Hepatitis B: are we edging closer to a cure?

Cure for hepatitis B

A viral infection that affects the liver and can cause both acute and chronic disease, hepatitis B affects around 296 million people worldwide. According to the latest statistics from the World Health Organization (WHO), it resulted in an estimated 820,000 deaths in 2019. 

The virus is most commonly transmitted to children during childbirth, but it can also be passed on through contact with blood and other bodily fluids during sex, unsafe injections, or exposure to sharp instruments.

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    How does chronic hepatitis B affect a person’s daily life?

    Although acute hepatitis B infections generally resolve within six months and do not require treatment, chronic infections – meaning the infection lasts for longer than six months – can be a lifelong problem, leading to serious long-term health issues, including liver damage, cirrhosis, and liver cancer. It can even be fatal.

    “Chronic hepatitis B profoundly impacts patients’ quality of life. Physically, individuals may suffer from symptoms including abdominal pain, fatigue, nausea, and vomiting. The psychological toll can be equally significant, encompassing fear of disclosure, and transmission. Experiences of discrimination and stigmatization can exacerbate social isolation, leading to depression, and anxiety,” commented Sandra Phillips, senior scientist in the Liver Immunology group at the Institute of Hepatology, King’s College London. 

    A cure, therefore, would significantly alter patients’ lives, alleviating both the symptomatic and psychological toll caused by chronic hepatitis B infections. But just how far away are we from a cure?

    Finding a functional cure for hepatitis B

    According to Phillips, the ultimate aim is to find a “functional cure” for hepatitis B, which can be defined as resulting in a sustained undetectable hepatitis B DNA level and a loss of hepatitis B surface antigens (HBsAg) post-treatment. 

    “This functional cure mimics natural resolution of infection, further decreasing hepatocellular carcinoma (HCC) risk, making it a highly desirable outcome for patients. A complete cure and a sterilizing cure remain elusive due to the persistence of the covalently closed circular DNA (cccDNA), the template for hepatitis B replication, the cause for hepatitis B chronicity, and the presence of integrated hepatitis B DNA fragments in the chromosomal host,” explained Phillips. 

    Currently, the main option for patients with chronic hepatitis B includes antiviral treatment with nucleoside/nucleotide analogs (NUCs).  

    “Direct-acting antivirals that target the viral polymerase, which replicates the genome, are the most common treatment options for chronic hepatitis B. They are well tolerated and effective in suppressing genome replication, but because the genome persists even in the absence of replication, cure is rarely achieved,” said Bill Schneider, research associate at Rockefeller University’s Laboratory of Virology and Infectious Disease.

    It is worth noting that there is also an established vaccine available that provides protection against hepatitis B, but it is solely a preventative measure and does not offer a cure for active infections.

    Latest research in search of a cure for hepatitis B

    There is, however, a lot of research taking place around finding a cure for hepatitis B, especially since its cousin virus, hepatitis C, can now be cured in around 95% of cases with antivirals. 

    In fact, Schneider was very recently involved in a study whereby researchers developed an approach for studying hepatitis B in the lab that allows a much better view of the virus’ behaviors and characteristics during a crucial part of its lifecycle. 

    “Hepatitis B is considered a DNA virus, but its genome passes through an RNA intermediate during replication. We exploited this feature by initiating hepatitis B genome replication with RNA. One benefit of this approach is that it has excellent signal-to-noise properties, which enabled us to identify and quantify rare drug resistant variants in the population,” explained Schneider.

    “Monitoring and addressing drug resistance is an important component of antiviral therapeutic development, and this approach may therefore be useful for the cure effort. We also envision the method being useful for earlier steps in drug discovery, such as in high-throughput screens.”  

    And, according to Phillips, the discovery of a cure for hepatitis C also seems to have galvanized pharmaceutical and biotech companies, which are now redoubling their efforts in search of a cure for hepatitis B.

    Bepirovirsen enters phase 3 clinical trial 

    A particularly promising therapeutic that is currently in development for hepatitis B is called bepirovirsen. It is an investigational antisense medicine designed to inhibit the production of viral proteins associated with hepatitis B. 

    These proteins are associated with infection and replication, including the hepatitis B surface antigen (HBsAg), which is also linked to a poor prognosis in people with chronic hepatitis B. By simultaneously reducing hepatitis B virus replication and suppressing viral antigens, it is hoped that the therapy will stimulate innate immunity and become a functional cure for patients. 

    The development of bepirovirsen is a collaborative effort between Ionis Pharmaceuticals and GSK, which licensed Ionis’ hepatitis B program in August 2019 under a collaborative development and license agreement. The companies announced earlier this year that two phase 3 trials had been initiated to further evaluate bepirovirsen. There are also plans for it to be tested in a phase 2 trial at some point this year in combination with Arrowhead Pharmaceuticals’ small interfering ribonucleic acid (siRNA) therapeutic hepatitis B medicine JNJ-3989, after GSK picked up the licensing deal for the therapy from Janssen in October. 

    Furthermore, based on promising results from the completed phase 2b trial of bepirovirsen, as well as its long-term follow-up trial, the U.S. Food and Drug Administration (FDA) decided to grant fast track status to the drug; a promising step forward toward bringing a hepatitis B cure to the market. 

    Barinthus Biotherapeutics’ hepatitis B candidate VTP-300 sees positive data 

    Another drug that has seen positive results so far in clinical trials for the treatment of chronic hepatitis B infection is Barinthus Biotherapeutics’ – formerly known as Vaccitech – VTP-300, which is a novel antigen-specific immunotherapy.

    In March last year, it was announced that the phase 1b/2a clinical trial of the drug had produced positive topline final data. The trial included 55 patients with chronic hepatitis B, and VTP-300 was observed to induce meaningful, sustained reductions of HBsAg in patients.

    More recently, Barinthus also presented positive interim data from a phase 2b and phase 2a trial of VTP-300. The first study pairs VTP-300 with a low dose of Opdivo (nivolumab) – an anti-PD-1 antibody – and standard-of-care nucleus(t)ide analog (NUC) therapy. The combination led to significant HBsAg reduction in patients in all treatment groups. 

    Meanwhile, the phase 2a trial, which combined VTP-300 with Arbutus Biopharma’s RNAi candidate imdusiran, showed “robust reductions” of HBsAg when patients initially received only imdusiran for 24 weeks. When the patients then received ATP-300 or placebo at week 26 and 30, in addition to ongoing NUC therapy, Barinthus’ treatment appeared to maintain the patients’ low HBsAg levels, while the placebo group saw an increase in their levels about 12 weeks after receiving their final dose of imdusiran. 

    New vaccine candidate TherVacB enters clinical trials for hepatitis B

    The most recent candidate to enter clinical trials for hepatitis B is another therapeutic vaccine, known as TherVacB, after a first-in-human clinical trial was initiated for it on January 25, 2024. 

    The vaccine has already gone through extensive preclinical testing, having progressed through 12 years of basic research. It was designed and developed under the leadership of Helmholtz Munich. The phase 1a trial will investigate the safety and immunogenicity of the vaccine in 24 healthy participants aged 18 to 65 years. 

    “TherVacB is based on a deep understanding of the challenges of the immune system in chronic HBV infection, and is the result of years of dedicated research here in Munich,” said professor Ulrike Protzer, the leading scientist behind the vaccine, in a press release by the German Center for Infection Research. “Our approach is designed to induce exactly the type of immunity required and cover a broad spectrum of over 95% of HBV strains worldwide.”

    Preparations are also underway for applying for the first-in-patient phase 1b/2a trial for TherVacB, which will aim to assess the safety and efficacy in patients with chronic hepatitis B. This study is planned to take place in Germany, Italy, Spain, England, and Tanzania, and is funded by the European Union as part of a Horizon 2020 research project.

    What are the barriers to hepatitis B cure progress?

    According to an article in Fierce Biotech, a database maintained by the Hepatitis B Foundation shows that the number of hepatitis B treatments in the clinic has risen from 26 in 2016 to 40 in 2023. While this might sound like a positive statistic, the number of preclinical candidates has fallen from 10 to nine, meaning that there are very few next-generation options coming in behind the current crop of clinical candidates. If a functional cure is not found within the current batch, then the wait for one could drag on even longer, leaving the community of people living with chronic infection in limbo.  

    The disheartening reality is that a lot of companies have already tried and failed to come up with a cure. Last year, Johnson & Johnson ended all of its hepatitis drug development as part of a larger closure of its infectious disease and vaccine unit. Most recently, announced just last week, Altimmune also decided to cut its hepatitis B program following a phase 2 trial failure.  

    Phillips pointed out that finding a cure for hepatitis B has proven so difficult because of the intricate nature of its replicative life cycle and the profound immune dysregulation that exists in chronic hepatitis B. 

    “It is increasingly apparent that combinatorial therapies involving direct-acting antivirals (DAAs) and immunomodulatory agents, each with a distinct mode of action, represent the future of hepatitis B therapeutics. However, determining the optimal combinations, appropriate scheduling and treatment duration that induce a functional cure present a significant challenge. Above all, these therapeutic strategies must exhibit excellent safety profiles,” said Phillips.

    What is certain is that, given the toll chronic infection has on a person’s life, as well as the fact that it is clearly a significant global health problem, eventually developing a cure for hepatitis B would be a “monumental achievement,” as Schneider put it. And with GSK’s bepirovirsen currently being tested in phase 3 trials, perhaps there is reason for the hepatitis B community to be hopeful that a cure might be just around the corner.

    This article was originally published in July 2023 and has since been updated by Willow Shah-Neville in April 2024.

    Explore other topics: GSKhepatitisLiver diseaseviruses

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