Editor’s Note: Chronic hepatitis B virus (HBV) infection is a global epidemic, yet we still lack a treatment that can completely conquer HBV. At present, most patients still need long-term or even lifelong antiviral therapy to suppress HBV replication in the body and control the progression of the disease. In recent years, the exploration of combination therapies in the development of new drugs for hepatitis B has noticeably accelerated, including combinations of new drugs and existing oral antivirals. This will likely be the main direction for achieving clinical cure of hepatitis B in the future. Among the many new drugs for hepatitis B, the HBV capsid assembly modulator ALG-000184 has already shown safety and antiviral activity in chronic hepatitis B (CHB) patients in early studies. At the 32nd Annual Meeting of the Asia Pacific Association for the Study of the Liver (APASL) in 2023, Professor Hou Jinlin from Southern Medical University’s affiliated Southern Hospital in China, as the principal investigator and first author, orally reported the latest research progress on the efficacy and safety of ALG-000184 in combination with entecavir in HBeAg-positive patients. This study indicates that ALG-000184 combined with entecavir has stronger antiviral activity in HBeAg-positive patients than entecavir alone, attracting widespread attention in the academic community. This report is a comprehensive coverage of these findings.
ALG-000184-201 is a multicenter, double-blind, randomized, placebo-controlled study (NCT04536337). As early as the 2021 APASL meeting, Professor Edward Gane from the University of Auckland in New Zealand reported the first and second part of this study, showing the linear PK characteristics and good tolerability of ALG-000184 at single doses below 500 mg and multiple doses below 250 mg in healthy volunteers.
At the APASL 2023 meeting, Professor Gane also orally reported data from the first five cohorts of the third part of the study. This segment assessed the safety, pharmacokinetics (PK), and antiviral activity of daily oral ALG-000184 or placebo for 28 days in treatment-naïve or currently untreated HBeAg-negative and HBeAg-positive CHB subjects.
This part of the study involved five cohorts with a total of 51 participants. Each cohort was randomly assigned to receive ALG-000184 or placebo for 28 days, followed by an 8-week observation period after discontinuation of the drug. There were 29 HBeAg-negative and 22 HBeAg-positive CHB participants, with 53% being male and 67% Asian. The average age was 39 years, and the average BMI was 24.2 kg/m2. The baseline viral load and HBsAg levels in HBeAg-positive participants were higher than in those who were HBeAg-negative, with HBV genotypes B, C, or D. The results showed that 28 consecutive days of once-daily oral ALG-000184 (10-300 mg) were well tolerated, exhibited predictable PK, and demonstrated significant and similar antiviral activity in both treatment-naïve or currently untreated HBeAg-positive or -negative CHB participants. Additionally, a decrease in HBsAg was observed in HBeAg-positive participants with elevated baseline ALT levels, with the highest reduction reaching 0.8log10 IU/mL.
The fourth part of the study is currently underway, mainly assessing the efficacy and safety of ALG-000184 or placebo combined with entecavir in treatment-naïve or currently untreated chronic HBV-infected and CHB patients. The design of this part of the study is shown in Figure 1. At the APASL 2023 conference, Professor Hou Jinlin orally reported the preliminary (12-week) data for this segment.
Figure 1: Overview of the Study Design (Adapted from Presentation Slides)
This part of the study is divided into two cohorts. Cohort 1 includes 11 chronic HBV-infected participants, and Cohort 2 includes 11 CHB patients. Participants were randomly assigned in a 3:1 ratio to receive treatment with 100 mg ALG-000184 + entecavir (Cohort 1) or 300 mg ALG-000184 + entecavir (Cohort 2), or placebo + entecavir. The inclusion criteria for each cohort are shown in Table 1.
Table 1: Inclusion Criteria for the Two Cohorts of Chronic HBV Infection and CHB
All participants in the study were of Asian descent, HBeAg-positive, with genotype B or C. In Cohort 1, all participants had baseline ALT levels within the normal range, with the average ALT values for male and female participants being 25 (normal range 0-41 U/L) and 15.6 (normal range 0-31 U/L) respectively. In Cohort 2, 82% of the participants had baseline ALT levels within the normal range, with average ALT values for male and female participants being 29.0 and 38.7 U/L respectively. The baseline average HBV DNA levels for Cohort 1 and Cohort 2 were 8.6log10 IU/mL and 8.1log10 IU/mL, HBV RNA levels were 7.2log10 copies/mL and 6.8log10 copies/mL, and HBsAg levels were 4.6log10 IU/mL and 4.4log10 IU/mL, respectively (see Table 2).
Table 2: Baseline Characteristics of Participants
The results showed that the combination therapy of ALG-000184 with entecavir was well tolerated; there were no reports of serious adverse events (SAEs), nor were any treatments prematurely discontinued due to adverse events (AEs). All AEs observed during the treatment were ≤ Grade 2 (see Table 3). A total of 11 cases of elevated ALT were reported, with 6 in Cohort 1 and 5 in Cohort 2. All instances of increased ALT were asymptomatic, and none met the criteria for an abrupt ALT increase requiring assessment by the ALT Flare Committee (AFC), nor were they accompanied by changes in other liver function indicators.
Table 3: Safety Report of Participants (Adapted from Presentation Slides)
No clinically relevant differences in plasma exposure of ALG-001075 (the active metabolite of ALG-000184 post-digestion and absorption) were observed between participants receiving monotherapy with ALG-000184 (Part 3 cohorts) and those receiving combination therapy with ALG-000184 and entecavir (Part 4). PK variability was low (CV<10%), with minimal (<10%) accumulation of plasma ALG-001075 by week 12. Plasma concentrations of entecavir were similar with or without the use of ALG-000184.
By week 10, participants treated with 100 mg and 300 mg ALG-000184 in combination with entecavir, and those treated with entecavir alone (placebo group), observed average reductions in HBV DNA of 4.9log10 IU/mL, 5.3log10 IU/mL, and 3.99 log10 IU/mL, respectively, and average reductions in HBV RNA of 2.7log10 IU/mL, 3.3log10 IU/mL, and 0.29log10 copies/mL, respectively (see Figure 2).
Figure 2: Changes in HBV DNA and RNA Levels at 12 Weeks in Participants Treated with ALG-000184 and Entecavir Combination Therapy Versus the Control Group (Adapted from Presentation Slides)
Furthermore, a decrease in HBsAg levels was observed in participants treated with ALG-000184 combined with entecavir, especially in most of those receiving 300 mg of ALG-000184, who showed a significant reduction in HBsAg around 4 weeks after administration (see Figure 3).
Figure 3: Changes in HBsAg Levels at 10 Weeks in Participants Treated with ALG-000184 and Entecavir Combination Therapy Versus the Control Group (Adapted from Presentation Slides)
In his report summary, Professor Hou Jinlin stated that the preliminary results of the study show that the 12-week data of ALG-000184 combined with entecavir treatment in treatment-naïve or currently untreated HBeAg-positive chronic HBV-infected individuals or CHB patients demonstrated good safety and PK characteristics. Compared to entecavir monotherapy, the combination of ALG-000184 and entecavir exhibited stronger antiviral activity, with a notable decrease in HBsAg levels, particularly at the 300 mg dose level of ALG-000184. These data suggest that ALG-000184 has the best antiviral performance among similar drugs and holds great promise in future combination strategies for the functional cure of CHB. Currently, the study plans to evaluate the safety, PK, and antiviral activity of longer treatment durations with ALG-000184 alone or in combination with entecavir in other cohorts.
Reference :
- Ed Gane, MF Yuen, Kosh Agarwal, et al. The Capsid Assembly Modulator ALG-000184 Dosed for 28 Days Was Well Tolerated and Rapidly Reduced Viral Markers in Subjects with Chronic Hepatitis B, Including HBsAg in a Subset of HBeAg Positive Subjects with Elevated Baseline ALT. APASL 2023 Abstract FP03-16
2. Jinlin Hou, Junqi Niu, Yanhua Ding, et al. ALG-000184, a Capsid Assembly Modulator, Demonstrates Superior Antiviral Activity in Combination with Entecavir Compared to Entecavir in HBeAg Positive Subjects with Chronic Hepatitis B infection. APASL 2023 Abstract FP03-17
TAG: APASL 2023, Voice of China, HBV, New treatment
