Immunocore's IMC-I109V Shows Promising Antiviral Activity in Phase 1 Hepatitis B Trial
核心洞察
Immunocore (搜索)'s Phase 1 trial of IMC-I109V demonstrated dose-dependent reductions in hepatitis B surface antigen (HBsAg) levels, with 4 out of 14 participants achieving clinically meaningful responses at higher doses.
The bispecific T cell receptor therapy showed a manageable safety profile with mostly Grade 1-2 adverse events, though one participant experienced Grade 2 cytokine release syndrome that resolved rapidly with treatment.
IMC-I109V represents a novel T cell receptor-based approach targeting HBV-infected hepatocytes, designed to overcome virus-specific T cell exhaustion and potentially achieve functional cures for chronic hepatitis B infection.
Immunocore (搜索) Holdings plc has reported encouraging Phase 1 data for IMC-I109V, a novel bispecific T cell receptor therapy for chronic hepatitis B virus (HBV) infection, demonstrating dose-dependent antiviral activity alongside a manageable safety profile. The data, presented at The Liver Meeting organized by the American Association for the Study of Liver Diseases, represents the first-in-human evidence of HBsAg reduction through this innovative mechanism.
Novel Mechanism Targets HBV-Infected Cells
IMC-I109V is a TCR bispecific (ENVxCD3) candidate designed to specifically eliminate HBV-infected hepatocytes expressing hepatitis B surface antigen (HBsAg) via T cell redirection. The therapy targets a peptide derived from HBsAg that is presented by HLA-A*02:01 (搜索) on the surface of infected hepatocytes, designed to overcome HBV-specific T cell exhaustion by recruiting non-exhausted T cells to eliminate hepatocytes harboring covalently closed circular DNA or integrated HBV DNA.
Dose-Dependent Antiviral Activity Observed
The Phase 1 trial enrolled 20 participants in sequential cohorts evaluating ascending doses of 0.8 mcg, 2.4 mcg, 7 mcg, and 20 mcg of IMC-I109V, administered as a single intravenous infusion on day 1. Participants were evaluated for safety, tolerability, pharmacokinetics, and pharmacodynamic activity up to week 4.
At doses ≥ 7 mcg, consistent pharmacodynamic activity was observed, including dose-dependent decreases in HBsAg levels that typically reached a nadir by day 8. Reductions meeting the predetermined threshold of ≥ 0.2 log10 IU/ml were achieved in 4 individuals: 2 out of 6 participants in the 7 mcg cohort and 2 out of 8 participants in the 20 mcg cohort. In 3 of these 4 participants, HBsAg remained below pre-dose levels throughout the follow-up period.
The reductions in HBsAg levels coincided with immune activation, evidenced by IL-6 elevations and transient elevations in alanine aminotransferase (ALT), which were expected based on the mechanism of action.
Safety Profile Demonstrates Tolerability
Treatment-related adverse events were observed in 8 participants, primarily consisting of transient systemic symptoms (mostly Grade 1-2) occurring within 24 hours following infusion. ALT elevations ranged from Grade 1-3 but resolved to ≤ Grade 1 within 14 days. Importantly, bilirubin and prothrombin values remained within normal ranges throughout the study.
One participant in the 20 mcg cohort developed Grade 2 cytokine release syndrome, characterized by fever, transient hypoxia, and transient hypotension within 4 hours of infusion completion. This event responded rapidly to supportive treatment and corticosteroid therapy, resolving within 4 hours. Although dose-limiting toxicity criteria were not met, this event was classified as a serious adverse event due to hospital stay extension of less than one day. Subsequently, two participants received the 20 mcg dose with corticosteroid premedication as a precautionary measure, with no serious adverse events occurring in these individuals.
The rapid resolution of all treatment-related adverse events was consistent with the short serum half-life of IMC-I109V, which is less than 24 hours.
Implications for Functional Cure Development
"Dose-dependent decreases in serum HBsAg following a single dose of IMC-I109V are promising and show that a T cell receptor-based approach to treating chronic HBV infection warrants further investigation," said David Berman, Head of Research and Development at Immunocore (搜索). "These data – alongside the encouraging safety profile and antiviral activity seen in our ImmTAV candidate for HIV – reinforce the potential of our platform to achieve functional cures for chronic infectious diseases."
The clearance of HBsAg is considered indicative of resolved hepatitis B infection, making these results particularly significant for the development of functional cures. Immunocore (搜索) aims to achieve sustained loss of circulating viral antigens and markers of viral replication after stopping medication for people living with chronic HBV.
Platform Technology Expansion
IMC-I109V is part of Immunocore (搜索)'s ImmTAV (Immune mobilizing monoclonal TCRs Against Virus) platform, which comprises novel bispecifics designed to enable the immune system to recognize and eliminate virally infected cells. The company is advancing clinical candidates for both HIV and hepatitis B virus, with the goal of achieving functional cures for these chronic infectious diseases.
Immunocore (搜索) believes this first-in-human evidence of HBsAg reductions via this novel mechanism supports further evaluation of IMC-I109V in multiple dose regimens, potentially advancing toward a new therapeutic approach for chronic hepatitis B infection.