delivered intravenously using an Adeno-Associated Virus capsid (AAV8) for transduction of hepatic tissues. Once introduced into hepatocytes, BB-HB-331 uses cellular transcriptional machinery to drive long-term expression of three independent short hairpin RNAs (shRNAs) that simultaneously target three well-conserved regions on the HBV viral RNA, including the sequences that encode the Core, S-antigen and X-protein.
The results presented during the conference showed that BB-HB-331 was able to successfully suppress multiple features of the hepatitis B virus (HBV) in infected human liver cells. Treatment with the drug was associated with a 90% decrease in the levels of hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg), in comparison to untreated controls or liver cells treated with a construct that produces unrelated short hairpin RNA (shRNAs).
After 23 days, the cells treated with BB-HB-331 showed an 85% reduction in intracellular hepatitis B DNA. In the same timeframe, the levels of cccDNA (covalently closed circular DNA, a special DNA structure that arises during the propagation of some viruses in the cell nucleus) were also reduced by 66%.
BB-HB-331 was designed to mimic TT-034, a ddRNAi therapeutic against the hepatitis C virus that is currently undergoing Phase 1/2a clinical studies in the U.S., with the development of BB-HB-331 based on the results from preclinical and clinical trials of TT-034.
Dr. David Suhy, Benitec’s chief scientific officer, said in a recent press release, “The data demonstrates that BB-HB-331 produces robust knockdown of many of the critical parameters of active HBV infection. It gives us confidence to further develop the compound into follow-on in vivo studies, which are currently in progress. We anticipate that this data could provide the foundation to develop an anti-HBV therapeutic that is able to provide long term therapeutic benefit from a single injection.”