Functional Cure of Chronic Hepatitis B: RNAi Therapeutics May Be the Only Game in Town (Part I)

Today, I wanted to post the first of a two-part series on the hepatitis B virus (HBV) candidate by Arrowhead Research which is set to enter clinical development in the first half of this year.  But as if on cue, the company just announced the publication of extremely potent ('multi-log') reductions in gene expression with their systemic DPC delivery technology.  This thus bodes very well for what is shaping up to be an RNAi Therapeutics pipeline highlight: ARC520 for the treatment of chronic hepatitis B viral (HBV) infection. 

Are you wondering what could be the next HCV-type or maybe even larger drug development opportunity?  HBV may well be the new HCV.  With HCV increasingly curable, the pharmaceutical industry has increased appetite for finally also developing a cure for chronic HBV.  Based on the potent preclinical data with DPC delivery technology and the view of thought leaders in the field that the specific suppression of HBV proteins may be the single most promising mechanism by which this can be achieved,  I am more and more thrilled by the prospect that ARC520 could become a poster child for an RNAi Therapeutics that addresses a major public health burden.

In anticipation of the March webinar by Arrowhead where the company wants to talk more about the concept behind ARC520 and their most recent data on the drug candidate, two blog entries over the coming week will first explain the rationale for why HBV is such an attractive RNAi Therapeutics opportunity and then discuss the features that make ARC520 a particularly promising (including in a commercial sense) RNAi Therapeutics candidate.

Only RNAi Can Suppress HBV Proteins in a Specific, Potent, and Rapid Manner

About 2 billion worldwide are infected with hepatitis B virus (HBV).  300-400 million of these have subsequently developed chronic HBV, meaning that they are at increased risk of prematurely dying from liver-related complications such as cirrhosis and liver cancer.   Every year, more than one million chronic HBV patients die of such complications.  In East Asia and developing countries where mother-to-child transmission is the predominant (and highly effective from a viral point of view) mode of infection, HBV is responsible for more than half of primary liver cancers; in Western countries where transmission largely occurs via body fluids, esp. blood, it still accounts for about one quarter of cases.

This means that the public health burden of chronic HBV infection already surpasses that of HCV and is extending its lead as the new direct antiviral agents against HCV prove quite effective at eliminating HCV.  An important difference between HBV and HCV is that HBV is a DNA virus that will persist for life in hepatocytes.  This explains we can only dream of a ‘functional’ cure, not a cure full-stop.  HCV, by contrast, is an RNA virus which, in the absence of replication, will disappear due to the relative instability of RNA.  

Vaccination works almost 100% well to protect us from HBV infection. but its therapeutic application so far has failed and it also does not address mother-to-child transmission. Interferon and viral polymerase inhibitors (nucs) are currently only recommended for those with active chronic HBV as determined by increased liver enzyme levels in the presence of HBV.  These drugs, however, only work to convert 10-30% of those treated into the inactive carrier state with normalized liver enzymes and very little HBV DNA in the blood.  Nucs have the added benefit of very effectively inhibiting active viral replication, meaning that it does a good job at minimizing the ongoing inflammation in the liver.  Unfortunately, only very few of these patients can be considered to be cured and they are thus still at risk for viral re-emergence.

It is widely accepted that a functional cure for chronic HBV, meaning viral suppression in the absence of drug treatment, can only be achieved by harnessing adaptive immunity.  Here, the name of the game is achieving hepatitis B surface antigen (HBsAg) seroconversion, meaning the development of antibodies to HBsAg.  People who stably carry such antibodies can be considered cured.  Although the exact mechanism by which this is supposed to occur is being debated, it is widely accepted that immune exhaustion due to the presence of abundant HBsAg in the serum in the form of subviral particles and in the liver is the cause of why our immune system tolerates HBV, instead of eradicating it.

While nucs, which inhibit viral polymerase, not mRNA transcription of viral mRNA which is performed by our own RNA polymerase II off the viral cccDNA, and interferon can have some suppressive effect on HBsAg levels (on the order of ½ log), it seems that RNAi Therapeutics is the only means to achieve the specific, potent, and rapid inhibition of HBsAg that is considered to be necessary for a successful relief from immune exhaustion. In doing so, an RNAi Therapeutics can do everything that a nuc can do and more.  This means that such an RNAi Therapeutic may also significantly expand the pool of chronic HBV patients on therapy and should become a core component in any combination therapy such as with an interferon.

Look out for the next post on why I think ARC520 is an excellent RNAi Therapeutics candidate to achieve the stated objective.