Highlights of the Phase 1 Study
Potent Antiviral Activity
ALG-000184 demonstrated a robust multi-log reduction in both serum HBV DNA (approximately 3-4 log10 IU/mL) and HBV RNA (approximately 0.5-3.0 log10 copies/mL) across all evaluated doses in a 28-day period.
High Response Rates in HBeAg-Negative Patients
In the HBeAg-negative cohort, 83% of participants achieved HBV DNA levels below the lower limit of quantification (LLOQ), and 100% achieved HBV RNA levels below LLOQ within the 28-day treatment window.
Favorable Safety and PK Profile
ALG-000184 was generally safe and well-tolerated, showing a dose-dependent linear pharmacokinetic profile, which supports its continued development as a cornerstone of future HBV regimens.
Background: The Challenge of Chronic Hepatitis B
Chronic hepatitis B (CHB) remains a global health crisis, affecting nearly 300 million people worldwide and contributing significantly to the incidence of cirrhosis and hepatocellular carcinoma. While the advent of nucleos(t)ide analogues (NAs) has revolutionized treatment by effectively suppressing HBV DNA replication, these therapies rarely lead to a functional cure—defined as the sustained loss of hepatitis B surface antigen (HBsAg). The persistence of covalently closed circular DNA (cccDNA) in the nucleus of hepatocytes serves as a stable template for viral transcription, ensuring that viral replication resumes once NA therapy is discontinued. Consequently, most patients require lifelong treatment.
To bridge the gap toward a functional cure, novel therapeutic classes are being explored. Among the most promising are Capsid Assembly Modulators (CAMs). These agents target the HBV core protein, which is essential for multiple stages of the viral lifecycle, including the assembly of the viral capsid, the encapsidation of pregenomic RNA (pgRNA), and the replenishment of the cccDNA reservoir.
The Mechanism of Class-E Capsid Assembly Modulators
ALG-000184 is a prodrug of ALG-001075, a member of the Class-E (Empty) CAMs. Unlike Class-A (Aberrant) CAMs, which induce the formation of large, non-capsid polymers of the core protein, Class-E CAMs promote the assembly of empty capsids that lack the viral pregenomic RNA. By preventing pgRNA encapsidation, CAM-Es effectively block the reverse transcription process required for HBV DNA synthesis. Furthermore, by interfering with the capsid structure, these agents may impede the transport of the viral genome back to the nucleus, thereby preventing the establishment or replenishment of the cccDNA pool. This dual action makes CAM-Es a potent tool for reducing both viral load and the markers of cccDNA activity, such as serum HBV RNA.
Study Design and Methodology
The ALG-000184-201 study was a Phase 1, multicentre, randomised, dose-escalation trial. Part 3 of this study, presented here, focused on treatment-naive or currently untreated participants with CHB. The inclusion criteria required participants to be between 18 and 65 years old, with a BMI of 18.0-35.0 kg/m2, serum HBV DNA >2000 IU/mL, and ALT levels <5 times the upper limit of normal (ULN).
A total of 59 participants were enrolled and randomized 4:1 to receive either ALG-000184 (at doses of 10 mg, 50 mg, 100 mg, or 300 mg) or a matching placebo once daily for 28 days. The primary objective was to assess safety and tolerability, while secondary objectives included pharmacokinetic (PK) analysis and short-term antiviral activity. The study was conducted across sites in Hong Kong, China, Moldova, New Zealand, and the UK, ensuring a diverse participant population, of which 68% were Asian.
Safety and Tolerability: A Critical Evaluation
Safety data indicated that ALG-000184 was well-tolerated. Treatment-emergent adverse events (TEAEs) occurred in 58% of the ALG-000184 group compared to 64% in the placebo group. The most frequent TEAEs were elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Specifically, 31% of participants receiving the active drug experienced ALT increases, compared to 18% in the placebo group. These elevations were generally mild to moderate and did not lead to treatment discontinuation during the 28-day period.
Other reported TEAEs included hyperuricemia (10%), headache (8%), and elevated amylase (6%). Two serious adverse events (SAEs) occurred—mild spinal pain and spontaneous pneumothorax—but both were determined to be unrelated to the study drug. Importantly, no deaths or life-threatening events were reported, suggesting that the safety profile of ALG-000184 is manageable for short-term administration.
Pharmacokinetic Properties
Pharmacokinetic analysis revealed that ALG-000184 has a dose-dependent linear profile. The conversion from the prodrug to the active moiety (ALG-001075) was efficient, and steady-state concentrations were reached predictably. This linearity is crucial for clinical practice as it allows for precise dose adjustments and predictable therapeutic outcomes in larger patient populations.
Antiviral Efficacy: DNA and RNA Suppression
HBV DNA Reductions
Across all dose levels (10 mg to 300 mg), ALG-000184 induced a rapid and significant decline in HBV DNA. The reductions ranged from 3 to 4 log10 IU/mL. In HBeAg-negative participants, who typically have lower baseline viral loads, 83% reached DNA levels below the LLOQ (10 IU/mL) within 28 days. In contrast, HBeAg-positive participants, who entered the study with much higher baseline DNA levels, showed significant declines but did not reach LLOQ within the short 28-day window.
HBV RNA: A Marker of cccDNA Activity
One of the standout findings of this trial was the impact on serum HBV RNA. HBV RNA is increasingly recognized as a vital biomarker because it is a direct product of cccDNA transcription. Traditional NAs have a limited effect on RNA levels. In this study, ALG-000184 reduced HBV RNA by 0.5 to 3.0 log10 copies/mL. Notably, 100% of HBeAg-negative participants achieved HBV RNA levels below LLOQ. This suggests that ALG-000184 is highly effective at inhibiting the encapsidation process, thereby preventing the release of RNA-containing virions into the circulation.
HBsAg Modulation and Clinical Implications
While 28 days is a very short duration to observe changes in HBsAg—a marker that typically requires months or years to decline—some early signals were noted. In the 300 mg HBeAg-positive cohort, four out of eight participants experienced HBsAg decreases ranging from 0.2 to 0.8 log10 IU/mL. One participant in the 100 mg cohort also showed a 0.5 log10 reduction. While these results are preliminary, they hint at the potential for ALG-000184 to impact the HBsAg reservoir when used over longer periods or in combination with other agents.
Expert Commentary and Limitations
Mechanistic Insights
From a clinical perspective, the ability of a CAM-E to suppress both DNA and RNA is a significant advantage over current standard-of-care NAs. By clearing serum HBV RNA, clinicians may better assess the transcriptional activity of the cccDNA in the liver. Furthermore, the reduction in HBsAg seen in the 300 mg cohort, albeit in a small number of patients, is highly encouraging. This suggests that ALG-000184 might interfere with the production or secretion of HBsAg, possibly through secondary effects on the viral lifecycle or by reducing the overall pool of viral proteins.
Study Limitations
As a Phase 1 trial, the primary limitation is the short duration of treatment (28 days). Chronic hepatitis B requires long-term management, and the durability of these viral reductions remains to be seen. Additionally, the ALT elevations observed, while mild, require careful monitoring in longer studies to distinguish between toxic drug effects and beneficial “therapeutic flares” that indicate immune-mediated clearance of infected hepatocytes.
Conclusion: A New Pillar in HBV Therapy?
ALG-000184 represents a potent new candidate in the hepatitis B therapeutic landscape. Its ability to achieve rapid DNA and RNA suppression with a linear PK profile and acceptable safety makes it a strong candidate for further study. The data support the transition to Phase 2 trials, focusing on the 300 mg dose over longer durations. Whether used as a monotherapy for chronic suppression or as part of a finite, multi-drug curative regimen alongside NAs or entry inhibitors, ALG-000184 has the potential to significantly advance the quest for an HBV functional cure.
Funding and Clinical Trial Information
This study was funded by Aligos Therapeutics. The trial is registered at ClinicalTrials.gov under the identifier NCT04536337. The study is now complete, and the results have paved the way for subsequent Phase 2 investigations.
References
1. Yuen MF, Agarwal K, Jucov A, et al. ALG-000184 (pevifoscorvir sodium) monotherapy in participants with chronic HBV infection: a phase 1, multicentre, randomised, dose escalation trial. Lancet Gastroenterol Hepatol. 2026 Mar;11(3):218-231.
2. Chow N, et al. Capsid assembly modulators as a novel class of antivirals for chronic hepatitis B. J Hepatol. 2023;78(2):410-425.
3. Cornberg M, et al. HBV RNA as a new biomarker in chronic hepatitis B. JHEP Rep. 2020;2(3):100103.