Pevifoscorvir Shows Strong HBV Activity, Durable Antigen Suppression

Capsid assembly modulators (CAMs) have emerged as one of the most active areas of therapeutic development in chronic hepatitis B (CHB), offering a mechanism of action distinct from approved nucleos(t)ide analogues (NAs) and the potential to address multiple aspects of the viral lifecycle simultaneously. Unlike NAs, which suppress viral replication without reducing hepatitis B surface antigen (HBsAg) or impacting covalently closed circular DNA (cccDNA), CAMs interfere with hepatitis B (HBV) core protein function, preventing pregenomic ribonucleic acid (RNA) encapsidation, blocking cccDNA establishment, and, in some cases, directly suppressing antigen secretion.^1,2

Pevifoscorvir (pevy) sodium (ALG-000184; Aligos Therapeutics), a prodrug of the active metabolite ALG-001075, is among the most advanced CAMs in clinical development and has demonstrated what study authors present as potential best-in-class reductions across HBV DNA, RNA, HBsAg, hepatitis B e-antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) in phase 1 studies. The program has since advanced into the phase 2 B-SUPREME (NCT06963710) trial, which initiated in August 2025, with interim data projected in 2026 and topline data expected in 2027, and has received FDA Fast Track Designation.³

At the European Association for the Study of the Liver (EASL) Congress 2026, 2 posters provided complementary data: one a head-to-head in vitro comparison of ALG-001075 against 2 competing CAMs in clinical development, and a second reporting long-term follow-up data from a cohort of HBeAg-positive participants who completed 96 weeks of pevy monotherapy.

3 Mechanisms, 3 Assays

CAMs of the type E class exert antiviral activity through 3 distinct but complementary mechanisms: primary suppression of HBV DNA production, inhibition of cccDNA establishment, and direct reduction of HBeAg secretion. Each of these was evaluated in a dedicated cell-based system.¹

HBV DNA antiviral activity was assessed in HepG2.117 cells using quantitative PCR. Effects on cccDNA establishment were evaluated in HBV genotype D-infected HepG2-NTCP cells or primary human hepatocytes (PHH), with HBsAg used as an indirect readout. Direct HBeAg effects were studied in HBeAg-overexpressing cells.

Potency Results

The potency differences across compounds were substantial. For primary HBV DNA suppression, ALG-001075 demonstrated an EC50 of 0.64 nM, compared with 5.8 nM for canocapavir and 24 nM for neracorvir, a roughly 9-fold advantage over canocapavir and a 37-fold advantage over neracorvir in this assay.

The differences were even more pronounced for the secondary mechanism of cccDNA establishment inhibition. In HepG2-NTCP cells, ALG-001075 blocked cccDNA establishment with a half-maximal effective concentration (EC50) of 18 nM (measured by HBsAg). In contrast, neracorvir showed an EC50 of 3350 nM in the same assay, a roughly 186-fold potency gap.

Canocapavir performed even less favorably, with an EC50 of approximately 1000 nM in PHH and greater than 5000 nM in HepG2-NTCP cells, indicating substantially limited activity against cccDNA establishment at clinically relevant concentrations.

For the third mechanism, direct HBeAg secretion inhibition, ALG-001075 demonstrated an EC50 of 855 nM, again outperforming both canocapavir and neracorvir. All 3 compounds displayed the characteristic CAM-E phenotype on immunofluorescent hepatitis core antibody staining: absence of nuclear aggregates with some cytoplasmic accumulation of core protein, confirming on-target activity across the class.

Resistance Profiling

The investigators also evaluated the activity of all 3 compounds against known CAM resistance mutations. The T33N mutation in HBV core protein—the principal resistance variant associated with first-generation CAMs—reduced the activity of ALG-001075 by 27-fold for HBV DNA and 23-fold for HBeAg suppression in vitro. However, this mutation has not been detected in any participant treated with pevy for up to 96 weeks in the clinical program, a finding that the investigators characterized as reassuring given the theoretical resistance risk.

Notably, the resistance profiles across the 3 agents differed in ways that may carry clinical relevance. Canocapavir was not susceptible to T33N but was sensitive to the Y118F mutation, with an 18-fold potency shift observed. ALG-001075 was not affected by Y118F, suggesting a distinct resistance profile that may complement canocapavir in future combination strategies.

The authors concluded that ALG-001075 displayed a highly potent in vitro antiviral profile across all three CAM-E mechanisms, confirming its potential as a best-in-class agent within the class. They noted that pevy is currently being developed as monotherapy for chronic HBV suppression, reflecting the compound's depth of activity as a single agent.

Sustained Antigen Suppression After 96-Week Monotherapy

The second poster reported long-term follow-up data from a subset of HBeAg-positive participants in the phase 1 ALG-000184-201 (NCT04536337) study. This cohort received oral pevy 300 mg once daily for 96 weeks as monotherapy, followed by an 8-week follow-up period on entecavir (ETV). Prior reporting had documented potent on-treatment suppression of HBV DNA, RNA, and viral antigens during the treatment period and through the initial 8-week ETV follow-up. The EASL poster extended this with data from 24 to 48 additional weeks of ETV-only follow-up, providing the first extended off-pevy assessment of antigen kinetics in this population.

Nine of the 10 HBeAg-positive participants in this part of the cohort were evaluable for the long-term follow-up analysis. Quantitative HBsAg and HBeAg were measured; HBV RNA was assessed using the Abbott RealTime HBV RNA assay; and HBsAg isoforms, including total HBsAg, medium surface protein (MHBs), and large surface protein (LHBs), were evaluated using prototype research-use-only assays.

HBsAg and HBeAg Show Sustained Reductions

The primary clinical findings centered on the durability of antigen suppression following cessation of pevy. Median HBsAg declined by 1.07 log₁₀ IU/mL over the course of pevy treatment, and this reduction was sustained through the extended follow-up period.

Median HBsAg at the end of treatment was 3.38 log₁₀ IU/mL and remained at 3.30 log₁₀ IU/mL at the end of long-term follow-up—both substantially below the median baseline level of 4.31 log₁₀ IU/mL, indicating that the antigen reduction achieved during pevy treatment was not reversed upon switch to ETV alone. Reductions in HBeAg observed during pevy treatment were similarly maintained during the long-term follow-up period.

HBV DNA and RNA Kinetics

HBV DNA remained below 10 IU/mL in 5 of 9 participants at long-term follow-up. The remaining 4 participants showed only modest increases, to 11.1, 26.8, 40.2, and 364 IU/mL, respectively, levels reflecting the transition from the direct antiviral activity of pevy to ETV-mediated suppression alone, with the higher value in 1 participant potentially reflecting a more limited ETV response in the absence of pevy's additional mechanisms.

HBV RNA and pre-core/core-related antigen, which are markers derived from cccDNA transcriptional activity, decreased substantially during pevy treatment but showed partial increases during long-term follow-up—a pattern the investigators characterized as mechanistically expected when transitioning from pevy's CAM-E activity to ETV, which does not directly suppress cccDNA transcription.

Evidence of cccDNA Pool Reduction

Among the most mechanistically informative findings from the poster was the analysis of HBsAg isoforms using prototype assays. Median declines at the end of pevy monotherapy were 0.40 log₁₀ for total HBsAg, 1.03 log₁₀ for MHBs, and 1.38 log₁₀ for LHBs. The disproportionately large reduction in LHBs, which is preferentially derived from cccDNA transcripts, relative to total HBsAg, led the investigators to conclude that pevy acts on the cccDNA-derived fraction of surface antigen and that the residual HBsAg persisting after treatment is predominantly derived from integrated HBV DNA rather than active episomal transcription.

This interpretation has meaningful clinical implications: reduction in cccDNA-derived antigen is considered a proxy for shrinkage of the active viral reservoir and is a more favorable end point than suppression of replication-derived antigens alone. If the sustained HBsAg reductions observed here reflect true cccDNA pool reduction, this would mechanistically support pevy's potential in finite treatment strategies aimed at functional cure.

The authors concluded that 96 weeks of oral pevy 300 mg monotherapy produced potent on-treatment effects on viral antigens consistent with cccDNA pool reduction and that these effects were sustained during at least 24 weeks of ETV-only follow-up in HBeAg-positive participants. They characterized the data as supporting the continued development of pevy for the suppressive treatment of patients with CHB.

References

1. Debing Y, Verheyen J, Vanrusselt H, et al. ALG-001075, the parent of pevifoscorvir sodium, exhibits potent in vitro antiviral properties compared to other HBV capsid assembly modulators in clinical development. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain.
2. Mak LYL, Jekle A, Anderson M, et al. Sustained reduction of HBV antigen levels at ≥6 months follow-up in HBeAg-positive participants with chronic hepatitis B infection after 96 weeks of 300 mg pevifoscorvir sodium monotherapy. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain.
3. Aligos Therapeutics announces first interim analysis results from the phase 2 B-SUPREME study of pevifoscorvir dodium in participants with chronic hepatitis B virus infection and grant of FDA Fast Track Designation. Aligos Therapeutics. Press release. April 14, 2026. Accessed May 28, 2026. https://investor.aligos.com/news-releases/news-release-details/aligos-therapeutics-announces-first-interim-analysis-results