Benitec Pivoting into HBV - Good move?

By Robert Kruse

Benitec is a biotech company focused around the delivery of shRNA vectors by adeno-associated viruses (AAVs). For the lay, host polymerases transcribe the DNA creating an RNA hairpin, that is then cleaved and processed into an siRNA molecule that can then proceed to silence targeted mRNAs. Benitec calls this strategy ddRNAi, or DNA-directed RNAi, to distinguish it from other competitors like Alnylam who focus on delivering siRNA alone. The central benefit is the ability to have siRNA stably expressed in transduced cells over time, whereas siRNA approaches must be intermittently delivered. The risk with transduction, depending on the vector, is that it will eventually be silenced, and that in the case of AAV, might even be silenced quickly by a host capsid immune response.

Benitec's big bet was on using shRNA-AAV therapies to cure Hepatitis C virus. The delivery of shRNA could knock down genomic HCV RNAs curing the virus across the liver. They progressed to phase II trials with good effectiveness. The problem, of course, is that Gilead or others succeeded in a cocktail regimen that could cure HCV in 3 months with small molecules posing limited risk to patients and straightforward manufacturing processes. This compares to the AAV strategy, which may only require one dose, but scaling up the number of doses to meet the current sizable demand might have taken significant time, not to mention cost. Benitec's best bet in this space would have been if all the HCV drugs failed in their clinical trials, allowing shRNA to emerge as the sole therapeutic option that could be curative. Still, for a potentially transient disease like HCV where RNA turnover is frequent, the competitors at Alnylam and others would have have been able to scale their programs faster to treat the same patients.

With Benitec searching for the next option, they now seem to have pivoted toward a Hepatitis B virus program. They bought the additional HBV IP from the Chinese company, Biomics Biotechnologies, and are likely marrying it with their own IP governing AAV vectors and shRNA cassettes.

On the surface, it makes perfect sense. They have insight into the development of therapies against viral infections of the liver with proven delivery strategies. However, unlike the HCV play, where the shRNA directly degrades HCV genomes to remove the virus, the mechanism of action for shRNA against HBV will be indirect, and therefore open up the same risks that the other HBV knockdown companies are dealing with.

Risks:

1. Transduction efficiency -  efficiency seems to be higher for infected cells with AAV, but significant coverage of the liver would still need to be reached in humans in order to hit most infected cells.

2. Mutational escape -  the mutation rate of virus may allow them to rapidly escape inhibition by the shRNA overtime. If combined with other therapeutics, such as nucs, this might delay or limit this possibility.

3. How much HBsAg knockdown?  - what amount needs to activate the immune system. A lower set point for HBsAg and HBV DNA might not necessarily lead to clearance.

4. Anti-vector immune response - in a round about way, any AAV immune response would likely help inhibit HBV through bystander effects on HBV infected cells, this would likely be transient in nature though.

5. Persistence of shRNA expression - the benefit of AAV driven shRNA will be the lack of dosing over time, but the question will be how long of a knockdown will be needed? 6 months? 12 months? Will the shRNA expression last for 12 months? Furthermore, the same immune response that could occur against HBV genomes might also wipe out the AAV genomes making the shRNA, neutralizing the therapy.

6. Safety - as with all gene therapies, the FDA does a risk benefit analysis. Whereas the siRNA therapies are more like drugs that could be stopped at any time, the AAV treatment is permanent. For HBV patients who are otherwise healthy, this risk might be too much, and the FDA could never approve this strategy. That said, the ongoing safety results of AAV in other clinical trials suggests it should be safe going forward.

On the upside, the utility in administering the knockdown therapy one-time into the patient will solve patient compliance problems and make it much easier to use. This is particularly the case for the knockdown strategies involving weekly or bi-weekly IV administration, such as Replicor. In my analysis, I would say that Benitec really needs whatever immune reactivation paradigm for HBV after HBsAg knockdown to take around 8-12 months or even more, a range that might make their siRNA competitors less appealing.

Testing in an appropriate animal model such as chimpanzees would be useful in order to gauge future success, since previous academic studies with AAV-shRNA against HBV could only validate knockdown alone. Here are two studies that are largely similar to what Benitec will be doing.

Inhibition of HBV replication and gene expression in vitro and in vivo with a single AAV vector delivering two shRNA molecules. - BMB Reports 2009

Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic. - Molecular Therapy 2008