Brii's HBV Functional Cure Rates Impress, But Durability Void Remains the Decisive Risk

Brii Bio Reports Positive EOT Data for HBV Trials

Brii Biosciences reported topline end-of-treatment (EOT) data from its Phase IIb ENRICH and ENHANCE trials, evaluating sequential and concurrent regimens of BRII-179, elebsiran, and PEG-IFNα for chronic hepatitis B virus (HBV) infection. The ENRICH study, using BRII-179 as a priming therapy, showed HBsAg loss rates of 42.9% (42 of 98 patients) with five doses and 40% (20 of 50 patients) with seven doses, aligning with previous ENSURE Cohort 4 data. The ENHANCE (Part A-1) concurrent triple combination achieved a 25.5% HBsAg loss rate (25 of 98), higher than the PEG-IFNα alone control arm (10.2%). Subgroup analyses in ENHANCE suggested BRII-179's immune response benefits across baseline HBsAg levels. The ENHANCE Part A-2 sequential therapy resulted in a 22.5% HBsAg loss rate (18 of 80). Brii Bio is in preliminary alignment with China's NMPA for a potential registrational trial, favoring the ENRICH study design. No new safety issues were reported.

• The ENRICH study, which investigated BRII-179 as a priming therapy followed by elebsiran and PEG-IFNα, demonstrated significant hepatitis B surface antigen (HBsAg) loss rates. Patients receiving five doses of BRII-179 achieved a 42.9% HBsAg loss (42 out of 98), while those on seven doses showed a 40% loss (20 out of 50). These results are consistent with prior ENSURE Cohort 4 data, reinforcing BRII-179's immune priming potential.
• The ENHANCE (Part A-1) trial, testing a concurrent triple combination, yielded an HBsAg loss rate of 25.5% (25 out of 98), which, while not exceeding previous ENSURE Cohorts 2 and 3, was notably higher than the 10.2% observed in the PEG-IFNα alone control arm. Subgroup analyses further indicated that BRII-179 may induce beneficial immune responses irrespective of baseline HBsAg levels, particularly in patients with higher initial readings (1,000IU/mL-3,000IU/mL).
• The ENHANCE Part A-2 study, employing a sequential therapy of BRII-179 plus elebsiran followed by elebsiran and PEG-IFNα, resulted in an HBsAg loss rate of 22.5% (18 out of 80), suggesting the necessity of a full course of PEG-IFNα for optimal efficacy. Based on these insights, Brii Bio has engaged with China’s NMPA and reached preliminary alignment for a potential registrational trial, with the ENRICH study design being preferred for future development.

Unpacking the ENRICH and ENHANCE Trial Designs for Chronic HBV

The clinical trial landscape for chronic hepatitis B (CHB) spans a broad range of study designs, from randomized controlled trials and meta-analyses to retrospective cohort studies, each deploying distinct virological, serological, and histological endpoints. Across this evidence base, primary endpoints have evolved from simple HBV DNA suppression toward more stringent goals, including functional cure defined as sustained HBsAg loss with HBV DNA below the lower limit of quantitation (LLOQ) at 24 weeks post-treatment. The table below synthesizes key design parameters and endpoints from pivotal and representative CHB trials.

Topline Efficacy and Safety of BRII-179 Combinations in HBV

Recent clinical investigations in chronic hepatitis B (CHB) have yielded meaningful efficacy and safety data across a range of antiviral strategies — from nucleos(t)ide analog switching trials to novel capsid assembly modulators and immunotherapy combinations. The studies summarized below span Phase II and Phase III designs, with several addressing unmet needs such as low-level viremia, functional cure, and HBV management in oncology settings.

• B-Well 1 and B-Well 2 (Phase 3) — Bepirovirsen: Two replicate, double-blind, placebo-controlled trials enrolled adults with noncirrhotic CHB on stable nucleos(t)ide analog (NA) therapy (HBsAg 100–3,000 IU/mL), randomized 2:1 to subcutaneous bepirovirsen 300 mg weekly or placebo for 24 weeks, with NA discontinuation at week 48. The primary endpoint — functional cure (sustained HBV DNA below LLOQ plus HBsAg loss for ≥24 weeks) at week 72 — was achieved in 20% of bepirovirsen-treated patients in B-Well 1 (127/650 vs. 0/328 placebo) and 19% in B-Well 2 (106/570 vs. 0/286 placebo). Pooled safety data showed adverse events in 91% of bepirovirsen recipients vs. 73% placebo; grade ≥3 adverse events occurred in 16% vs. 3%, with ALT elevations being the most common grade 3 event (6%). Serious adverse events were reported in 7% vs. 4% (NCT05630807; NCT05630820; funded by GSK).

• Besifovir Switching Trial (2025) — Besifovir vs. Tenofovir Disoproxil Fumarate: This non-inferiority randomized trial enrolled 153 CHB patients with HBV DNA <20 IU/mL after ≥48 weeks of TDF therapy (median prior TDF duration: 4.14 years), randomized to besifovir (BSV) 150 mg or TDF 300 mg for 48 weeks. Per-protocol analysis (n=130) demonstrated non-inferior virologic suppression: 100.0% of the BSV group vs. 98.5% of the TDF group maintained HBV DNA <20 IU/mL (95% CI −0.01 to 0.04; P>0.999; predefined margin −0.18). BSV was associated with improved renal function (eGFR change: +1.67±11.73% vs. −1.24±11.02%) and significant improvements in bone turnover biomarkers, with increases in hip and spine bone mineral density, suggesting a favorable long-term safety profile relative to continued TDF.

• GST-HG141 Phase II Trial (2025) — GST-HG141 (Capsid Assembly Modulator): A randomized, double-blind, placebo-controlled, multicenter trial (NCT05637541) conducted across ten Chinese centers enrolled 90 CHB patients with low-level viremia (HBV DNA 20–2,000 IU/mL) on NA therapy for >1 year, randomized 1:1:1 to GST-HG141 50 mg BID, 100 mg BID, or placebo for 24 weeks. At week 24, HBV DNA <20 IU/mL was achieved in 84.0% (low-dose) and 81.5% (high-dose) vs. 32.1% placebo (p<0.05 for both comparisons). Mean HBV DNA reductions exceeded 1 log IU/mL in both active arms; pregenomic RNA (pgRNA) declined by an average of 1.7 log copies/mL, with undetectable pgRNA in 60% and 55% of low- and high-dose groups respectively, vs. 9.5% placebo. Adverse event rates were comparable across all groups, supporting a favorable tolerability profile.

• KEYNOTE-966 HBV Subgroup Post Hoc Analysis (2026) — Pembrolizumab + Gemcitabine/Cisplatin: This post hoc analysis of the Phase 3 KEYNOTE-966 trial examined whether HBV infection status affected outcomes in 1,069 patients with advanced biliary tract cancer randomized 1:1 to pembrolizumab 200 mg IV Q3W or placebo, combined with gemcitabine and cisplatin for ≤35 cycles. Of 329 HBV-positive participants (30.8%), 30 had chronic and 299 had clinically resolved HBV; antiviral prophylaxis was mandated for chronic HBV patients. Overall survival HRs were closely aligned: 0.87 (95% CI 0.69–1.10) for HBV-positive and 0.85 (95% CI 0.73–0.99) for HBV-negative subgroups, with consistent safety profiles. Eight cases of HBV reactivation occurred (5 pembrolizumab, 3 placebo); no HBV-associated hepatitis was observed, supporting the safety of pembrolizumab-based regimens in HBV-positive oncology patients with appropriate antiviral monitoring.

• DLBCL with CHB Multicentre Cohort Study (2026) — Entecavir Antiviral Prophylaxis: This retrospective multicentre study identified 112 CHB patients among 1,120 newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients, stratified by baseline HBV DNA load (low: <10 IU/mL, n=82; high: ≥10 IU/mL, n=30). Entecavir-based antiviral prophylaxis effectively suppressed HBV DNA to undetectable levels in high-load patients (median baseline 1.65×10 IU/mL; p=0.001). Three-year cumulative HBV reactivation rates were low overall (4.2%), with no significant difference between high- and low-load groups (4.5% vs. 4.1%; p=0.955), though one fatal reactivation occurred following antiviral discontinuation. Hepatotoxicity was mild (grade 1–2 transaminase elevations in 33.3%–36.7%), and oncologic outcomes were comparable between strata: 3-year PFS 80.9% vs. 70.6% (p=0.137), ORR 86.7% vs. 82.9%, and CR rates 70.0% vs. 64.6%, findings confirmed on propensity score–matched analysis.

BRII-179's Role in Advancing Combination Therapies for HBV

Recent clinical investigation into chronic hepatitis B (CHB) has increasingly focused on combination regimens capable of achieving functional cure — defined as sustained HBsAg loss — rather than mere virological suppression. One of the more compelling direct-acting antiviral combinations to emerge is GST-HG141, an HBV capsid assembly modulator, evaluated in combination with nucleos(t)ide analogs (NUCs) in a Phase II randomized, double-blind, placebo-controlled multicenter trial (NCT05637541) conducted across ten centers in China between January 2023 and July 2024. Among 90 participants on background NUC therapy for over one year with residual low-level viremia (HBV DNA 20–2,000 IU/mL), those receiving GST-HG141 at 50 mg BID or 100 mg BID for 24 weeks achieved HBV DNA levels below 20 IU/mL in 84.0% and 81.5% of cases, respectively, versus 32.1% in the placebo arm (p < 0.05). Mean HBV DNA reductions exceeded 1 log IU/mL in both active treatment groups, and pregenomic RNA (pgRNA) declined by an average of 1.7 log copies/mL, with 60% and 55% of patients achieving undetectable pgRNA compared to just 9.5% on placebo — underscoring the potential of capsid assembly modulators to address residual viral replication in NUC-experienced patients.

At the immunomodulatory end of the combination spectrum, pegylated interferon-α (Peg-IFNα) combined with NUCs has been rigorously evaluated in a meta-analysis of 11 controlled trials encompassing 2,439 patients. At 48 weeks of treatment, HBsAg clearance rates were significantly higher in the combination arm versus Peg-IFNα monotherapy (OR = 1.59, 95% CI: 1.01–2.52, P = 0.05); however, this advantage did not persist at 24 weeks post-treatment follow-up (OR = 1.33, 95% CI: 0.76–2.33, P = 0.31), and HBsAg seroconversion rates were not significantly different at either timepoint. These findings suggest that while the combination confers a meaningful short-term antigen clearance benefit, durable responses require prolonged treatment duration. Consistent with this, a nationwide survey of 151 Chinese attending physicians found that 76.1% favored Peg-IFNα-containing combination regimens as their preferred functional cure strategy, with a consensus benchmark of at least 30% functional cure rate for novel therapeutic candidates and a recommendation for a minimum of one year of post-treatment follow-up alongside consolidation therapy to mitigate relapse risk.

Looking at the broader therapeutic architecture, the emerging paradigm for CHB functional cure integrates NUCs as a virological backbone with two complementary layers: RNA-targeting agents — including small interfering RNAs, antisense oligonucleotides, and RNA destabilizers — to reduce viral transcripts and antigen burden, and immunomodulatory agents — including Peg-IFNα, checkpoint inhibitors, and therapeutic vaccines — to restore HBV-specific immune responses. This framework is exemplified by the tobevibart (VIR-3434) and elebsiran (VIR-2218) combination, where the Fc-engineered anti-HBsAg monoclonal antibody is paired with an siRNA targeting a conserved region of the HBV genome; elebsiran demonstrated an EC50 of 2.5 nM for HBeAg and 1.4 nM for HBsAg in primary human hepatocytes, and combined treatment in mouse models achieved maximum mean HBsAg reductions of 2.81 log in the AAV-HBV model and 2.51 log in human liver-chimeric mice — outperforming either agent as monotherapy. Quantitative HBsAg and hepatitis B core-related antigen (HBcrAg) are increasingly recognized as essential biomarkers to guide these combination strategies, with HBcrAg providing complementary insight into covalently closed circular DNA transcriptional activity alongside integrated HBV DNA contributions captured by qHBsAg.

Brii Bio's Data Ignites Hope for HBV Functional Cure

The recent topline data from Brii Biosciences' Phase IIb ENRICH and ENHANCE trials mark a potentially pivotal moment in the long-standing quest for a functional cure in chronic hepatitis B virus (CHB) infection. For decades, treatment strategies have largely focused on suppressing viral replication with nucleos(t)ide analogues (NAs), which, while effective in controlling the disease, rarely lead to the coveted hepatitis B surface antigen (HBsAg) loss—the closest marker to a functional cure. Pegylated interferon alpha (PEG-IFNα) offers a finite treatment course and the potential for HBsAg loss, but its efficacy is limited, typically achieving HBsAg clearance in only 30-44% of patients.

Brii Bio's results, particularly the 40-42.9% HBsAg loss rate in the ENRICH study using BRII-179 as a priming therapy, are highly encouraging. This outcome, achieved through a multi-modal combination of BRII-179 (a therapeutic vaccine designed to restore HBV-specific immune responses), elebsiran (an investigational antiviral targeting HBV RNAs), and PEG-IFNα, aligns with the growing consensus in the literature that novel, synergistic therapies are essential to overcome the persistence of covalently closed circular DNA (cccDNA) and achieve durable HBsAg loss. The preliminary alignment with China's NMPA for a registrational trial further solidifies the strategic importance of these findings, potentially paving the way for a new standard of care in a region with a high CHB burden.

However, as with any emerging therapy, critical considerations remain. The long-term durability of these HBsAg loss rates post-treatment cessation needs to be established, given the historical challenge of viral relapse. Furthermore, while promising, these results will require rigorous comparison against existing combination therapies in larger Phase III trials to fully ascertain their comparative efficacy and safety profile. The observed variability in HBsAg loss rates between the ENRICH and ENHANCE regimens also underscores the need for further research into optimal patient selection and treatment sequencing. Despite these considerations, the data offer a compelling vision for a future where functional cure for CHB is a more attainable reality, moving beyond mere viral suppression to truly resolve the infection.