Replicate Phase 3 Functional Cure at 20 Percent Leaves 80 Percent Uncured

FDA Approves GSK's Hibsago for Chronic Hepatitis B

GSK announced that the US FDA has approved Hibsago (bepirovirsen) for chronic hepatitis B (CHB) virus infection in adult patients without cirrhosis, who are on NrtI therapy for at least six months, have suppressed HBV DNA, and HBsAg levels ≤3000 IU/ml. This first-in-class antisense oligonucleotide (ASO) offers unprecedented functional cure rates, with 19% observed in the B-WELL Phase III trials for the approved population, significantly higher than the less than 1% typically seen with standard of care. The approval was granted under FDA priority review and Breakthrough Therapy Designation, highlighting its potential to transform CHB management with a six-month treatment course and the option for self-administration.

• Hibsago demonstrated a clinically meaningful 19% functional cure rate in the B-WELL Phase III trials for adults with baseline HBsAg ≤3000 IU/ml, compared to less than 1% with standard of care. Functional cure is defined as undetectable HBV DNA and HBsAg for at least 24 weeks post-treatment, indicating immune system control without medication. A higher rate of 26% was achieved in patients with HBsAg ≤1000 IU/ml, representing a significant portion of diagnosed CHB cases.
• The FDA granted approval under Priority Review and Breakthrough Therapy Designation, acknowledging bepirovirsen's significant improvement over existing treatments. This approval offers patients a six-month treatment course with the added convenience of self-administration after the initial dose, addressing the long-standing need for a finite treatment duration in CHB management.
• Bepirovirsen, an antisense oligonucleotide (ASO), works by inhibiting the production of HBV genetic components, thereby reducing viral proteins like HBsAg and potentially enabling the immune system to regain control. This innovative approach aims to mitigate the risk of serious liver complications and liver cancer associated with chronic hepatitis B, which affects approximately 1.7 million people in the US and is a leading cause of global liver cancer cases.

Unpacking the B-WELL Phase III Data for Hibsago (Bepirovirsen)

Key chronic hepatitis B trials have evaluated nucleoside/nucleotide analogues, peginterferon regimens, and AnluoHuaxian pill using histologic, virologic, and biochemical endpoints. Most pivotal designs were randomized, double-blind comparisons with 48 weeks to a minimum of 52 weeks of treatment and paired liver biopsies.

Hibsago: Ushering in a New Era for CHB Treatment

Chronic hepatitis B (CHB) remains a major threat to global public health, affecting 296 million people worldwide. Nucleos(t)ide analogs provide durable suppression of hepatitis B virus (HBV) replication but rarely achieve hepatitis B surface antigen (HBsAg) loss, and HBsAg loss can rarely (1%) be achieved with current nucleos(t)ide analogues (NA) options. Consequently, functional cure, defined as sustained HBsAg loss with undetectable HBV DNA after treatment, has become the central therapeutic goal. In recent years, guidelines have stated that long-term NA treatments can be discontinued for HBeAg-negative patients without achieving HBsAg loss. The best candidates for NA withdrawal are virally suppressed, HBeAg-negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. In the international, multicenter, multiethnic cohort (RETRACT-B Study) among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. In a prospective study from April 2022 to August 2024 in 46 non-cirrhotic, HBeAg-negative, HBV DNA-negative patients on nucleos(t)ide analogue therapy for more than three years, HBsAg loss was observed in 3 (13%) patients in the treatment discontinuation group at the end of 24-month follow-up, whereas 69.6% of patients had HBV DNA levels <2000 IU/mL and remained in treatment-free follow-up, with no HBsAg loss observed in the control group.

Relapse patterns after NA discontinuation have been further defined, with the agent used in NA treatment itself affecting the pattern of relapse development. After cessation of NA therapy, a relapse was observed in 38 patients (56.7%) among 67 patients who received NA therapy for at least 65 months, with relapse rate 71.0% in patients treated with tenofovir disoproxil fumarate (TDF) as the last NA type and 37.9% in patients treated with entecavir (ETV) (p=0.017). Relapse after NA treatment occurs significantly slower and less frequently with entecavir compared to other regimens, including tenofovir dipivoxil. In 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421), HBsAg loss occurred in 96 (6.8%) patients overall during a median off-treatment follow-up of 18 months, with virological relapse occurring earlier among TDF-treated patients (P < .01) and TDF significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). In 162 noncirrhotic HBeAg-negative patients, the 2-year cumulative incidence of virological relapse was significantly higher in the off-TAF group (85.0%) compared to the off-TDF group (69.5%, p = 0.024) and the off-ETV group (51.5%, p = 0.010), and the 2-year cumulative incidence of clinical relapse was significantly higher in the off-TAF group (62.4%) compared to the off-TDF group (39.0%, p = 0.026) and the off-ETV group (22.5%, p = 0.024). In 891 patients followed post-treatment for at least 12 months, cumulative rates of HBsAg loss at 7 years were 22.6% and 35.4% in the entecavir and TDF groups respectively, with patients who discontinued TDF having significantly higher rates of HBsAg loss than patients who discontinued entecavir therapy in all (p = 0.019) and propensity score-matched (p = 0.015) patients.

The pursuit of functional cure is shifting toward multidrug strategies that combine potent viral suppression, antigen reduction, and immune restoration. Recent advances highlight the promise of RNA-targeting agents, including small interfering RNAs, antisense oligonucleotides, and RNA destabilizers, which directly reduce viral transcripts and antigen production. In parallel, immunomodulators such as pegylated interferon, checkpoint inhibitors, and therapeutic vaccines aim to restore HBV-specific immunity, and rationally designed combination regimens, integrating nucleos(t)ide analogs as a backbone with antigen-lowering agents and immunotherapies, can synergistically enhance functional cure rates. Piranga is a Phase 2 platform trial that evaluated 4 xalnesiran regimens with or without an immunomodulator in virologically suppressed participants with CHB (NCT04225715). Among 121 participants, 58 (48%) met NA stopping criteria and 40 (33%) discontinued NA, of whom 17 (43%) met NA restarting criteria, 16 (40%) restarted NA, and 24 (60%) remained off NA by the end of the study (EOS). Among participants who remained off NA, 5 achieved and maintained HBsAg loss (HBsAg <0.05 IU/mL) and HBV DNA undetectable (HBV DNA <10 IU/mL), all in treatment arms with an immunomodulator, while of the 40 participants who discontinued NA, 19 (48%) experienced virological relapse (VR), 3 (8%) of whom further developed clinical relapse (CR). Within this framework, monitoring biomarkers beyond HBV DNA is critical, with quantitative HBsAg reflecting both covalently closed circular DNA and integrated HBV DNA activity, whereas hepatitis B core-related antigens (HBcrAgs) provide complementary information on covalently closed circular DNA transcriptional activity.

A New Era for Chronic Hepatitis B Functional Cure

The recent FDA approval of bepirovirsen marks a pivotal moment in the long-standing battle against chronic hepatitis B (CHB). For decades, the primary goal of CHB management has been viral suppression through nucleos(t)ide analogs (NAs), a lifelong commitment that rarely leads to a functional cure. This new antisense oligonucleotide (ASO) offers a tangible path to HBsAg seroclearance, a critical endpoint that has remained largely elusive.

The 19% functional cure rate observed in the B-WELL Phase III trials, specifically in noncirrhotic patients on NA therapy with suppressed HBV DNA and HBsAg levels ≤3000 IU/ml, represents a significant advancement. This outcome, achieved with a finite six-month treatment course and the convenience of self-administration, positions bepirovirsen as a transformative option for a well-defined patient segment. Its mechanism, targeting all HBV messenger RNAs and inducing innate immune activation, addresses the multifaceted nature of CHB pathogenesis, moving beyond mere viral replication inhibition.

However, the introduction of any novel therapy comes with considerations:

• Patient Selection and Expectations: While 19% is a breakthrough, it means 81% of treated patients will not achieve a functional cure. Managing patient expectations and ensuring appropriate selection based on the approved criteria will be crucial for successful integration into clinical practice.

• Safety Profile Management: The observed transient ALT flares and higher rates of Grade 3 or higher adverse events, particularly ALT elevations, underscore the need for robust patient monitoring protocols. Clinicians will need to be prepared to manage these events, which could influence prescribing decisions.

• Long-term Durability and Resistance: Although initial data suggest minimal impact from bepirovirsen binding site SNPs, ongoing surveillance for resistance mechanisms and long-term durability of the functional cure will be essential as real-world data accumulates.

This approval not only offers a new hope for CHB patients but also validates the ASO platform as a powerful tool in infectious disease therapeutics. It sets a new benchmark for functional cure rates, compelling future drug development to aim higher and potentially paving the way for combination therapies that could further enhance efficacy and broaden the treatable population. The journey towards eradicating CHB by 2030 has just gained significant momentum.