Sydney, Australia, 20 December 2016: Benitec Biopharma Limited (ASX:BLT; NASDAQ: BNTC; NASDAQ: BNTCW) today announced significant progress on use of the company’s technology for development of a ddRNAi based therapeutic for the treatment of hepatitis B virus (HBV). A combination approach of using a single administration of the DNA--directed RNA interference (ddRNAi) agents BB--101, BB--102 or BB--103 with current standard of care agents used to treat the disease, demonstrates a robust and sustained suppression of HBV in an in vivo model.
Benitec’s ddRNAi technology is a unique combination of gene silencing using RNA interference coupled with the long term therapeutic activity of gene therapy vectors. For the HBV program, the lead candidates are comprised of an adeno associated virus capsid (AAV8) and a recombinant DNA cassette engineered to express steady state levels of three short hairpin RNA (shRNA) that inhibit HBV viral RNA at three regions well conserved across all major genotypes.
This current in vivo study assessed the activity of BB--101, BB--102 and BB--103 in the PhoenixBio (PXB) mouse model, in which a substantial portion of the mouse liver cells have been replaced with human hepatocytes making the animals susceptible to HBV infection. BB--101 is comprised of a single stranded recombinant DNA vector expressing three anti--HBV shRNA. BB--102 is similar to BB--101, with the exception that the recombinant genome is packaged as a self--complementary, double stranded DNA. BB--103 is a next generation vector in which the anti--HBV shRNA have been modeled into miRNA backbones for expression from wildtype pol III promoters.
The ddRNAi components were administered only once, at the beginning of treatment, and anti--HBV activity was monitored over the course of 13 weeks by following serum HBV DNA, HBsAg and HBeAg on a weekly basis. At the conclusion of the study, intracellular HBV DNA as well as cccDNA was quantified. In combination studies, a single dose of ddRNAi vectors was administered with daily entecavir (ETV), a nucleoside reverse transcriptase inhibitor, or a pegylated interferon agent that was administered twice a week for the duration of the study.
Benitec’s Chief Scientific Officer, Dr. David Suhy said, “It is remarkable that these ddRNAi treatments, administered as a single infusion on top of an existing treatment regimen have this magnitude of impact on the viral burden in this model of HBV infection. With a high degree of confidence in our efficacy studies, we look forward to take the next steps of being able to move these compounds towards human clinical testing. To this end, we anticipate meeting with a number of regulatory agencies in early 2017.” The key findings are:
• Dosed individually in the absence of other anti--viral drugs, BB--103 and BB--102 resulted in corresponding maximum drop of serum HBV DNA levels at 2.17 log and 1.87 log reduction. A modest rebound of HBV DNA levels were noted following 56 days of treatment. A treatment arm consisting only of daily entecavir resulted in in a 2.63 log drop in serum HBV DNA levels.
• In combination with daily entecavir, a single dose of BB--103 and BB--102 dropped the serum HBV DNA levels below 3.72 log, the lower limit of quantification (LLOQ) for the assay. The LLOQ represents the lowest value that can result in accurate quantification of HBV DNA levels. Although HBV DNA is detectable below this level, it cannot be quantified. The reduction in viral burden continued to diminish until the end of the the 91 day experiment.
