Hepatitis B is a serious and globally prevalent disease with 296 million people worldwide living with chronic hepatitis B virus (HBV) infections. Recent advances in HBV therapeutics have made infection a treatable disease, but they only disrupt certain areas of the HBV lifecycle. As a result, if the therapeutics are withdrawn, patients can relapse. What’s more, long-term use can cause antiviral resistance.
To cure the disease, therapeutics need to address every stage of the HBV lifecycle, providing both seroclearance of the hepatitis B surface antigen (HBsAg) and silencing of the genomically integrated HBV DNA. However, investment in this space carries considerable risk as developers struggle to move treatments from animal models to human studies. Notably, human responses to HBV therapies are notoriously difficult to predict and traditional animal models translate poorly to the human environment, causing significant delays, as well as safety, cost, and efficacy concerns.
The main problem with translatability lies in the fact that human HBV only infects human and chimpanzee hepatocytes. This makes finding an appropriate animal model challenging since chimpanzees can no longer be used for this type of research. Only humanized liver animal models have been truly effective in this space since they are the only preclinical model to truly recapitulate infection.
The HBV lifecycle is multifaceted and unique, with many stages and a highly stable molecular template DNA that confers the chronic nature of the disease. Although each stage provides a potential target for therapies, a complete cure requires the disruption of every stage of the viral lifecycle. Therefore, to measure the effectiveness of a potential therapeutic, every part of the cycle must be assessed during preclinical testing. This adds an extra layer of complexity, particularly as measurements must be made at both the liver and serum levels.
HBV’s complicated lifecycle also impacts study design. It can be hard to define the study length and the toxicity and efficacy parameters, making it difficult to predict what data will be available, and when, to decision-makers and the total cost of this preclinical work.
If insufficient or uninterpretable data is gathered in preclinical stages, due to the limited scope of measurable parameters or the timelines needed to measure efficacy or toxicity, testing is unlikely to progress to clinical stages. This could mean that promising therapies may be dropped in error when they could show success in human trials.
More worryingly, if the preclinical model cannot accurately predict human responses, then it has limited clinical relevance. As such, even if the data produced in suboptimal rodent models indicates a potential clinical benefit, the chances of failure are high when such therapeutics are tested in patients. They may not show efficacy, for example, and could carry additional, unknown toxicity risks, wasting precious time and money and raising safety concerns.
Powerful humanized liver models now exist that enable accurate translation to the human environment, allowing true infection and the measurement of all stages of the viral lifecycle in both liver and serum assays.
When choosing a preclinical model, ensuring that it guarantees a high and predictable baseline of viral infection to make lifecycle measurements possible, and that it provides the most accurate efficacy and toxicity data, is imperative. Moreover, it is vital that it exhibits key features of the HBV lifecycle, including the presence of cccDNA.
Choosing the right model is only the first step. All animal models are unpredictable, and unexpected in-life instances can quickly derail a project. To keep your project on track, choose a trusted partner with skilled personnel that are highly experienced in HBV preclinical studies, and ensure they offer biosafety level 2 laboratories. Additionally, a trusted partner can make sure animal health is guaranteed, for both ethical and efficacy reasons.
The team you work with will be crucial at all stages of study design and execution and will bring in-depth knowledge to ensure your studies are set up in the most timely and cost-effective manner. Together with an expert partner, you can be more confident in your preclinical studies, and mitigate risks before they become challenges — ultimately helping to streamline your route to clinical trials.