Editor’s Note: Antiviral therapy is the primary treatment strategy for chronic hepatitis B (CHB), aiming to inhibit HBV replication, alleviate liver cell inflammation and fibrosis, and reduce the risk of liver failure, decompensated cirrhosis, and hepatocellular carcinoma (HCC). However, there is currently no treatment that can completely clear covalently closed circular DNA (cccDNA) in infected liver cells, which is a major obstacle to achieving clinical cure for CHB. In recent years, with the continuous development and clinical trials of new drugs targeting different points, exploration of new treatment strategies for the clinical cure of CHB is gradually progressing. To this end, this journal invited Dr. Guiqiang Wang from the Department of Infectious Diseases at Peking University First Hospital to share the latest developments in the field of new drug development for the clinical cure of CHB over the past year.

01 Clinical Cure Status and New Drug Development Targets for CHB

Clinical cure is only achievable for a subset of the population treated with Nucleos(t)ide analogs (NAs). The mid-term data analysis (n=23,412 cases) from the “Mount Everest Project” led by Dr. Zhiliang Gao showed that the clinical cure rate for patients with a baseline HBsAg level of ≤100 IU/mL was 39.01%[1].

The targets for the development of anti-HBV drugs mainly include key steps in the virus life cycle and the host immune system. These targets can be broadly categorized into two classes (see Figure 1): direct antiviral drugs and immunomodulators. Direct antiviral drugs target the virus and interfere with the HBV replication process. This category includes siRNA, entry inhibitors, capsid inhibitors, HBsAg inhibitors, viral protein inhibitors, viral gene editing, and more. Immunomodulators enhance the body’s ability to clear HBV by modulating the immune system and include therapeutic vaccines, toll-like receptor (TLR-7/8) agonists, host-targeting approaches, monoclonal antibodies, PD-L1/PD-1 inhibitors, and other immunological substances. Additionally, other target drugs include immunoglobulins, PAPD5/7 inhibitors, MicroRNA, FXR agonists, and HBV cccDNA inhibitors.

Figure 1. Targets for Anti-HBV Drug Development (excerpt from the presenter’s slides)

02 RNA Interference Therapy

Small nucleic acid drugs, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO), play a crucial role in HBV treatment. These drugs operate through the RNA interference mechanism (see Figure 2), targeting mRNA and pgRNA to effectively inhibit the production of HBV antigens and viral replication. In terms of reducing HBsAg, small nucleic acid drugs have shown promising results [2-3]. Representative drugs in development for siRNA and ASO include VIR-2218, among others (see Table 1) [3-5].

Figure 2. Mechanism of RNA Interference (excerpt from the presenter’s slides)

Table 1. Representative Drugs Under Research for siRNA and ASO.

  1.  VIR-2218

VIR-2218 is a new siRNA drug targeting the HBx region of the HBV genome. In a Phase 2 study presented at EASL 2023 [6], adult subjects with non-cirrhotic chronic HBV infection, HBsAg > 50 IU/mL, and virological suppression were included. The study comprised 5 cohorts, with VIR-2218 (200 mg) administered subcutaneously every 4 weeks, and PEG IFNα (180 μg) administered subcutaneously weekly. Follow-up of at least 24 weeks was conducted after completion of treatment. The results (Figure 3) showed that the longer the duration of combined treatment with VIR-2218 + PEG IFNα, the greater the reduction in HBsAg and the higher the HBsAg clearance rate. Patients who received 13 doses of VIR-2218 combined with PEG IFNα for 44 weeks showed a significant increase in HBsAg clearance rate at the end of treatment (4/13, 30.8%), and all four of these patients developed anti-HBs > 10mIU/mL. At 24 weeks after the end of treatment, two patients (2/13, 15.4%) maintained continuous negativity for HBsAg.

  • JNJ-3898

In a study on CHB patients treated with JNJ-3898 in combination with NAs [7], JNJ-3989 was administered subcutaneously once every four weeks for a total of three doses. NAs (ETV/TDF) were continuously administered for up to 392 days. The study focused on the HBsAg response of patients after discontinuation, with the specific criterion being a reduction in HBsAg ≥1 log IU/mL from baseline to day 392. The results showed a significant decrease in HBsAg levels in patients treated with JNJ-3989. Particularly noteworthy is that 39% of patients maintained a sustained HBsAg response 48 weeks after stopping JNJ-3989. However, after 8 weeks of discontinuation, patients’ HBsAg levels showed a rising trend.

In the Phase IIb REEF-I study (Figure 4), the efficacy and safety of JNJ-3989 in combination with JNJ-6379 and NAs for treating CHB patients were evaluated. The primary efficacy endpoint of the study was the proportion of patients meeting the criteria for NA discontinuation at week 48. These criteria included ALT lower than three times the upper limit of normal, HBV DNA lower than the detection limit, HBeAg negativity, and HBsAg lower than 10 IU/mL. The results showed that the efficacy of the JNJ-3989 200mg + NA group was the most significant, with the highest proportion of patients meeting the primary efficacy endpoint at 19.1%. Additionally, this group had the highest proportion of patients achieving HBsAg lower than 10 IU/mL at 33%; lower than 100 IU/mL at 72%; and an average reduction in HBsAg of 2.58 log10 IU/mL. Moreover, the HBsAg clearance rate was less than 3%. Due to the inferior efficacy of the combination therapy of JNJ-3989 and JNJ-6379 compared to JNJ-3989 monotherapy, further development of JNJ-6379 has been halted. To optimize treatment outcomes, JNJ-3989 is exploring its combination with other treatment strategies.

Figure 4. Phase II REEF-I Study: Methods and Results(excerpt from the presenter’s slides)

In the Phase II REEF-IT study presented at AASLD 2023 [8], the effectiveness of siRNA JNJ-3989 in combination with CAM JNJ-6379 and PEG-IFNα for treating CHB patients was explored. The study included non-cirrhotic, HBeAg-positive chronic HBV-infected individuals aged 18-55 who were either treatment-naïve or had not received treatment for a period. Participants were screened for HBV DNA levels ≥20,000 IU/mL and normal ALT <2×ULN. The entry criterion was ≥30% of patients with HBV DNA >10^7 IU/mL. Patients received treatment with JNJ-3989 200 mg Q4W+NA±JNJ-6379 250 mg QD for 36-52 weeks (induction phase), followed by PegIFN-α2a 180 mcg QW for 12 weeks (consolidation phase). The primary endpoint was the proportion of patients with HBsAg seroclearance 24 weeks after stopping all treatment, and changes in viral markers (HBsAg, HBV DNA, HBeAg) were observed at the end of treatment (EOT) and follow-up at 24 weeks (FU24). The study observed that 66.7% of patients achieved HBV DNA <LLOQ, 91.7% had HBV DNA <100 IU/mL; in addition, the HBsAg clearance rate was 20% (11/54), the HBeAg clearance rate was 28% (15/53), and 11 out of 15 cases maintained negativity at the end of the follow-up period (Figure 5, 6).

Figure 5. HBsAg Decrease and Clearance Rate with HBV-DNA Decrease(excerpt from the presenter’s slides)

Figure 6. HBsAg and HBeAg Clearance and Changes(excerpt from the presenter’s slides)

  • Xalnesiran (RG6346)

Xalnesiran (RG6346) is an siRNA drug targeting the HBV genome’s HBsAg coding region. An ongoing Phase II platform study is mainly investigating its effectiveness in combination with NUC, with or without PegIFN-α or Ruzotolimod (a TLRs 7 agonist). Partial trial data were presented at AASLD 2023 [3]. The results indicate that the HBsAg clearance rates after 48 weeks of treatment with Xalnesiran alone, Xalnesiran + Ruzotolimod, and Xalnesiran + Peg-IFN-α were 6.7%, 17.6%, and 30.0%, respectively. The HBsAg clearance rates after treatment cessation and a 24-week follow-up were 6.7%, 11.8%, and 23.3%, respectively (Figure 7).

Figure 7. illustrates the HBsAg clearance rate after 48 weeks of treatment with Xalnesiran alone or in combination with Ruzotolimod and Peg-IFN-α (excerpt from the presenter’s slides).

  • Bepirovirsen

Antisense RNA refers to RNA molecules that are complementary to mRNA, capable of specifically binding to mRNA, thereby inhibiting its translation. Gene editing is a precise technology for modifying human genes by inserting exogenous DNA fragments into specific sites of the target cell’s genome to achieve the desired outcome. Currently, the ongoing research on antisense RNA and gene editing methods is outlined in Table 2.

Table 2. Currently Investigated Antisense RNA and Gene Editing Methods (excerpt from the presenter’s slides)

ASOs primarily exert their effects through two distinct mechanisms [9-10]. Firstly, the steric hindrance mechanism: ASOs bind to target RNA, occupying positions crucial for interactions with key proteins. This binding leads to alterations in RNA processing, translation inhibition or enhancement, thereby inhibiting the function of the target RNA. Secondly, the degradation mechanism: When ASOs form a complementary double-stranded structure with target RNA, it can activate ribonuclease H (RNase H), an enzyme capable of cleaving the target RNA, inducing its degradation. Importantly, ASOs can induce cleavage both in the cytoplasm and the cell nucleus.

BPV is an ASO drug targeting all HBV RNAs, including mRNA and pgRNA. The BPV phase 2b trial (B-Clear) [11] is a multicenter, randomized, partially blinded, parallel-group study stratified based on HBeAg status (positive or negative) and baseline HBsAg levels (≤3 or >3 log10IU/mL). Subjects were randomly assigned (3:3:3:1) to four treatment groups, with once-weekly dosing. AASLD 2023 disclosed the analysis results of HBsAg response and ALT elevation during the first 12 weeks of treatment in the B-Clear study [12]. Serum samples were collected at baseline, week 4, and week 12 from 359 patients for analysis. The study found that the rate of ALT elevation in BPV treatment responders was significantly higher than non-responders (40.5% vs. 2.3%, Figure 8). Early responders were more likely to experience ALT elevation compared to late responders (P<0.01), suggesting a correlation between ALT elevation and the rate of HBsAg decline.


Figure 8. Relationship between ALT elevation and HBsAg response in the B-Clear study (excerpt from the presenter’s slides).

AASLD 2023 also presented the results of the phase IIb, multicenter, randomized, open-label B-TOGETHER study [13]. This study aimed to evaluate whether sequential treatment with BPV and PegIFN could enhance the observed efficacy of BPV in the B-Clear study. The results indicated that after 24 weeks of BPV treatment, 51% of patients with baseline HBsAg ≤3000 IU/mL achieved HBsAg clearance, and 65% of patients with baseline HBsAg ≤1000 IU/mL achieved HBsAg clearance (Figure 9). However, the sequential treatment of BPV followed by PegIFN did not effectively maintain virological response in patients. Overall, BPV demonstrated certain efficacy in treating chronic hepatitis B (CHB), especially in patients with lower baseline HBsAg. However, sequential PegIFN treatment did not effectively sustain patients’ virological responses. Future efforts are needed to further optimize treatment regimens, enhance therapeutic outcomes, and explore more effective combination treatment strategies.

Figure 9. Results from the B-TOGETHER study (excerpt from the presenter’s slides).

Another oral presentation at AASLD 2023 suggested that sequential treatment with BPV followed by PegIFN reduces relapse after discontinuation [14]. In the B-TOGETHER study, 58% of participants in each group responded at the end of BPV treatment and did not experience relapse during PegIFN treatment. Only 2 participants (both in the second group) showed partial response at the end of BPV treatment and responded at the end of PegIFN treatment. Among participants who responded at the end of PegIFN treatment, 58% (first group) experienced relapse after treatment cessation, while 0% (second group) did not relapse.

03 Therapeutic Vaccines

Therapeutic vaccines primarily stimulate the human immune system with specific antigens to generate antibodies or immune cells with specificity, thereby altering the body’s immune status to resist pathological changes caused by diseases. Currently, therapeutic vaccines under investigation are listed in Table 3.

Table 3. Investigated Therapeutic Vaccines (excerpt from the presenter’s slides)

The therapeutic vaccine BRII-179 is a curative hepatitis B vaccine based on recombinant virus-like particles, containing large, medium, and small hepatitis B surface antigens. It employs a novel adjuvant to enhance Th1 immune response against HBV surface antigens. In a clinical study [15], more than 30% of patients across all cohorts developed anti-HBs antibodies induced by BRII-179. Moderate responses against anti-Pre S1 or anti-PreS2 were observed only in patients receiving combined treatment with BRII-179 and IFN-α. No significant reduction in HBsAg or only minimal reductions were observed after 4 doses of BRII-179 treatment.

A phase II clinical trial combining BRII-179 with PEG-IFNα was presented at AASLD 2023 [16]. The results showed a significant increase in HBsAg serological conversion rate at the end of treatment (24 weeks) with BRII-179 combined with PEGIFNα compared to PEG-IFNα monotherapy in both the Full Analysis Set (FAS) and Per Protocol Set (PPS) analyses (FAS: 15.8% vs 1.8%, 17.5% vs 7.0%). The combination therapy induced higher HBsAb titers, with 17.5% and 19.3% of patients having titers exceeding 100 IU/L at 24 and 36 weeks, respectively, significantly higher than the PEG-IFNα monotherapy group (1.8% and 3.5%). The sustained clearance rate of HBsAg at 36 weeks was significantly increased in patients with HBsAb ≥100 IU/L compared to those with HBsAb <10 IU/L (aOR=21.08, 95%CI: 3.92-113.32).

04 Combination Treatment Strategies

Combination strategies aim to comprehensively suppress HBV replication by targeting both viral replication and host immunity, thereby restoring patients’ immune function. Strategies targeting viral replication focus on inhibiting the processes of HBV replication, including drugs directly targeting HBV DNA and those targeting HBsAg production. Strategies targeting host immunity aim to restore patients’ immune function by modulating the immune system to reduce liver damage caused by HBV. Currently, antiviral therapy remains the mainstay for the treatment of chronic hepatitis B, and research on combination strategies is still in the exploratory stage. Ongoing studies on combination treatment are listed in Table 4.

Table 4. Ongoing Combination Treatment Studies

Summary and Outlook

Chronic HBV infection is a complex issue involving the persistent presence of cccDNA and the formation of immune tolerance. Further research and optimization of existing NUC and interferon treatment strategies are needed to pursue clinical cure. Additionally, small nucleic acid drugs such as siRNA and ASO have shown promising initial results in reducing HBsAg, providing new possibilities for treatment. To enhance cure rates, combination treatment strategies can be considered, such as the combined use of NUC and siRNA or the sequential use of immunomodulators or therapeutic vaccines.

References:

  1. Professor Gao Zhiliang: Five years of clinical cure “summit” for chronic hepatitis B. Link
  2. Dusheiko G, Agarwal K, Maini MK. New Approaches to Chronic Hepatitis B. N Engl J Med. 2023 Jan 5;388(1):55-69.
  3. Hui RW, Mak LY, Seto WK, Yuen MF. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol. 2022 Jul;28(3):408-424.
  4. ClinicalTrials.gov: NCT05630807
  5. ClinicalTrials.gov: NCT06115993
  6. Yuen MF, et al. EASL 2023 Abstract: LBO-02.
  7. Gane E, et al. Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen supression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment. J Hepatol, EASL2020 Abstract: GS10.
  8. Kennedy PT, et al. AASLD 2023 Poster-1468-C
  9. Hou Jinlin, et al. AASLD 2023 Abstract: LBO-5006
  10. Yang Yangchen. A novel antisense oligonucleotide drug for the treatment of chronic hepatitis B—bepirovirsen. Journal of Clinical Drug Therapy, 2023, 21(3):12-17.
  11. Yuen MF, Lim SG, Plesniak R, et al. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. N Engl J Med. 2022 Nov 24;387(21):1957-1968.
  12. William Jordan, et al. Protein Expression Associated With Alanine Aminotransferase Increase During Bepirovirsen Treatment: Analysis of the B-Clear Study. 2023 AASLD #1484-C. poster & abstract
  13. Amir Youssef, et al. Mechanistic PK/PD Modeling and Simulation of Bepirovirsen, HBsAg, and ALT After Sequential Bepirovirsen-Pegylated Interferon α-2a Therapy to Inform Phase 3 Study Design: B-Together Study. AASLD 2023 Abstract: 1478-C
  14. Buti M, et al. AASLD 2023 Abstract: Oral 49.
  15. Yuan MF, et al. EASL 2021 Abstract: PO-2575
  16. Gao Zhiliang, et al. AASLD 2023 Abstract: LB-5031-C

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Last updated on 2024.03.12