Benitec Biopharma Ltd (BNTC)

[Blane]

Benitec Due Diligence – March 1, 2016

Stock Tickers
US:BNTC
Australian: ASX:BLT

If you are new Benitec, this post has the majority of due diligence nuggets dug out for you by various board members. Welcome to Benitec Biopharma Ltd!

Benitec Biopharma is an Australian Biotech Company that is currently developing a platform method of treating diseases. Unlike traditional drugs, Benitec has developed a system of treatment utilizing viral vectors and a patented process known as ddRNAi, or DNA-directed RNA interference. What this means is that when their treatment is delivered, the modified virus takes the treatment into the target cell, and modifies that cell's DNA so that it effectively produces the therapy/cure itself. Benitec is currently utilizing this technology, in its first clinical trial, to target Hepatitic C. Other disease targets in development in-house are Hepatitis B, Non Small Cell Lung Cancer, Cancer Associated Pain, Age Related Macular Degeneration & Oculophayngeal Muscular Dystrophy.

Out-licenced Programs include HIV through Calimmune, Cancer Vaccine through Regen Biopharma, Retinitis Pigmentosa through Genable, Huntington's through uniQure, and Intractable Pain through Circuit Therapeutics.

To see Benitec’s in-house and out-licenced programs, click here:http://www.benitec.com/pipeline/in-house-programs

Presentations: A more recent updated presentation in September of 2015 can be seen here: http://blt.live.irmau.com/IRM/PDF/1609/PRESENTATIONATCHI13THANNUALCONFERENCE


ddRNAi:

Here is a brief synopsis of what ddRNAi (also called Short Hairpin RNA, or shRNA) is, and how it compares to siRNA, taken from the company website: http://www.benitec.com/technology/what-is-ddrnai


“Benitec Biopharma’s patented approach to gene silencing overcomes most of the challenges of siRNA-based methods, because it utilizes a DNA-based approach, called DNA-directed RNAi (ddRNAi). The difference lies in the method of introducing siRNA into the cell: ddRNAi causes the cell to produce siRNA itself, rather than introducing synthetic siRNA. ddRNAi achieves this by producing a precursor molecule called short hairpin RNA (shRNA) in the nucleus, which enters the cytoplasm and is processed to siRNA by the cell’s own machinery. The specific shRNA is coded for in the nucleus as a result of transfecting the cell with a DNA-based construct, hence the concept of RNAi directed by DNA.

ddRNAi introduces a DNA sequence directly into the cell’s nucleus, and to do that, a range of well-characterized gene therapy vectors, viral and non-viral, like lentivirus, adenovirus, AAV or modified polyethylenimine can be used. The DNA sequence codes for specific shRNAs which are processed to siRNAs and complete the RNAi cycle in the cytoplasm. Herein lies another major difference: because of the delivery mechanism and site, only a minute dose (perhaps as few as 5 copies) of the DNA construct is needed, yet the genetic change is long-lasting, because the shRNA continues to be expressed for long periods, potentially up to years from the integrated DNA construct (Sci Trans Med 2010).

Due to the low dose and short term administration (potentially as little as one dose) many of the drawbacks of siRNA methods, including toxicity, immune activation and unwanted gene effects (off-target effects) are overcome. Thus ddRNAi promises to deliver long lasting, relatively safe treatments (or potentially cures) for many human genetic conditions.

ddRNAi can also be used to target multiple genes or multiple parts of one gene, so more complex conditions can be treated with tiny doses, without the side-effects of high-dose, long term administration.

A major benefit for researchers and biopharma companies worldwide is that ddRNAi is a globally patented platform technology, rather than a proprietary gene specific technology or delivery mechanism. Thus, ddRNAi technology may be licensed from Benitec for therapeutic gene silencing of a wide range range of disease-associated genes in humans.”


Short Hairpin RNA (short hairpin RNA “shRNA”) scientific videos can be seen here. These are more scientific in nature, and walkthrough the pathophysiology of how this functions:
Part 1
https://m.youtube.com/watch?v=tKDN4TSDw-Y

Part 2
https://m.youtube.com/watch?v=3qmHJlCn4FA

Part 3
https://m.youtube.com/watch?v=pjqwalEodTk

Part 4
https://m.youtube.com/watch?v=__tfPZv-qvg

Hepatitis C:

*** On Feb. 26th, 2016, Benitec decided to discontinue the Hepatitis C trial based on a changing Hepatitis C treatment landscape. According to Benitec, remaining funds from the Hepatitis C trial will be used to advance its other indications, which it believes have a greater potential for partnerships or deals.

For further information regarding this decision, please see the attached Interim Report Transcript, which can be seen here: http://blt.live.irmau.com/IRM/PDF/1660/BUSINESSUPDATECONFERENCECALLTRANSCRIPT


Hepatitis B:
Despite the Hepatitis C trial coming to a close, the company has stated that the information gathered during its trial will be invaluable to Hepatitis B. A portion of the Interim Report released on March 1, 2016 states:
“We understand that following the recent TT-034 announcement, that many of you are concerned with the impact on the HBV program, but let me assure you that we feel confident in regards to its progress. Because many components of TT-034 are mimicked in our HBV candidate, BB-HB-331, we believe that the clinical results that have been presented publicly to date substantially de-risk that the HBV program in terms of safety and delivery. We also believe that the TT-034 data that we have in hand may decrease the timeline required for the development of BB-HB-331. For instance, if we were to maintain the same AAV8 viral capsid for delivery, the relationship between the dose administered and the level of liver transduction, a measure of how much drug gets into those tissues would be expected to be nearly identical. Likewise, we would expect no change in biodistribution of the drug into non-hepatic tissues. Finally, because the safety profile established in the HCV trial, we would hope that we would be able to make a compelling case to start the HBV trial at drug concentration levels closer to the anticipated therapeutic dose.”

Hepatitis B in-vitro data was released in Q4 of 2015, and in-vivo data is soon to be released.
There is no current cure for Hepatitis B, and the Hepatitis B market is huge (350 Million Worldwide) compared to Hepatitis C.


AMD:
(1.75 Million people). This therapy uses ddrnai to suppress the expression VEGFA protein.
Collaboration with 4D Therapeutics on developing a vector that transduces cells of the whole eye are underway.

Again, a portion of the Interim Report from March 1, 2016 states:
“One of the major limitations of most ocular gene therapy applications is that many use a highly complex surgical technique called subretinal injection for delivery into the eye. In this procedure, a needle bent with a 90 degree angle is inserted into the eye and used to carefully tease apart retinal cell layers to create a pocket in which to inject the gene therapy agent. This is an intensive medical procedure that requires an exceptionally skilled surgeon. In our collaboration with 4D, we are developing AAV capsids which can efficiently transduce cells within the retina following an office friendly, intravitreal injection which is a route of administration no different than Lucentis or Eylea, used as the current standard of care for treating AMD. Yet, these drugs require intravitreal injection once a month or once every other month. It is our intention to develop a gene therapy-based ddRNAi approach that will only require a single injection to stop the progression of this disease.”


OPMD (Ocularpharyngeal Muscular Dystrophy

OPMD is a rare disease and has been reported in at least 33 countries. Patients suffering from OPMD are well identified and are aggregated in particular regions, which we believe should simplify clinical development and commercialization of Pabparna, if it is approved. The largest OPMD cluster is in the French-Canadian population, with estimated prevalence of one in every one thousand people, and its highest prevalence is among Bukhara Jews living in Israel, where it affects one in six hundred people. In Europe, the estimated prevalence is one in one hundred thousand people. The relatively low abundance of patients afflicted by this disease allows this indication to be characterized as a rare disease, potentially supporting an orphan drug designation.

From the Interim Report from March 1, 2016.....
"Ocularpharyngeal muscular dystrophy (OPMD) is a unique program that has strategic advantages in the fact that it is an orphan disease, meaning that there is significantly less competitive pressure through competing drugs and programs. Because it is a small market indication, it also means that we may have the ability to take this program through to commercialization ourselves. In August 2015, Benitec signed an extension to the Collaboration Agreement with Royal Holloway University of London which continues to enable us to work with world class scientists who have initiated the primary work in the program to identify a genetic basis for this disease. As part of this collaboration, we are also working with researchers at the Institute de Myologie in Paris, a centre of expertise for muscular based disorder that has access to a large proportion of OPMD patients in France. The clinical vector being developed uses a silence and replace approach. Part of the vector uses ddRNAi to knockdown the mutant form of the PABPN1 gene and a separate portion of the construct encodes for a healthy wildtype version of the same gene in order to restore function. We aim to complete preclinical proof of concept studies by Q4 of 2016."

Stock Blogs and Outside Investor Info:

If you’re interested in viewing an Australian stock blog like Investorhub, you can view this one:http://www.topstocks.com.au/new_asx_stock_forum.php
as well as this one: http://hotcopper.com.au/search_do.asp?fid=1&symbol=382

Other ddRNAi programs are potentially in the works for possibly ALS and can be read in a blog here: http://seekingalpha.com/author/pannobhaso/instablog

I will try to continually update this post when new information comes out. Again, Welcome!

For more information regarding the Australian releases on the ASX, please refer to this link: http://www.benitec.com/investor-centre/asx-announcements

Blane