Nanalyze

When Will There Ever Be a Cure for Hepatitis B?

You’ve probably seen the bumper stickers, T-shirts, and memes that declare: “The liver is evil, it must be punished.” We have been known to indulge in a little BDSM with our own meaty organ in a local dive bar or three, hoping that we don’t drink it under the table some day. While there are plenty of ways to cause self-inflicted damage to the body’s largest detoxifying organ, most conditions that affect the liver are not necessarily caused by excessive drinking. Among those diseases is hepatitis B.

What is Hepatitis B?

According to everyone’s favorite online physician, WebMD, hepatitis B is a viral infection that causes inflammation to the liver and can be fatal if left untreated. Warning signs for hepatitis B include jaundice (yellowing of skin), fever, long-term fatigue, stomach pains, nausea, and vomiting. These symptoms don’t usually show up until months after contracting the virus and are shared by all types of hepatitis, so a blood test is usually needed to determine if hepatitis B viruses are the ones circulating throughout your body.

Types of hepatitis.

Types of hepatitis. Credit: Bigstock

Viral hepatitis comes in three flavors: A, B, and C. The term hepatitis itself refers to any type of inflammation of the liver. Hepatitis A is typically a mild, garden-variety hepatitis caused by contaminated water or food that will go away after a few weeks or months. Hepatitis C is pretty brutal, with a high mortality rate, but is starting to become curable, or at the very least, manageable. Some pretty famous celebrities carry hep C – including Pamela Anderson, Steven Tyler, and Naomi Judd – giving it a certain cachet. Then there’s Hepatitis D which only occurs in people who are infected with the hepatitis B virus.

Unfortunately, not a whole of publicity surrounds hepatitis B. And unlike the other two forms of hepatitis, there is no known cure for hepatitis B and it also can result in hepatitis D. Currently, research into the disease is drastically underfunded and has been compared to a neglected tropical disease.

Causes and Spread of Hepatitis B

Hepatitis B is caused by the hepatitis B virus (HBV), a noncytopathic virus, which means it doesn’t cause damage to the body through its own replication and propagation, but rather, the immune system aggressively responds to the virus and causes damage to the liver through inflammation. The virus is spread by contact with blood, bodily fluids, and open sores with another infected individual. The disease is commonly spread through sexual contact, with two-thirds of acute hepatitis B cases caused by sexual transmission. Unlike HIV, the virus is rather hardy and can survive outside the body for up to seven days. The disease can also be passed on from mother to child or transmitted between individuals without any symptoms.

Hepatitis B facts. Credit: Generic Hepatitis Drugs

HBV is unique in that it creates a minichromosome-like structure after infecting liver cells, called covalently closed circular DNA (cccDNA), which can be replicated and passed down to daughter cells during cell division. The cellular machinery of the liver cells continues to form capsid particles using the cccDNA as a template, which activates the host’s immune system to attack the infected liver cell. Over time, the overactive immune response can result in scarring of the organ, liver failure, and liver cancer. To make matters worse, cccDNA is something of a nearly indestructible form of DNA, and it can remain dormant for a long time and cause liver cancer in the long term, even with treatment. Any true cure would need to completely silence or destroy the cccDNA to prevent future reactivation.

Market for a Hepatitis B Cure

According to the World Health Organization, hepatitis B is responsible for more than 887,000 deaths per year with 257 million chronically infected with the disease. HBV is also responsible for 40% of all liver cancers. Of all the infected individuals worldwide, one-third are living in China, and the disease disproportionately affects Asians. People who test positive for the disease are frequently discriminated against in social and work settings.

Viral hepatitis B demographics around the world. Credit: World Health Organization

A vaccine exists to prevent future HBV infection. Routine HBV vaccination has led to a significant decrease in hepatitis B incidences, from 260,000 per year in the 1980s to 21,000 new cases in 2015 in the United States. However, those who are currently infected require life-long maintenance of disease symptoms. Researchers at Stanford University recently evaluated the economic burden of HBV in California, and found that the cost of liver-related hospital charges per individual came to be $123,239 per year. Estimates suggest the hepatitis B will generate $3.5 billion in global revenues by 2021. A cure for the disease could be quite valuable for everyone involved.

Companies Developing a Cure for Hepatitis B

So let’s take a look at some of the companies working on developing a cure for hepatitis B.

Click for company websiteFounded in 2018, San Francisco-based Brii Biosciences received a whopping $260 million in a venture round that included the China branch of premiere VC firm Sequoia Capital to embark on a mission to find new medicines for infectious diseases that are prevalent in China, including hepatitis B. The startup is dipping its toes by building new partnerships with other companies to jumpstart its development pipeline. Brii has entered into a license and collaboration agreement with a small-cap biotech company called VBI Vaccines (VBIV) for up to $129 million for  VBI-2601, which is designed to help boost the immune system against the virus. Brii also has a partnership with San Francisco-based Vir Biotechnology for a RNA interference drug that attempts to “turn off” production of hepatitis B proteins.

Click for company websiteArrowhead Pharmaceuticals (ARWR) is a pharmaceutical company based in Pasadena, California that currently licenses one of its drug candidates for hepatitis B to Johnson & Johnson (J&J) in a cash and stock deal valued at $250 million. The company is also developing ARO-HBV using RNA interference (RNAi) technology to target and inhibit the transcription of viral material.

Click for company websiteFounded in 2006, Precision BioSciences is a commercial-stage genome editing startup spun out of Duke University with $135.7 million in funding to date that we profiled last month on the news it would IPO. The company is currently developing the proprietary ARCUS genome editing technology to insert, remove, and modify DNA at any point to excise hepatitis B viral sequences in liver cell genomes. Precision BioSciences entered into a partnership with Gilead Sciences (GILD) and is currently setting up to raise $100 million in an IPO.

Arbutus Biopharma (ABUS) is a Canadian biopharmaceutical company that is developing a number of drug candidates that attack multiple targets of the HBV lifecycle, including the “aggressive suppression of HBV replication and the formation inhibition and elimination of cccDNA.”  These drug candidates may also boost the host immune response to chronic HBV infection. Its HBV inhibiting product, AB-506, is currently in Phase 2 clinical trials.

Founded in 2014, ENYO Pharma is a French biopharmaceutical company with $73 million in funding, following a $45 million Series B last June. The startup is developing an orally bioavailable compound called EYP001 for chronic hepatitis B, which targets the cccDNA viral reservoir as a potential permanent cure, and has launched Phase 2 clinical trials on the product.

Click for company websiteContraVir Pharmaceuticals (CTRV), headquartered in Edison, New Jersey, received the license for and developed tenofovir exalidex (TXL), an HBV inhibitor that works by jamming the machinery used by the virus to replicate, decreasing their numbers over time. The drug is a variant of other similar HBV drugs on the market, like Gilead’s (GILD) Viread, and works in similar ways. ContraVir has successfully completed Phase 2 trials on the drug.

Mechanism of action for tenofovir-type drugs. Credit: Nature Publishing Group

Founded in 2015, Chromis Therapeutics is a San Diego-based biopharmaceutical company that’s focused on the development of viral inhibitors against chronic HBV infection. It has raised $3 million in disclosed funding, as it works to advance its lead cccDNA inhibitor, CHR101, to prevent viral maintenance and replication in infected liver cells.

Companies Developing New Vaccines for Hepatitis B

In addition to finding a cure for hepatitis B, companies are trying to develop new vaccines to help spread immunity in order to help eradicate the disease.

Dynavax Technologies Corporation (DVAX) is a Berkeley, California-based early commercial-stage biotech company. Last month, Dynavax saw a drop in shares by 15.9% and recently exercised its option to draw down $75 million of non-dilutive capital to help commercialize its lead hepatitis B vaccine, HEPLISAV-B, which is the only two-dose vaccine on the market. The vaccine is expected to achieve profitability by the end of 2019.

Dynavax business goals for Heplisav-B. Credit: Dynavax

The aforementioned Cambridge-based VBI Vaccines is also working on a hepatitis B vaccine, Sci-B-Vac. The drug is currently in a Phase 3 study and also serves as an immuno-therapeutic for chronic hepatitis B.

Conclusions

Hepatitis B is truly a devastating disease with life-long consequences and medical challenges faced by infected patients. The number of companies currently working on developing a cure for hepatitis B is decent, and so there’s a possibility that a lot of patients suffering from the disease could receive the help they sorely need in the next decade, as pipelines begin to mature. And while only Precision BioSciences is using gene-editing tools to treat hepatitis B, the power of gene editing to treat viral diseases will only become more apparent as time goes on. For now, standard oral pharmaceuticals and vaccines, with some novel RNAi technologies thrown in the mix, will be the way forward for these companies, which leads us to the question: When will there ever be a cure for HBV?

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