Precision BioSciences (DTIL) Study update summary

Study background and objectives

• PBGENE-HBV is designed to directly and permanently eliminate cccDNA, the source of HBV replication, aiming for a finite, curative treatment rather than functional suppression.

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

• The ELIMINATE-B study evaluates PBGENE-HBV in chronic hepatitis B patients, focusing on cccDNA elimination, pgRNA as a biomarker, and S-antigen reduction.

• The study enrolled 16 patients across five cohorts, testing various dose levels and intervals.

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

Mechanism of action and biomarker validation

• PBGENE-HBV uses ARCUS gene editing to target and eliminate cccDNA, confirmed by liver biopsies.

• Secondary mechanism edits integrated viral DNA, reducing HBsAg production.

• pgRNA, derived exclusively from cccDNA, is validated as a specific blood biomarker for cccDNA elimination and a strong predictor of successful NUC withdrawal.

• The study's methodology used long-read RNA sequencing to differentiate cccDNA from integrated HBV DNA transcripts.

• HBsAg is not a reliable biomarker for cccDNA elimination, especially in HBeAg-negative patients.

Key efficacy findings

• Liver biopsies showed a 10-fold (1-log) reduction in cccDNA-derived transcripts after PBGENE-HBV treatment, with indels in the remaining <1% of cccDNA inactivating viral replication.

• 100% of patients with detectable pgRNA at baseline became undetectable post-treatment, across multiple dosing regimens.

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

• Repeat dosing led to cumulative editing, with inactivating indels increasing from 23% after two doses to 80% after three.

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