Huashan Hospital Launches Clinical Trial to Achieve Functional Cure for Chronic Hepatitis B with Sequential Administration of ASO/siRNA Followed by Pegasys
Background of the Sequential Administration Study for Functional Cure of Hepatitis B
Existing standard treatments (SoC) for chronic hepatitis B (CHB), such as Viread (tenofovir disoproxil fumarate) and other nucleoside analogs, suppress the virus but do not completely eliminate the hepatitis B surface antigen (HBsAg), resulting in a functional cure rate of only 1-9%. Consequently, the development of next-generation RNA-targeted therapies, such as bepirovirsen (Bepirovirsen, ASO) and elebsiran (Elebsiran, siRNA), which directly block viral protein production, is actively underway. However, RNA therapy alone raises concerns about recurrence after treatment discontinuation. Therefore, sequential therapy with Pegasys (Pegasys, peginterferon alfa-2a), which stimulates an immune response and induces antibody formation, is emerging as an alternative. The SPHERE clinical trial (NCT06923280), led by Huashan Hospital at Fudan University in China, aims to establish this new paradigm of combination therapy.
Design of the SPHERE Trial and Patient-Specific Treatment Strategy
This study is an investigator-initiated trial (IIT) conducted on 72 patients who have received RNA-targeted therapy at least once and experienced a significant reduction (≥ 1 log10 IU/mL) in HBsAg levels compared to baseline but did not achieve a complete cure. In Phase 1 (0-48 weeks), patients are randomly assigned to either an immediate Pegasys 180 ug once-weekly administration group (Group A) or a delayed administration group with a 24-week observation period (Group B) to evaluate the impact of treatment timing. In Phase 2 (48-96 weeks), an adaptive design is adopted, where patients who have not achieved HBsAg clearance receive additional Pegasys administration or have their observation period extended. This strategy aims to precisely determine the optimal intervention timing based on each patient's individual immune recovery rate, thereby maximizing treatment efficacy.
Unmet Needs in the Global Hepatitis B Market and Commercial Value
The global market for chronic hepatitis B treatments is estimated at approximately $3.93 billion in 2025 and is projected to expand to $4.74 billion by 2030, driven by the emergence of new drugs targeting functional cure. Major global pharmaceutical companies, including Gilead and GSK, are fiercely competing to gain a leading position in the functional cure market. In this process, therapies that enhance patient compliance and shorten the treatment duration are key differentiators. Pegasys has been approved by the FDA since 2005 and has a proven safety profile. If its efficacy in sequential administration with new drugs is demonstrated, it could also boost the clinical success rate and market value of the next-generation RNA pipelines under development.
Shift to a New Standard of Care Paradigm and Regulatory Implications
GSK's bepirovirsen has already received FDA Fast Track designation and is currently undergoing a global Phase 3 clinical trial. The results of this trial are expected to serve as a crucial milestone in establishing post-market guidelines for the approval and prescription of RNA therapies. If sequential administration of interferon significantly improves HBsAg clearance and seroconversion rates, it could usher in an era of finite therapy for hepatitis B patients who previously had to take medication for life. Regulatory agencies are also likely to adopt more favorable clinical evaluation criteria for combination and sequential therapies that induce complete cure of chronic diseases.
With the global market for chronic hepatitis B treatments expected to grow from $3.93 billion in 2025 to $4.74 billion in 2030, sequential administration of RNA-targeted agents and immunomodulators to increase functional cure rates has become a key research theme in the industry. This study, which targets patients with HBsAg levels reduced by ≥ 1 log10 IU/mL after prior treatment and administers the already-approved Pegasys (Pegasys, peginterferon alfa-2a) to determine the optimal intervention timing, will provide direct data for the commercialization strategy of GSK's bepirovirsen (Phase 3) and Vir's elebsiran (Phase 2) and other follow-up pipelines. In the short term, it is expected to demonstrate the possibility of controlling immunological rebound that occurs after discontinuation of RNA therapy, thereby providing clinical evidence for finite therapy. In the medium to long term, it will reshape the competitive landscape of next-generation combination pipelines among global pharmaceutical companies and revolutionize the prescription paradigm of existing nucleoside analog standard of care (SoC), which previously required lifelong medication, thereby creating significant regulatory and commercial ripple effects throughout the pharmaceutical ecosystem.
Source: ClinicalTrials.gov (api_ct)