Potential Breakthrough Cure for Chronic Hepatitis B Enters Clinical Development

Arrowhead Research announced yesterday that it had filed with Australian authorities to commence clinical development for ARC520.  ARC520 is the RNAi Therapeutics candidate for chronic Hepatitis B that aims at suppressing both viral load and the immune-suppressive Hepatitis B surface antigen (HBsAg).  This is thought to be one of the most attractive ways to achieve a (functional) cure for chronic HepB infection, and I believe that ARC520 has what it takes to be a serious contender.  

The first study will test how much of ARC520 can be safely given to volunteers.  While this may not sound all that exciting, safety with the unproven DPC delivery technology is probably the biggest risk factor with the program.  Based on the pre-clinical, rodent and chimpanzee, efficacy data, I would like to see at least 1mg/kg, ideally up to 3mg/kg ARC520-siRNA being safe and well tolerated.  With expected 95% and more HBsAg knockdown at these doses in many patients, it would all seem to come down to the validity of the HBsAg hypothesis.

Formal proof of knockdown potency will come soon thereafter in the form of the Hong Kong trial in which ARC520 will be given to chronic HepB carriers.  That study should get rolling in late 2013/early 2014.   

One nice thing about trials in HepB, just as in HepC, is that drug potency can be readily determined very early on by looking at viral titers in the blood.  Although this in itself is no proof of cure, in most viral infections, a rapid reduction is a good predictor of eventual outcome.  For ARC520, this should be no different. 

An advantage for Arrowhead Research in being early in aiming for a functional cure for chronic HepB is that the current treatment landscape is fairly simple (interferons and nukes).  This should greatly simplify pivotal phase III trial design and allow it to be positioned well on the market.

For biotech investors and traders, having frequent catalysts on a company’s lead candidate is obviously also very attractive.  This should keep the market entertained until 2017/8 when a potential approval could happen.

With 200-300 million chronically infected, ARC520 is definitely the popular choice in today’s drug development.   I will obviously be rooting for it, partly because I am invested in ARC520, but also for a number of other reasons.  

One of them is that I have worked for 3 post-doc years on identifying and characterizing small RNAs derived from the Hepatitis D virus, a virus that only exist in the presence of HepB.  By the way, HepD, basically HepB on steroids, is an orphan disease that I would like to see addressed with an RNAi Therapeutic.  If you are looking for potential targets, check out this paper by Dan Cao, myself and other colleagues at Stanford for potential gene targets.

And lastly, it reminds me of Professor Sir Kenneth Murray who just passed away following a quiet and productive life in which, among many other accomplishments, he was responsible for the first recombinant DNA vaccine.  The indication, of course, was for preventing HepB, and through this millions of lives were saved by his work.  Professor Murray was a co-founder of Biogen and the vaccine was eventually approved by the FDA in 1989 (licensed to GSK).  

With the money he made from his involvement with Biogen and the vaccine, he founded the Darwin Trust of Edinburgh and through this my undergrad and postgrad studies on RNA(i) molecular biology.  If you are still reading this, he shared with you enjoying both fundamental science and its industrial applications.  I also know that he liked to invest in biotech stocks. R.I.P.