Precision BioSciences (DTIL) Study update summary

Study background and objectives

• PBGENE-HBV is designed to directly and permanently eliminate cccDNA, the root cause of chronic hepatitis B infection, using an mRNA-encoded ARCUS nuclease delivered via lipid nanoparticles.

• The ELIMINATE-B trial evaluates PBGENE-HBV across multiple dosing cohorts, focusing on efficacy, safety, and biomarker response in e-antigen negative patients on nucleos(t)ide analogues.

• Chronic hepatitis B cure requires eradication of cccDNA, as current therapies rarely achieve cure and do not eliminate cccDNA.

• FDA guidance emphasizes HBV DNA elimination as a key approval criterion.

• The study aims to demonstrate cccDNA elimination, establish pgRNA as a specific blood biomarker, and assess the durability and safety of gene editing in humans.

Mechanism of action and biomarker validation

• PBGENE-HBV uses ARCUS gene editing to target and eliminate cccDNA, confirmed by liver biopsies, with cumulative editing and permanent inactivation of viral replication.

• Indels in the remaining <1% of cccDNA inactivate viral polymerase, preventing replication.

• pgRNA, derived exclusively from cccDNA, is validated as a specific and predictive blood biomarker for cccDNA elimination and potential cure.

• Loss of pgRNA is associated with a tenfold increase in probability of cure upon nucleoside analog withdrawal.

• S-antigen declines serve as a supportive, though less specific, marker for cccDNA targeting.

Key efficacy findings

• Liver biopsies showed a 10-fold (1-log) reduction in cccDNA transcripts after PBGENE-HBV treatment, with cumulative effects after repeat dosing.

• 100% of patients with detectable pgRNA at baseline achieved undetectable levels post-treatment, across various dosing regimens.

• Substantial and durable S-antigen declines were observed in all treated patients, with responses lasting over a year in some cases.

• Efficacy was consistent across diverse patient populations and HBV genotypes.

• Multiple datasets confirm permanence of effect and broad antiviral activity across dosing cohorts.