VRON-0200: A First-in-class treatment for chronic HBV infection

Where Is The Unmet Need?

Where Is The Unmet Need?

Despite HBV Preventative Vaccines, Chronic Infection is a High Unmet Need​, with 1 in 4 People Infected, Dying Prematurely

Globally, 279.9 million people were estimated to be infected with HBV in 2020.1 HBV infection impairs CD8+ T cells resulting in the loss of viral control. This makes HBV an ideal target for immune modulators, though therapies using currently available technology have shown limited long-term clinical benefits. There is an urgent unmet need for effective therapies that stimulate new functional CD8+ T cells and restore viral control, to address the goal of functional cure for persons with chronic HBV.

Chronic HBV remains a global public health problem despite vaccination2​

1 in 4 people with chronic HBV will die prematurely from liver cirrhosis, HCC, ​or liver failure3​

Antivirals rarely achieve functional cure and require lifelong drug therapy4​

CD8+ T cells become impaired during chronic HBV infection, resulting in loss of viral control​

Immune modulators for functional cure of chronic HBV have shown limited clinical benefits5–9​

Novel treatments are needed to stimulate new functional CD8+ T cells​

Vaccine approaches that stimulate naïve T cells to de novo epitopes may restore viral control10

OUR APPROACH​ FOR CHRONIC HBV FUNCTIONAL CURE

ELIMINATE
cccDNA-infected hepatocytes

STIMULATE & EXPAND
NEW HBV-specific ​CD8+ T cells to RESTORE  immune control​

How Does VRON-0200 Work?

How Does VRON-0200 Work?

VRON-0200 is designed with the goal of providing a functional cure for chronic HBV infection. While the virus itself stimulates expansion of HBV-specific CD8+ T cells, they soon become exhausted, placing limits on their ability to proliferate and control the virus.11 VRON-0200, through checkpoint modification, is able to mitigate this exhaustion by lowering the activation threshold and stimulating T cells to sub-dominant epitopes that are not activated by HBV infection, which promotes further CD8+ T cell expansion and viral control.12–17

Checkpoint modification by gD lowers the CD8+ T cell activation threshold​.

Addresses a global high unmet medical need​

Unique design for multiple HBV functional cure programs using selected HBV core & pol antigens​

HBV T cell immunotherapy with checkpoint modifier

  • Amplified & expanded immunogenicity of CD8+ T cell responses​
  • Required for antiviral activity​
  • By mechanism, may lower risk for serious “off-target” side effects​

Heterologous chimpanzee adenoviral vectors​

  • Limited pre-existing vector immunity​
  • Limited cross-vector immunity​
  • Allows for optimal prime/boost strategies​

VRON-0200: Targeted Antigen Selection​

Our goal is to develop a functional cure for chronic HBV infection. Research has shown that expansion of HBV-specific CD8+ T cells induced by the infection is limited by CD8+ T cell exhaustion. VRON-0200 induces a very potent and broad CD8+ T cell response that includes responses to the core and pol regions not normally induced by the infection; as such, a new and highly functional immune response is stimulated to help clear the virus.12–14

HBV DNA & S antigen Titers Produced By Different Hepatocyte Cell Types​

VRON-0200 targets the core & pol of HBV​.

VRON-0200: Antigen Selection & Testing​

The selection of components for our VIACT™ platform involved screening a total of 8,629 HBV viral genomes for consensus sequences across genotypes A through D. Discrepancies were adjudicated via HLA prediction algorithms for broadest possible human responses.

Individual regions tested separately for immunogenicity and breadth of responses​15,16

VRON-0200: Candidate Optimization​

Antigenic regions, with no immunity, within each target, were removed​.

Remaining antigenic regions were combined, fused to gD (VRON-0200) and compared to gDPolN (most immunogenic region)​.15,17

VRON-0200: Efficacy Evaluation

Multi-log HBV DNA viral load declines were observed with single intramuscular injection (AAV; gDPolN).15

 

† P-value <0.0001 by ordinary one-way ANOVA.

In preclinical studies, combining gD into a therapeutic HBV vaccine enhanced antiviral activity, including reducing viral loads, which also correlated with more potent and sustained CD8+ T cell responses.10

 

Mouse model: AAV8-1.3HBV

Abbreviations and References (including figures)

AAV, adeno-associated virus; AdC6, heterologous chimpanzee adenoviral viral vector of serotype 6; ANOVA, analysis of variance; BL, baseline; cccDNA, covalently closed circular DNA; CD, cluster of differentiation; F, flare; gD, glycoprotein D; HBV, hepatitis B virus; HBV2, core & pol without gD; HCC, hepatocellular carcinoma; HLA, human leukocyte antigen; IFN, interferon; IM, intramuscular; NF, no flare; NRTI, nucleos(t)ide reverse transcriptase inhibitor; pol, polymerase; PolN, N terminus of polymerase; PolC, C terminus of polymerase; vp, viral particles; VRON-0200, core and pol fused with gD.

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