MEXICO CITY – A hepatitis B virus (HBV) cure was considered “a pipe dream for many years,” Anna Kramvis, of the University of Witwatersrand, told the audience at the 2019 HIV & HBV Cure Forum, co-organized by the International AIDS Society (IAS) Towards an HIV Cure initiative and the International Coalition to Eliminate Hepatitis B (ICE-HBV). Kramvis is also on the board of ICE-HBV

And with the existence of both an effective vaccine and good treatment options, there was also some complacency about such a cure.

So, although there are more than a quarter billion people living with chronic HBV infection, and the cirrhosis, liver failure and liver cancer that can result from chronic HBV infection kill as many people annually as HIV – about 900,000 worldwide – “there is no sense of emergency,” Massimo Levrero, researcher at the Cancer Center of Lyon and INSERM and another ICE-HBV board member, told the audience. “HBV is killing you softly, and very, very slowly.”

However, with the advent of HCV direct-acting antivirals (DAAs), which can cure hepatitis C in a matter of months, there came a sense of possibility. HCV DAAs “led to a rethinking of the unquestioned dogma that HBV could not be cured,” Kramvis said.

Not coincidentally, the success of HCV DAAs also freed up teams of hepatitis drug development experts in the biopharma industry. Many of those teams set their sights on new options for HBV.

As a result, John Tavis told BioWorld Insight, there has been a “feeding frenzy” in the biopharma industry to develop new drugs against hepatitis B. Tavis, a professor of molecular microbiology and immunology at the St. Louis University School of Medicine, gave an overview of potential cure biomarkers and their challenges at the forum.

A major challenge in curing HBV is that the virus forms a plasmid of covalent closed circular DNA (cccDNA) that has been challenging to target.

At the 2019 annual meeting of the European Association for the Study of the Liver (EASL), researchers from Roche Holding AG reported on a small molecule, ccc-R08, that was able to degrade cccDNA in an animal model of HBV. Gene editing, though still at the preclinical stage in HBV, also has the potential to directly degrade cccDNA.

CccDNA also degrades over time – though current estimates on how long it takes to do so range from months to decades – and so the goal of most cure strategies is to prevent new cells from becoming infected long enough for complete degradation.

Another challenge in HBV cure work is the sheer amount of surface antigen (HBsAg) produced by the virus. “It’s amazing how this virus can make so much viral antigen – up to mg/ml in infected patients,” Jake Liang, chief of liver diseases at the National Institute of Diabetes and Digestive and Kidney Diseases, said at the forum.

Such large amounts of antigen lead to immune exhaustion. Furthermore, HBV can sometimes integrate into the host genome. Such integration is a dead end in terms of producing functional virus. But it does produce proteins, including, said SLU’s Tavis, “some of our best biomarkers” such as HBsAg. As a result, “we can have won, but our biomarkers say the person is infected” because integrated DNA continues to produce HBsAg.

Meanwhile, as far as drug development is concerned, the nonprofit Hepatitis B Foundation might well agree with Tavis’ estimate of a feeding frenzy. On its Drug Watch website, the foundation lists more than 30 compounds that are in clinical development, plus more than a dozen preclinical research projects.

Many approaches to a complex disease

Furthest along, in phase IIb, is Myrcludex B (bulevirtide, Myr Pharma), which blocks the entry of hepatitis B as well as hepatitis delta into cells. Myrcludex has FDA breakthrough status in hepatitis delta, where it is in a phase III trial.

Myrcludex is the only entry inhibitor listed by the Hepatitis B Foundation, in part because NCTP was only recently identified as the entry receptor for hepatitis B.

The viral capsid, in contrast, is an obvious target. It is “essential for viral entry, but also, most importantly, nuclear trafficking,” Raymond Schinazi told the forum audience.

The capsid is also conserved among all HBV genotypes, so capsid-targeting agents are broad-spectrum, and capsid inhibitors (CpAMs) retain effectiveness against nucleoside-resistant strains.

There are three CpAMs in phase II trials: Janssen’s JNJ-56136379, Assembly Biosciences Inc.’s ABI-H0731 and Hec Pharma’s morphothiadin.

Schinazi is Frances Winship Walters Professor and director, scientific working group on viral eradication, at Emory University’s Center for Drug Discovery, as well as a co-founder of Cocrystal Pharma Inc. and member of the Hepatitis B Foundation’s scientific advisory board.

At the conference, he gave an overview of his laboratory’s efforts to develop a CpAM. GLP-26 is currently at the preclinical stage, but Schinazi was enthusiastic about the compound, which, he said “for the first time ever in a mouse model, demonstrated a reduction in HBeAg,” a processing variant of HBcAg and a marker of active viral replication.

Furthermore, after the end of a 10-week course of treatment, HBeAg did not rebound. GLP-26 also synergized with Baraclude (entecavir, Bristol-Myers Squibb Co.), one of the frontline drugs in the treatment of HBV.

Schinazi said the goal is for GLP-26 to be in the clinic by mid-2020. More generally, he predicted that “it is likely that CpAM candidates will become a backbone compound in many future HBV curing regimens analogous to the NS5B inhibitor that is present in all current HCV regimens.”

Another group of HBV drugs is united by its method rather than by its target. Both RNAi and antisense developmental therapeutics use RNA to interfere with different steps in the production of viral proteins.

RNA drugs, as a class, face delivery challenges. However, they tend to accumulate in the liver (as well as in the cerebrospinal fluid, as the success of Spinraza and similar drugs attests), and there is general optimism that the liver disease HBV and the liver-accumulating RNA drugs are a good fit.

RNAi and antisense RNA target multiple proteins, but a number of them take aim at HBsAg, a surface antigen that is also the antigen used in the HBV vaccine.

HBsAg is an immunosuppressant and many researchers believe that depleting HBsAg could allow the immune system to rally and clear the virus. Previous work has shown that repeated doses of the HBsAg-targeting siRNA ARC-520 (Arrowhead Pharmaceuticals Inc.), which is the precursor to Arrowhead’s ARO-HBV, led to sustained reduction of HBsAg.

HBsAg is a key target, but also a challenging one, as it is one of the proteins that can be produced when HBV integrates into the host genome. HBsAg produced from integrated DNA, however, is subtly different from that produced by cccDNA, meaning that researchers need to make sure their drugs target both forms.

At the forum, Man-Fung Yuen Li Shu Fam, medical foundation professor in medicine, Hong Kong University, who has conducted clinical trials with ARC-520 and ARO-HBV, told the audience that reduction in HBsAg was associated with rises in liver enzymes, reflecting the immune system’s taking up the fight against the virus.

Targeting the host immune system

There is general agreement that in order to obtain a functional HBV cure, let alone an eradication cure where cccDNA is not just suppressed but eliminated, will necessitate rallying the host immune system.

More controversial is whether that rallying will take drugs that directly target the host immune system. Some researchers believe that DAAs can help tip the balance between the virus and the immune system without direct targeting.

However, there are more than a dozen immune-stimulating agents in the anti-HBV pipeline as well.

Most of those are therapeutic vaccines, but several also stimulate the innate immune system.

Abishek Garg, senior research scientist at Gilead Sciences Inc., presented on both the company’s TLR8 agonist, GS-9688, which reduces T-cell exhaustion in preclinical experiments, and its investigational therapeutic vaccine, GS-4774, which is engineered to activate an HBV-specific T-cell response.

Curing HBV faces significant challenges. As several researchers noted during the forum, even the definition of what a functional cure means is still being actively debated, as are the biomarkers that might reliably tell clinicians when they have won the fight. Liver enzyme flares as HBV antigens are decreased, illustrating the inherent trade-off between immunity and immunopathology in attempting to cure the disease, and cccDNA has similarities to the viral reservoir that continues to thwart an HIV cure.

But, Tavis said, 90% to 95% of HBV infections in adults are cleared.

“The immune system can do it,” he said. “That right there is a ray of hope . . . We’ve got to learn to tell it how to do it.”