Please can you describe RNA interference (RNAi)? When was it first discovered and how has our understanding developed over time?
RNA interference (RNAi) is a naturally occurring process, which cells can use to silence, or ‘turn off’ unwanted genes.
RNAi therapeutic companies utilise this process by synthetically manufacturing double-stranded RNA (dsRNA), which is specifically targeted to a sequence in the gene they are trying to silence. This dsRNA is delivered to the target cell where the cell’s internal machinery splits the molecule into small interfering RNA (siRNA). The highly specific siRNA binds to the target gene ‘turning off’ or silencing that gene.
RNAi developed from early research, in 1991, when it was being used to deepen the colour of petunias. Since that time RNAi has emerged as a real therapeutic modality with significant potential to manage a range of diseases.
How does DNA-directed RNAi, also called “Expressed RNAi” (ddRNAi) differ from small interfering RNAi (siRNAi)?
Benitec’s ddRNAi approach involves the delivery of a DNA construct or set of instructions to the nucleus of the target cell. This construct instructs the nucleus to produce a highly specific short hairpin RNA (shRNA). The specific shRNA moves into the cytoplasm of the cell where it follows the same pathway as the dsRNA finishing up as siRNA once again specific for the gene that is being targeted for silencing.
Thus, the major difference between the two approaches is that in RNAi the siRNA needs to be continually administered to maintain its therapeutic effect. However in the ddRNAi approach the cell continues to produce the therapeutic shRNA for its life time, offering the opportunity for a “one time” administration.
Which diseases does ddRNAi have the potential to treat?
The potential for ddRNAi technology as a therapeutic approach to treat disease is enormous. Essentially ddRNAi can be used to treat any disease caused by a gene where the “silencing” or “turning off” of that gene will cause a cure.
Benitec’s lead program, TT-034, a treatment for Hepatitis C, is perfect example; in this disease we use ddRNAi to target genes that are specific to the Hepatitis C virus. By silencing those genes the virus is unable to replicate and is cleared from the liver.
The company’s pipeline reflects the breadth of diseases we are potentially able to treat with ddRNAi. Diseases that include Hepatitis B, wet age-related macular degeneration (AMD), cancer-associated pain, drug resistant lung cancer and oculopharyngeal muscular dystrophy (OPMD). In addition, Benitec has licensed ddRNAi technology to other biopharmaceutical companies who are progressing programs towards the clinic for applications including HIV/AIDS, retinitis pigmentosa and Huntington disease.
Other diseases that could be treated using ddRNAi are those, in particular, where single genes are active in the disease process. Some examples are cancers involving specific oncogenes that can be silenced for patient remission; autoimmune disorders where the silencing of specific genes can reverse the disease process; neurological diseases; chronic degenerative viral infections where programming cells to silence critical viral genes can prevent infection; genetic diseases and other afflictions associated with the expression of a small number of key genes.
Why is Benitec focussing on hepatitis C?
Hepatitis C remains a major focus for Benitec for a number of reasons, the most important of which is the program’s proximity to the clinic. Pfizer originally partnered TT-034 pre-clinically and toxicity testing has been conducted at a rigorous “Big Pharma” standard that gives us confidence the program has good chance of success once dosing of patients begins.
We believe that to ultimately prove the therapeutic value of ddRNAi we need to be able to demonstrate that the technology is safe and effective and TT-034 is close to being able to prove that.
In addition we believe that Hepatitis C remains a significant opportunity where the development of a ‘single dose cure’ will become a superior approach and take an appropriate market share. The thing that has captured attention with TT-034 is its potential to treat patients so simply. The treatment would involve only one intravenous infusion.
Part of the reason why Hepatitis C is so difficult to treat is the fact that the existing drugs for treating the virus are so debilitating and administered over long periods of time. The standard course for Hepatitis C has until recently been between 24 – 48 weeks; that’s a long time to be taking drugs that make you feel awful. As a result, patients take a “drug holiday”, which causes drug resistance, potentially rendering the treatment ineffective.
TT-034, with its single dose format, removes those problems associated with patient compliance and drug resistance. We believe those things combined will make it attractive to insurers and payors, since it will positively affect the health economics involved with treating these difficult patients.
Hepatitis C infects over 170 million people worldwide and has been shown to be the main cause of cirrhosis and hepatocellular carcinoma, which often requires costly liver transplant surgeries. It is anticipated that by 2017, the therapeutic HCV market will be worth ~$18billion.
Benitec recently completed their IND application with the US FDA for TT-034. The Company also secured $31.5 million from global institutional investors which will allow the Company to take the HCV trial to completion of Phase IIb. Currently, Benitec expects to commence the dosing of several patients in the Duke Clinical Research Unit in North Carolina for TT-034 Phase I/IIa clinical trial.
Do you have plans to conduct trials on other conditions?
Yes, the next program we expect to begin clinical trials for is our Lung Cancer program. We are planning to commence a safety and toxicity trial this year with an expectation we could commence a Phase I/II(a) clinical trial in late 2014 or early 2015.
Our recent funding also enables the company to advance pre-clinical testing for the other programs targeting Hepatitis B (HBV); age related macular degeneration (AMD); chronic pain program and ocular pharyngeal muscular dystrophy (OPMD).
What excites you most about ddRNAi?
Many things, but the most important in my mind is to provide a long-term cure for range of diseases that to date create great misery for many patients worldwide. Although it is cliché I truly believe this technology has the ability to really make a difference.
What do you think the future holds for ddRNAi?
Once ddRNAi is proven to be safe and effective for Hepatitis C, I can see interest from potential “Big Pharma” partners growing substantially. I would expect that those organisations have disease targets that would benefit from our approach. I can see ddRNAi leading the way in proving that gene therapy is a safe and beneficial therapeutic approach
What are Benitec’s next steps?
I expect we will commence dosing patients in the near future with TT-034 – this will be a very exciting moment for the company and also potentially for the patients as it offers them an ideal solution to their treatment.
Benitec will advance our Lung Cancer program into the clinic and accelerate the development of the other programs; HBV, AMD, Cancer Associated Pain & OPMD. We will also look to expand the range of possible targets that ddRNAi can be used to treat.
At the same time Benitec will continue to look to partner each of our programs at the optimal time – giving the company the opportunity to deliver an appropriate level of return to our stakeholders
Where can readers find more information?
For more information, readers can review http://www.benitec.com/index.php
About Carl Stubbings
Mr Stubbings is a highly qualified senior executive with over thirty years’ experience in biotechnology and medical diagnostics. His background includes manufacturing, administration, and extensive international sales and marketing expertise in North America, Latin America, Asia Pacific and Europe. Prior to joining Benitec Carl was Vice President of Sales & Marketing for Focus Diagnostics a subsidiary of Quest Diagnostics (NASDAQ DGX), one of world’s largest pathology providers.
Prior to moving back to Australia, Carl and his family had lived and worked in the USA for more than 12 years.
In December 2011 Carl was appointed as a non-executive director of Sienna Diagnostics (a public unlisted company).
Carl Stubbings holds a B.Sc. degree from the Queensland University of Technology; he holds dual Australian and US citizenship.
Quest Diagnostics performs RNA testing on patient specimens to detect more cases of HCV