The Dawn of Functional Cure: Global Advances in Hepatitis B Small Nucleic Acid Therapies

According to statistics from the World Health Organization,Two billion people worldwide have been infected with the hepatitis B virus, of which 257 million are unable to clear the virus through their own immune systems and become chronically infected. Hepatitis B virus infection can lead not only to acute or chronic hepatitis but is also a major cause of cirrhosis and liver cancer. It is estimated that 700,000 people die each year from hepatitis B and its complications. The results of China's fourth national seroepidemiological survey of hepatitis B show that the prevalence rate of hepatitis B surface antigen (HBsAg) carriers in China is approximately 5.86%, meaning that about 75 million people in the general population in China are chronically infected with the hepatitis B virus (HBV), accounting for nearly one-third of the global infected population.

In recent years, with the advancement of medical research and a deeper understanding of treatment strategies for chronic hepatitis B, hepatitis BFunctional Cure (also known as Clinical Cure)The concept has been proposed. Functional cure refers to the situation after completing a limited course of treatment, where serum HBsAg and HBV DNA remain undetectable, HBeAg turns negative, with or without HBsAg seroconversion. Residual cccDNA may persist, liver inflammation is alleviated, liver histopathology is improved, and the incidence of end-stage liver disease is significantly reduced. Functional cure is currently the ideal therapeutic goal recommended by guidelines both in and outside China.

For chronic hepatitis B, current conventional drugs such as nucleos(t)ide analogs (NAs) inhibit the reverse transcriptase activity of the hepatitis B virus (HBV) to block viral DNA synthesis, and pegylated interferon (PEG-IFN) combats HBV infection by enhancing the host's immune response against the virus; however, only a small number of patients achieve functional cure.Of course, all kinds of therapies are striving to conquer hepatitis B.(Such asHeppla Peptide Combined with PEG Interferon Shows Promise in Clearing cccDNA in Chronic Hepatitis B Patients). The following will focus on the small nucleic acid field.

In recent years, small nucleic acid drugs have made significant progress in the field of hepatitis B treatment. Small nucleic acid drugs include antisense oligonucleotides (ASO) and small interfering RNA (siRNA), among others. These drugs are characterized by high specificity, strong efficacy, and direct action on the genetic material of the virus, offering new possibilities for the functional cure of hepatitis B.

Pharnex Cloud data, www.pharnexcloud.com;Renamed to Mose Medical Data

The globally fastest-progressing small nucleic acid drug for chronic hepatitis B is being co-developed by Ionis Pharmaceuticals and GSK.Bepirovirsen（GSK3228836）This is an ASO therapy that specifically targets all RNA forms of the hepatitis B virus (HBV), including messenger RNA (mRNA) and pregenomic RNA (pgRNA). Bepirovirsen is currently in Phase 3 clinical trials. According to GSK's 2024 financial report, this product is expected to be submitted for marketing approval in the United States, the European Union, China, and Japan by 2026.

According to the interim analysis of the previously published Phase 2b trial (B-Clear trial), for patients receiving standard nucleoside analog therapy (NA) (n=227), 28% of patients achieved hepatitis B surface antigen (HBsAg) levels below the lower limit of quantification (LLOQ) and hepatitis B virus (HBV) DNA levels below LLOQ at the end of 300 mg Bepirovirsen treatment for 24 weeks; for patients not receiving NA treatment (n=230), this proportion was 29%. Additionally, according to the results of the Phase 2b B-Clear trial published in The New England Journal of Medicine, 9% to 10% of chronic hepatitis B patients achieved sustained clearance of HBsAg and HBV DNA after 24 weeks of once-weekly 300 mg Bepirovirsen treatment.

Arbutus Biopharma and Qilu Pharmaceutical Co., Ltd. jointly developedImdusiran（AB-729）Is a subcutaneous delivery of siRNA. In November 2024, Arbutus Biopharma presented new data from its IM-PROVE I Phase 2a clinical trial (AB-729-201) at the AASLD 2024 Annual Meeting. The data showed that, on the basis of continued NA treatment, using six doses of Imdusiran combined with 24 weeks of PEG-IFNα-2a treatment, the functional cure rate reached 50% (3/6) in HBeAg-negative patients with baseline HBsAg levels below 1000 IU/mL, and the overall functional cure rate was 25% (3/12). According to Arbutus' annual report, the company is reassessing its plans for a Phase 2b clinical trial of Imdusiran in combination with IFN and NA therapies.

AHB-137AHB-137 is an ASO therapy developed by Haobo Pharmaceuticals for the treatment of chronic hepatitis B. In March 2025, the company presented the latest data from the ongoing Phase 2a study of AHB-137 at the APASL 2025 Annual Meeting. The study showed that a total of 55 patients were enrolled and completed 24 weeks of AHB-137 treatment, with 30 patients completing 32 weeks of follow-up (8 weeks after discontinuation of AHB-137). At the completion of 24 weeks of treatment, 63% (20/32) and 57% (13/23) of patients in the 300 mg and 225 mg groups, respectively, achieved complete virologic response. Among these patients, 75% (15/20) and 62% (8/13) in the 300 mg and 225 mg groups, respectively, achieved seroconversion at week 24. As of February 2025, AHB-137 has completed dosing in the Phase 2b clinical trial and has been officially unblinded. Haobo Pharmaceuticals has raised substantial financing.

Elebsiran(VIR-2218/BRII-835) is a subcutaneously injectable siRNA therapy targeting HBV, jointly developed by Vir Biotechnology and Alnylam Pharmaceuticals. Brii Biosciences has obtained exclusive rights to the drug in Greater China from Vir Biotechnology.

In November 2024, Brii Biosciences presented new data from the Phase 2 ENSURE study of Elebsiran + pegylated interferon alpha (PEG-IFNα) combination therapy for patients with chronic hepatitis B at the AASLD 2024 Annual Meeting. The 48-week treatment completion data showed that at the end of treatment, 26.3% (5/19) or 33.3% (6/18) of participants receiving 200mg or 100mg Elebsiran combined with PEG-IFNα achieved HBsAg seroclearance, respectively, compared to only 5.6% (1/18) of participants receiving PEG-IFNα monotherapy.

2025Year5In the month, Bowang Pharmaceutical inEASLChronic Hepatitis B was announced at the annual meeting.siRNAMedicineBW-20507TheI/IIaPhase Clinical Research Data:BW-20507Subcutaneous injection, once every four weeks for a total of three doses, can significantly reduceHBsAgLevel, and showed dose-dependency, in200mgAnd400mgThe maximum reduction observed in the dose group was2.9~3.2 log10 IU/mL. At baselineHBsAgBelow the level1000 IU/mLIn the subjects,56%（5/9Example) Occurred during the study periodHBsAgClear. The company plans to2025Year LaunchBW-20507TheIIbPhase clinical development.Recently,Proposed for inclusion in the NMPA/CDE breakthrough therapy category。

Pharnex Cloud data, www.pharnexcloud.com;Renamed to Mosentropy Medical DataAnd related public information shows that several other companies in China have laid out plans for small nucleic acid therapies for hepatitis B, such asCTTQ、Hengrui Medicine、RiboBio、Stellar Kун Zé、Kawin Technology、Shi'an Bio, In additionCSPCThis year, a patent for a dsRNA (double-stranded ribonucleic acid) molecule that inhibits HBV gene expression and its application was disclosed, representing a new dual-target RNAi therapy. Other companies involved in this field include Vision and more.

Despite numerous companies actively investing in the research and development of small nucleic acid drugs for hepatitis B, the development of hepatitis B drugs has always been challenging due to the complex life cycle of the hepatitis B virus and the difficulty in targeting and eliminating cccDNA. Even for multinational pharmaceutical giants like Johnson & Johnson and Roche, achieving a functional cure for hepatitis B remains no easy task.

In 2018, Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, introduced the siRNA therapy JNJ-3989 (ARO-HBV) from Arrowhead and attempted to achieve a breakthrough by combining it with other drugs. However, in Phase 2 studies, the drug did not deliver the expected functional cure. Subsequently, Johnson & Johnson decided to exit the field of hepatitis B drug development.

In 2023, Johnson & Johnson licensed JNJ-3989 to GlaxoSmithKline (GSK) for global development and commercialization, and its current research and development code isGSK5637608(Also known as Daplusiran/Tomligisiran). GSK will pay Janssen and Arrowhead an upfront payment and potential milestone payments, totaling approximately $1 billion. GSK is currently conducting a Phase 2 clinical study of GSK5637608 in combination with its own ASO therapy Bepirovirsen for the treatment of hepatitis B.

Roche has a long history in hepatitis B treatment and was one of the earlier companies to enter the field of hepatitis B drug development, launching pegylated interferon alpha-2a (Pegasys). However, its subsequent hepatitis B projects failed to replicate the earlier success. In 2024, Roche decided to halt the development of all hepatitis B new drug pipelines that had entered clinical trials, including an siRNA therapy in Phase 2 clinical trials.Xalnesiran(RG6346). Xalnesiran was originally acquired by Roche from Dicerna Pharmaceuticals (now part of Novo Nordisk) in 2019 for an upfront payment of $200 million. Roche did not explicitly disclose the specific reasons for halting these projects, which may be related to clinical data not meeting expectations, pipeline optimization, financial considerations, etc.

Besides MNCs like Johnson & Johnson and Roche, many biotech companies have also terminated some hepatitis B small nucleic acid projects, such as Aligos Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, and Alnylam Pharmaceuticals.

Hepatitis B is a global public health issue, with more than 257 million people chronically infected.In cases where traditional drugs struggle to achieve functional cures, the rise of small nucleic acid drugs has brought new hope for hepatitis B treatment. Despite challenges such as the complexity of the viral life cycle and the stability of cccDNA, continuous technological advancements and a deeper understanding of the biological mechanisms of the hepatitis B virus may position small nucleic acid drugs as a breakthrough for achieving functional cures for hepatitis B.

Reference:

Moxie Pharma Data pharma.bcpmdata.com (formerly PharmaCloud Data);

https://www.hepb.org/；

https://health.cnr.cn/sy/zx/20241107/t20241107_526967550.shtml；

Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association. Expert consensus on clinical cure (functional cure) of chronic hepatitis B[J]. Chinese Journal of Infectious Diseases, 2019, 37(8): 461-472. DOI:10.3760/cma.j.issn.1000-6680.2019.08.003.

https://www.nejm.org/doi/full/10.1056/NEJMoa2210027；

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