Precision BioSciences Reports First Clinical Evidence of Hepatitis B Gene Editing Therapy PBGENE-HBV
核心洞察
Precision BioSciences' PBGENE-HBV demonstrated substantial antiviral activity in all three patients in the lowest dose cohort, achieving 47-69% reductions in hepatitis B surface antigen levels.
The gene editing therapy showed a well-tolerated safety profile with no serious adverse events or dose-limiting toxicities observed across multiple dose administrations.
One patient maintained a durable 50% reduction in HBsAg levels seven months after initial treatment, providing first clinical evidence of sustained viral DNA editing.
Precision BioSciences announced breakthrough Phase 1 clinical data for PBGENE-HBV, marking the first clinical evidence of a gene editing therapy designed to potentially cure chronic hepatitis B by directly targeting the viral DNA source. The ELIMINATE-B trial results demonstrate substantial antiviral activity and a favorable safety profile in the lowest dose cohort, establishing proof-of-activity for this novel therapeutic approach.
Safety Profile Establishes Foundation for Dose Escalation
PBGENE-HBV demonstrated a well-tolerated safety profile across all three patients in Cohort 1, who each received three planned administrations of 0.2 mg/kg dosed approximately eight weeks apart. No patient experienced above a Grade 2 treatment-related adverse event, serious adverse event, or dose-limiting toxicity. Additionally, no clinically significant laboratory abnormalities were observed, including liver enzymes and platelets.
"We are pleased to continue to observe an impressive clinical safety profile, with transient changes in liver transaminases remaining less than three times the upper limit of normal with no clinical symptoms for both dose levels," said Cassie Gorsuch, PhD, Chief Scientific Officer at Precision BioSciences.
The favorable safety data has enabled progression to higher dose levels, with the Data Monitoring Committee endorsing enrollment of Cohort 3 to test the next higher dose level.
Substantial Antiviral Activity Across All Patients
At the 0.2 mg/kg dose level, PBGENE-HBV demonstrated substantial hepatitis B surface antigen (HBsAg) reduction in all three patients, with best response reductions of 56% (0.36 log), 69% (0.51 log), and 47% (0.28 log) compared to baseline levels. Notably, one of three patients (33%) achieved a durable HBsAg reduction of approximately 50% (0.3 log) from baseline that was maintained seven months after the initial dose administration.
"This exciting dataset provides the first clinical evidence of substantial HBsAg reductions as a result of direct cccDNA (搜索) elimination and/or inactivation of integrated HBV DNA (搜索) in all patients, even at this lowest dose level," said Man-Fung Yuen, MBBS, M.D., PhD, DSc, ELIMINATE-B Investigator and Chair Professor of The University of Hong Kong.
The other two patients demonstrated antiviral response after each dose administration but eventually returned to baseline HBsAg levels. According to the researchers, transcriptional upregulation from unedited viral DNA remaining after administration at the lowest dose is likely responsible for the HBsAg increase in these patients.
Addressing Critical Unmet Medical Need
Chronic hepatitis B affects an estimated 300 million people worldwide, with current treatments providing viral suppression but rarely achieving functional cure rates above 1-3%. The disease is primarily driven by persistence of HBV covalently closed circular DNA (cccDNA (搜索)), which enables continued viral replication, and integration of HBV DNA (搜索) into the human genome in liver cells.
"For decades investments in potential new treatments aimed to cure chronic hepatitis B have focused on modalities that cannot alter cccDNA (搜索), the genetic source of the disease," said Jordan Feld, M.D., M.P.H., Professor of Medicine at the University of Toronto and Precision Hepatitis Scientific Advisory Board Member. "We are hopeful that this approach will offer a safe drug that will raise the achievable functional cure rate from the current 1-3% to the global goal of 30%."
An estimated 15% to 40% of patients with HBV infections may develop complications such as cirrhosis, liver failure, or liver cancer (hepatocellular carcinoma), which affects over 500,000 patients globally on an annual basis and accounts for the majority of HBV-related deaths.
Clinical Development Strategy and Next Steps
The ELIMINATE-B trial is designed with two optimization levers: dose escalation and shortened dosing intervals. Cohort 2 is currently evaluating PBGENE-HBV at 0.4 mg/kg, with initial safety data showing no adverse events above Grade 2, no serious adverse events, and no dose-limiting toxicities in the patients who have received treatment.
The company intends to evaluate PBGENE-HBV at increasing and more frequent doses until a maximum tolerated dose is reached, with the goal of establishing the optimal dose and administration schedule for achieving complete cure. Based on dose-dependency observed in nonclinical models, researchers anticipate deeper and more durable responses as the study progresses.
"Given our mechanism, proof of sustained viral marker reduction as a result of viral editing in one patient was critical to reinforce the thesis behind PBGENE-HBV," said Gorsuch. "The ELIMINATE-B protocol permits shortening the dosing interval, which is now supported by human safety data from Cohort 1 and Cohort 2 currently in progress."
The company is generating molecular data using liver biopsies to demonstrate PBGENE-HBV's mechanism of action in eliminating cccDNA (搜索) and inactivating integrated HBV DNA (搜索). Precision BioSciences expects to provide a data update later in 2025 and has extended its expected cash runway to the second half of 2027, enabling potential commencement of Phase 2 studies.