Renewed Attention Sees New Progress For Hepatitis B

By Anjani Shah 

August 31, 2017 | Hepatitis B is a serious liver infection, caused by the hepatitis B virus (HBV), with indications ranging from a mild illness lasting a few weeks to a life-long, chronic liver infection. There is a prophylactic hepatitis B vaccine for infants and children, but with an estimated 257 million people living with a hepatitis B virus infection, the virus is still an active target for drug discovery.

The HBV field has seen increased attention from industry research in the past few years, influenced by the success of new hepatitis C virus (HCV) therapies. After scientists realized HCV could be cured, they turned their attention to hepatitis B, hoping to develop a cure for it also.

There are major difference between the two viruses. The HBV worldwide incidence is twice that of HCV’s, and research into HBV is at the stage that hepatitis C research was about 10 years ago. HBV is more challenging because the virus has a unique way of controlling the host response; often a reservoir of hepatitis B virus remains even after treatment.

I spoke recently with Mike Sofia, Ph.D., chief science officer and co-founder of Arbutus Pharmaceuticals, about the latest HBV research. Sofia was one of the pioneering researchers of the recently launched new class of hepatitis C virus inhibitors when he was senior VP of chemistry at Pharmasset, a company now part of Gilead, and has now turned his attention to HBV.

“The two main approaches [for targeting HBV] are immune modulators and direct-acting antivirals (DAA),” Sofia told me.

These classes of drugs have been used for years. The original immune modulator class refers to interferon-based therapies and came into use in the early 1990s. These medicines boost one’s immune system and help by reducing inflammation of the liver, but because they are non-specific to the virus, they have significant side effects such as causing depression, fatigue and making one more prone to infections.

Ten years later, in the early 2000s, the other main class of drugs for HBV were launched—nucleoside analogs (NUCs such as lamivudine) which are considered DAAs because they directly inhibit the virus’ replication machinery. NUCs are oral drugs, thus more convenient for the patient than weekly (or more frequent) interferon-based injections. However, while they reduce the production of HBV in the infected cells, they do not completely cure the patient; some virus still remains and these medicines need to be taken for life. Moreover, a subset of patients develop resistance to the NUCs, so it’s clear that more therapeutic options are necessary.

“Today”, Sofia explained, “we believe a combination of therapies will likely be most successful in fully eradicating the virus, and will need to involve reducing viral replication, activating host responses, and finally clearing the viral DNA reserve from the nucleus.”

“Of the DAA approaches, short interfering (siRNA) is leading the way with Arbutus’ therapies in phase II clinical trials,” Sofia said.

Arbutus’ siRNA aim to inhibit viral replication, cleave HBV transcripts, and lower all viral antigens. Arrowhead Pharmaceuticals also has siRNAs in development designed to silence all of the HBV gene products by intervening upstream of the virus’ reverse transcription step. The hope for all siRNA approaches is that once production of the virus is diminished, the body’s natural immune defense will have a chance to clear the virus and lead to a permanent cure, most likely in combination with current therapies.

Inhibitors against specific HBV proteins is another DAA strategy. Johnson & Johnson’s capsid inhibitors are the farthest along using that approach but others are rapidly catching up. Inhibiting the capsid protein disrupts assembly of the HBV particle which suppresses its replication.

“Immunomodulator approaches, besides interferon, are still in the early stages of research,” Sofia said. “A promising line of investigation includes reactivating tolerized T cells via pattern recognition receptors. Some of the ‘T cell reactivating’ molecules being studied are STING, RIG1, PD1, PD-L1, TIN3 and Lag3.”

In addition to these oral-based therapies for HBV, progress is also being made on the vaccines front and other therapeutic modalities as well. It’s an exciting time to be involved in this field, especially with the increased understanding of liver-related diseases such as fibrosis and fatty liver disease, which often appear in conjunction with HBV.

CORRECTION 9/8/17: Sofia's job title was corrected in paragraph 4. He is co-founder and CSO of Arbutus, not CEO. 

Anjani Shah, Ph.D. is a conference director at Cambridge Healthtech Institute, the parent company of Bio-IT World. Dr. Shah has planned a symposium on Sept. 25 on drug development for Hepatitis B to be held at the upcoming Discovery On Target event in Boston, Mass. Sept 25-29, 2017.