SOLUBLE IMMUNE BIOMARKER PROFILING OF CHRONIC HEPATITIS B SUBJECTS TREATED WITH IMDUSIRAN IN COMBINATION WITH PEGYLATED INTERFERON ALFA REVEALS PHASES OF IMMUNE ACTIVATION
Recommended Citation
Espiritu C, Ganchua S, Eley T, Gray K, Yuen M, Heo J, Nahass R, Wong G, Burda T, Ram K, Tsung-Hui B, Tuan H, Nguyen T, Lim Y, Chen C, Gordon S, Holmes J, Chuang WL, Kohli A, Alkhouri N, Lam A, Sofia M, Sims K, Thi E. SOLUBLE IMMUNE BIOMARKER PROFILING OF CHRONIC HEPATITIS B SUBJECTS TREATED WITH IMDUSIRAN IN COMBINATION WITH PEGYLATED INTERFERON ALFA REVEALS PHASES OF IMMUNE ACTIVATION. Hepatology 2024; 80:S307-S308.
Document Type
Conference Proceeding
Publication Date
10-9-2024
Publication Title
Hepatology
Abstract
Background: Functional cure of chronic hepatitis B (CHB) requires suppression of viral replication, reduction of HBV antigens and induction of anti-HBV immune response. Pegylated interferon alfa-2a (IFN) is a standard of care immunomodulator with limited efficacy against HBV. Imdusiran (AB-729, IDR) is an N-Acetylgalactosamine- conjugated single trigger siRNA targeting all HBV RNA transcripts, resulting in suppression of all viral antigens including HBsAg. In an ongoing Phase 2a study assessing IDR as lead-in (24 weeks) followed by 12 or 24 weeks of IFN ± additional IDR doses in HBeAg-negative CHB subjects virally suppressed on nucleos(t)ide analog (NA) therapy (AB-729-201, IM-PROVE I), soluble immune biomarkers were profiled and association with HBsAg response assessed. Methods: Longitudinal plasma samples were collected from 43 subjects during the 24-week IDR lead-in, IFN treatment and follow-up periods. Soluble immune biomarkers were assessed using Luminex multiplex panels (58 analytes). Results: Transient increases ≥3 to 31-fold from baseline in immune biomarkers associated with immune activation (sCD40, sCD28, sCD80, sCD86), Th1 cell-mediated response (IL- 6, IL-12 p40, IL-12 p70, IL-7, IL-10), inflammation regulation (GROa, PDGF-AA, PDGF-AB, VEGF), and immune checkpoint proteins (PD-1, PD-L1, CTLA-4, LAG- 3, BTLA) were observed during IDR lead-in, with peaks occurring during the plateau of HBsAg reduction in assessed subjects to date. Elevations occurred again during IFN treatment, during which time increase in the Th2 cytokine IL-5 was also observed. At 24 weeks post IFN treatment, 6 subjects achieved HBsAg loss and HBsAg seroconversion. 5/6 subjects with HBsAg loss had greater Th1/inflammation-related responses during IDR lead-in or IFN treatment compared to those without HBsAg loss. Further increases in Th2 cytokines IL-4 and IL-13 after end of IFN treatment were associated with HBsAg seroconversion. Conclusion: IDR treatment in combination with IFN was associated with distinct phases of soluble immune biomarker signatures. Immune biomarkers associated with Th1 immune activation and regulation of inflammation were observed in subjects during IDR lead-in, coinciding with the establishment of a plateau in HBsAg reduction. Secondary transient elevations of these immune biomarkers were observed to occur during IFN treatment and were followed by appearance of Th2 immune biomarker signatures that were associated with HBsAg seroconversion.
Volume
80
First Page
S307
Last Page
S308
