Direct Elimination of cccDNA: Proof from Liver Biopsies

The most critical barrier to curing hepatitis B is cccDNA, a stable minichromosome that hides in the nucleus of liver cells and constantly replenishes the infection. Current treatments can suppress the virus but cannot destroy this reservoir. PBGENE-HBV is designed to do exactly that.

Liver biopsies from the trial, analyzed with long-read transcript sequencing, delivered the first clinical proof that this is happening in humans .

• Direct elimination: After only two doses at the 0.4 mg/kg level, researchers observed a 1-log (10-fold) reduction in cccDNA-derived transcripts, marking the first-ever clinical evidence of direct cccDNA elimination .
• Permanent inactivation: In the small fraction of cccDNA that remained, the gene editor introduced insertion/deletion mutations (indels) that permanently knocked out polymerase function, rendering any remaining viral copies unable to replicate .
• Cumulative editing: The effect of PBGENE-HBV compounded with repeat dosing, reaching 80% editing of the surviving cccDNA pool after three administrations, demonstrating deep, cumulative impact on the viral reservoir .

These biopsy results validate the drug's primary mechanism of action and provide a direct biomarker link between editing and antiviral effect.

pgRNA as a Biomarker for a Cure

Because liver biopsies are invasive, a reliable blood-based biomarker is crucial for broader clinical trials. Pregenomic RNA (pgRNA) is a direct transcript of cccDNA, making it an ideal surrogate for viral activity in the liver. The data showed it is also a precise indicator of gene-editing success.

• 100% pgRNA loss: Every evaluable patient with detectable pgRNA at baseline (6 of 6) achieved a durable loss of blood pgRNA across four distinct dosing cohorts .
• Validated biomarker: This loss of blood pgRNA directly correlated with an undetectable pgRNA in post-treatment liver biopsy, conclusively validating pgRNA as the appropriate clinical biomarker for confirming cccDNA editing .

The finding means that future trials can non-invasively track the drug's ability to eliminate the liver's viral reservoir.

Broad Antiviral Activity Across All Patients

The gene-editing effect translated into clinically meaningful reductions in HBsAg, a key viral protein linked to immune dysfunction. The response was broad, consistent, and durable.

• Universal activity: 100% of the 15 patients treated experienced substantial HBsAg declines. This was observed across all dose levels, different geographies, a wide range of baseline HBsAg levels, and multiple HBV genotypes .
• Sustained durability: In the first patient treated, the HBsAg decline has been maintained for more than 12 months after the initial dose, providing early evidence that the gene-editing effect is permanent, as intended .

Earlier data from the first three cohorts, presented at a previous medical meeting, confirmed that this antiviral activity is dose-dependent and consistent regardless of a patient's starting HBsAg level .

A Manageable Safety Profile

As of the May 4, 2026 data cutoff, 38 doses had been administered across 16 patients in 5 cohorts . The safety picture is a critical factor for a curative therapy aimed at treating a chronic infection with existing, well-tolerated antivirals.

• No dose-limiting toxicities have been observed at any dose level .
• The most common side effects were infusion-related reactions, which were generally mild and manageable .
• The company describes PBGENE-HBV as having a "well-characterized and manageable safety profile" with a clear therapeutic window .

Previous data from cohorts 1 and 2 showed that PBGENE-HBV was well-tolerated upon repeat dosing, with no serious adverse events or clinically significant laboratory abnormalities. All adverse events were mild (grade 1 or 2) and transient .

The Road Ahead: From Suppression to Cure

With the primary mechanism clinically validated, Precision BioSciences is moving aggressively to expand the trial and prepare for registration studies.

• Toward pivotal trials: Enrollment expansion is ongoing in the Phase 1 ELIMINATE-B trial, with plans to advance toward a Phase 2/3 pivotal program .
• Regulatory alignment: The company highlights that PBGENE-HBV's mechanism of eliminating HBV DNA aligns with FDA guidance identifying viral DNA eradication as the optimal endpoint for approval in hepatitis B .

Precision BioSciences sees this data as foundational for a paradigm shift: a move from lifelong, suppressive therapy toward a finite, biomarker-guided, complete viral cure for chronic hepatitis B . With a validated non-invasive biomarker and a safe, effective, and permanent mechanism to destroy the viral reservoir, the path to a functional cure is no longer just a hope—it is a clinical reality in progress.

Direct Elimination of cccDNA: Proof from Liver Biopsies

The most critical barrier to curing hepatitis B is cccDNA, a stable minichromosome that hides in the nucleus of liver cells and constantly replenishes the infection. Current treatments can suppress the virus but cannot destroy this reservoir. PBGENE-HBV is designed to do exactly that.

Liver biopsies from the trial, analyzed with long-read transcript sequencing, delivered the first clinical proof that this is happening in humans .

• Direct elimination: After only two doses at the 0.4 mg/kg level, researchers observed a 1-log (10-fold) reduction in cccDNA-derived transcripts, marking the first-ever clinical evidence of direct cccDNA elimination .
• Permanent inactivation: In the small fraction of cccDNA that remained, the gene editor introduced insertion/deletion mutations (indels) that permanently knocked out polymerase function, rendering any remaining viral copies unable to replicate .
• Cumulative editing: The effect of PBGENE-HBV compounded with repeat dosing, reaching 80% editing of the surviving cccDNA pool after three administrations, demonstrating deep, cumulative impact on the viral reservoir .

These biopsy results validate the drug's primary mechanism of action and provide a direct biomarker link between editing and antiviral effect.

pgRNA as a Biomarker for a Cure

Because liver biopsies are invasive, a reliable blood-based biomarker is crucial for broader clinical trials. Pregenomic RNA (pgRNA) is a direct transcript of cccDNA, making it an ideal surrogate for viral activity in the liver. The data showed it is also a precise indicator of gene-editing success.

• 100% pgRNA loss: Every evaluable patient with detectable pgRNA at baseline (6 of 6) achieved a durable loss of blood pgRNA across four distinct dosing cohorts .
• Validated biomarker: This loss of blood pgRNA directly correlated with an undetectable pgRNA in post-treatment liver biopsy, conclusively validating pgRNA as the appropriate clinical biomarker for confirming cccDNA editing .

The finding means that future trials can non-invasively track the drug's ability to eliminate the liver's viral reservoir.

Broad Antiviral Activity Across All Patients

The gene-editing effect translated into clinically meaningful reductions in HBsAg, a key viral protein linked to immune dysfunction. The response was broad, consistent, and durable.

• Universal activity: 100% of the 15 patients treated experienced substantial HBsAg declines. This was observed across all dose levels, different geographies, a wide range of baseline HBsAg levels, and multiple HBV genotypes .
• Sustained durability: In the first patient treated, the HBsAg decline has been maintained for more than 12 months after the initial dose, providing early evidence that the gene-editing effect is permanent, as intended .

Earlier data from the first three cohorts, presented at a previous medical meeting, confirmed that this antiviral activity is dose-dependent and consistent regardless of a patient's starting HBsAg level .

A Manageable Safety Profile

As of the May 4, 2026 data cutoff, 38 doses had been administered across 16 patients in 5 cohorts . The safety picture is a critical factor for a curative therapy aimed at treating a chronic infection with existing, well-tolerated antivirals.

• No dose-limiting toxicities have been observed at any dose level .
• The most common side effects were infusion-related reactions, which were generally mild and manageable .
• The company describes PBGENE-HBV as having a "well-characterized and manageable safety profile" with a clear therapeutic window .

Previous data from cohorts 1 and 2 showed that PBGENE-HBV was well-tolerated upon repeat dosing, with no serious adverse events or clinically significant laboratory abnormalities. All adverse events were mild (grade 1 or 2) and transient .

The Road Ahead: From Suppression to Cure

With the primary mechanism clinically validated, Precision BioSciences is moving aggressively to expand the trial and prepare for registration studies.

• Toward pivotal trials: Enrollment expansion is ongoing in the Phase 1 ELIMINATE-B trial, with plans to advance toward a Phase 2/3 pivotal program .
• Regulatory alignment: The company highlights that PBGENE-HBV's mechanism of eliminating HBV DNA aligns with FDA guidance identifying viral DNA eradication as the optimal endpoint for approval in hepatitis B .

Precision BioSciences sees this data as foundational for a paradigm shift: a move from lifelong, suppressive therapy toward a finite, biomarker-guided, complete viral cure for chronic hepatitis B . With a validated non-invasive biomarker and a safe, effective, and permanent mechanism to destroy the viral reservoir, the path to a functional cure is no longer just a hope—it is a clinical reality in progress.