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The Newest Clinical RNAi Company

|Includes: Benitec Biopharma Ltd (BNIKF)

While the giants of the gene silencing Alnylam ($ALNY) and ISIS ($ISIS) have stolen the news through collaborations and milestone payments the announcement that there is a new clinical RNAi company has largely been overlooked. Today, Benitec Biopharma ($BNIKF) (ASX:BLT) announced that it has been give the all clear by the Food and Drug Administration (FDA) to commence its clinical trial for the treatment of Hepatitis C (HCV).

Benitec's subsidiary, Tacere, worked with Pfizer ($PFE) in the early stages of the development of this treatment, now referred to as TT-034. To-date, two papers (paper 1, paper 2) have been published in peer reviewed journals and a third is about to be published. TT-34 is a "one-shot" treatment which involves the delivery of a multiple shrna expression cassette via an adreno associated virus (AAV8). The novel triple shrna approach is designed to eradicate HCV while minimising the virus's opportunity to mutate its way around the treatment.

HCV is notoriously difficult to assess in animal models because it only occurs naturally in humans and chimpanzees. However, the efficacy and low toxicity of TT-034 in non-human primates was outstanding, showing ~ 99% clearances in hepatocytes with no toxicity. This exciting result bodes well for the new trial and this was acknowledged by the unanimous support of the Recombinant DNA Advisory Committee (RAC).

In the last month, two papers have been published which bring into doubt the efficiency of the AAV8 vector and its transduction capacity in the human liver. This could be a problem for TT-034 as AAV8 is the means by which the shrna enters the human liver cells. However, in considering the possible effects of this new research on Benitec's trial the following needs to be taken into consideration.

Paper 1 suggests that current animal models of AAV8 transduction are inaccurate predictors of human transduction. However, because there is little data on human liver transduction levels this team proposes a new animal model. As of yet, there is no clinical human data to supports the claim that the new model is a more accurate predictor of human transduction than the old models. So, at this stage, there is no reason to assume that human AAV8 transduction levels in the TT-034 trial will be anything less than the company is expecting, based on its own and Pfizer's pre-clinical work.

Paper 2 does use human clinical data gathered from a gene therapy clinical trial for haemophilia. It says that at an AAV8 dose rate starting at 2x1012 vg/kg the body, in some patients, may initiate an immune response which would significantly reduce the AAV8 transduction rate. Again the limited dataset makes it impossible to define predictive parameters. As far as the trial of TT-034 is concerned, the dosing rates shown in the presentation to the RAC indicate that only the cohort dosed at the highest rate will breach this threshold. This being the case, 1) it is possible that a lower dose will be efficacious, or 2) the higher dose could be managed or re-engineered to avoid the problems identified by the haemophilia team, should that be necessary.

Benitec seems to have all the bases covered as best as can be given the very uncertain world of biotech and drug development. Early safety results from the trial should start coming in a few months after the first cohort is dosed and efficacy results several months later. Only then will we know if the company has got it right. If they do get it right, expect Benitec to steal the headlines on that day!

Disclosure: I am long BNIKF, .