FDA Clears First-Ever In Vivo Gene-Editing Trial for Chronic Hepatitis B in the United States

Precision BioSciences announced on Monday that the FDA has cleared its Investigational New Drug (IND) application for PBGENE-HBV, a meganuclease-edited in vivo therapeutic candidate in development as a curative treatment for chronic hepatitis B virus (HBV) infection.

PBGENE-HBV is Precision’s lead gene-editing programme and is currently being evaluated in the ELIMINATE-B trial. IND clearance for the candidate, which was developed using Precision’s proprietary meganuclease platform ARCUS, not only allows Precision to expand the ELIMINATE-B trial to the United States but also represents the first-ever investigational in vivo gene-editing therapy cleared to enter a clinical trial for the treatment of chronic HBV in the United States.

According to the official press release, PBGENE-HBV will now be evaluated at the Liver Center at Massachusetts General Hospital, joining the ongoing ELIMINATE-B trial currently enrolling patients in Moldova, Hong Kong, and New Zealand. The company disclosed in the same press release that it is in the final stages of U.S. site activation to begin patient enrolment.

»We are conducting a Phase 1 study across five countries, involving up to 45 patients. Our site selection was based on several criteria, including a large prevalent patient population and regions that are leaders in chronic hepatitis B (cHBV) Phase 1 drug development, and certain sites have experience working with genetic therapies,« said Murray Abramson, MD, MPH, Head of Clinical Development at Precision BioSciences.

PBGENE-HBV targets the root cause of chronic HBV infection

Chronic HBV affects approximately 300 million people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. Current standard-of-care treatments suppress viral replication but rarely achieve functional cure.

PBGENE-HBV comprises a meganuclease-encoding mRNA encapsulated in a lipid nanoparticle (LNP) and is designed to eliminate covalently closed circular DNA (cccDNA) and inactivate integrated HBV DNA; these are the persistent forms of the virus that serve as templates for viral replication and antigen production. By targeting these, PBGENE-HBV is designed to be curative by addressing the root cause of chronic HBV infection.

»Our therapy is designed to deliver a cure. We measure this through a regulatory endpoint called functional cure where the two key viral markers, HBV DNA and hepatitis B surface antigen (HBsAg) remain undetectable in the blood for at least 6 months off-treatment. Since our modality is the only clinical approach designed to eliminate cccDNA and inactivate integrated HBV DNA, we believe we may assess whether a patient is cured earlier than the 6-month timepoint, but this is the standard endpoint utilised for most therapies today,« explained Cassie Gorsuch, Chief Scientific Officer at Precision BioSciences.

Clinical data from ELIMINATE-B trial expected later this year

Investigators leading the ELIMINATE-B trial recruited the first cohort of patients within the first month of open enrolment and are currently administering additional doses to patients in Cohort 1 at the lowest dose level (0.2 mg/kg). The company expects to escalate to a higher dose level in Cohort 2 with the goal of defining the optimal dose and number of dose administrations for safely eliminating cccDNA and inactivating integrated HBV DNA.

Precision notes in its press release that it also plans to expand the study to the United Kingdom and continue accelerating recruitment and evaluation of a genetically-diverse patient population. More detailed clinical data from the ELIMINATE-B trial is expected throughout 2025.

The IND clearance represents the latest development for Precision's ARCUS in vivo gene-editing platform this year, following last month’s positive clinical data from the first cohort of the ELIMINATE-B trial. In that update, which we wrote about here, Precision BioSciences reported that PBGENE-HBV was safe and well tolerated in all three participants after the first administration at the lowest dose level (0.2 mg/kg). Two of the three participants demonstrated substantial reductions in hepatitis B surface antigen (HBsAg) following this initial administration, suggesting anti-viral activity even at the lowest dose tested.

The ELIMINATE-B protocol is designed for three dose administrations at each dose level, with the goal of maximising cumulative viral editing to achieve undetectable levels of HBsAg.

»In the Phase 1 ELIMINATE-B trial, we will primarily focus on determining the safety and efficacy of PBGENE-HBV. For efficacy, we will monitor anti-viral activity through a finite treatment up to three dose administration and we will investigate this regimen across different dose levels to answer the question: What is the right number of doses and what dose level moves a patient towards cure? We will be measuring any changes from baseline levels of biomarkers such as HBsAg and anti-HBs levels as well as other exploratory markers like HBcrAg and HBV RNA,« said Gorsuch.

Commenting on the safety and efficacy of PBGENE_HBV, Gorsuch said: »We have been highly encouraged with our early clinical data that demonstrated good tolerability of PBGENE-HBV. It is our view that the safety of PBGENE-HBV is driven by both the LNP formulation as well as the mRNA that is encapsulated in the LNP. During our preclinical development of PBGENE-HBV, we did extensive optimisation work on the mRNA design, manufacturing process, and analytics. We can produce very high-quality mRNA, enabled by the very small size of ARCUS nucleases, requiring production of a short mRNA sequence. Smaller or shorter mRNAs are easier to produce in high quality, and ARCUS is anywhere from 4-8 times smaller than some of the other gene-editing technologies utilising LNP delivery. We have also optimised the mRNA sequence and manufacturing parameters to ensure high quality and high yield mRNA and LNPs. Together, these optimisation steps have resulted in high potency and good safety of PBGENE-HBV.«

Speaking about how patients might respond to the latest news about PBGENE-HBV, Chari Cohen, President of the Hepatitis B Foundation, said »I am sure the hepatitis B community will be excited to learn of this progress, as we at the Hepatitis B Foundation are - especially given the challenges with targeting cccDNA. People living with chronic hepatitis B are eagerly waiting potential new treatment options, especially options that might lead to functional cure. We are very pleased to see industry prioritising hepatitis B and advancing new treatment options.«

Stay tuned for more updates

We will continue to update you on the ELIMINATE-B trial and other gene-editing trials as new details emerge. In the meantime, you can find all of our coverage on clinical-stage gene editing programmes here.

For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.

This article was originally published on 19 March 2025, and was updated on 24 March 2025, to include insights from Murray Abramson, MD, MPH, Head of Clinical Development at Precision BioSciences, Cassie Gorsuch, Chief Scientific Officer at Precision BioSciences, and Chari Cohen, President of the Hepatitis B Foundation (United States).