Comprehensive Report on ALN-HBV-02 (Elebsiran/VIR-2218/BRII-835): An Investigational RNAi Therapeutic for Chronic Hepatitis B and D

1. Executive Summary

ALN-HBV-02, also known by its developmental codenames VIR-2218 and BRII-835, and the proposed international non-proprietary name elebsiran, is an investigational small interfering RNA (siRNA) therapeutic. Originating from Alnylam Pharmaceuticals and co-developed with Vir Biotechnology and Brii Biosciences, ALN-HBV-02 targets hepatitis B virus (HBV) transcripts, primarily aiming to reduce hepatitis B surface antigen (HBsAg) levels. A key innovation is its Enhanced Stabilization Chemistry Plus (ESC+) technology, designed to improve hepatic safety and specificity compared to its precursor, ALN-HBV. Administered subcutaneously, ALN-HBV-02 has demonstrated potent HBsAg reduction in clinical trials for chronic hepatitis B (CHB). While monotherapy shows significant HBsAg knockdown, achieving functional cure (sustained HBsAg loss and anti-HBs seroconversion) typically requires combination with immunomodulators (e.g., pegylated interferon-alfa, therapeutic vaccines) or other antiviral agents (e.g., HBsAg-targeting monoclonal antibodies like tobevibart). The safety profile of ALN-HBV-02 monotherapy appears favorable; in combination regimens, adverse events are generally consistent with the known profiles of the partner drugs. Notably, the combination of elebsiran and tobevibart has shown substantial promise for chronic hepatitis D (CHD), leading to expedited regulatory pathways, including FDA Breakthrough Therapy and Fast Track designations, and EMA PRIME status, with global Phase 3 trials (ECLIPSE program) underway. Ongoing research continues to define optimal combination strategies and long-term outcomes, positioning ALN-HBV-02 as a potentially pivotal component in future curative regimens for CHB and a new therapeutic option for CHD.