Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials.

Abstract

BACKGROUND & AIMS:

Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts.

METHODS:

We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection.

RESULTS:

In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion.

CONCLUSIONS:

VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure.

TRIAL REGISTRATION:

ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188.

IMPACT AND IMPLICATIONS:

A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.

• Authors: Ed Gane, Young-Suk Lim, Jae B Kim, Vasant Jadhav, Ling Shen, Anna I Bakardjiev, Stephen A Huang, Andrea L Cathcart, Florian A Lempp, Maja M Janas, Daniel J Cloutier, Charalambos Kaittanis, Laura Sepp-Lorenzino, Gregory Hinkle, Jorg Taubel, Patrick Haslett, Stuart Milstein, Yesseinia I Anglero-Rodriguez, Christy M Hebner, Phillip S Pang, Man-Fung Yuen
• Journal: Journal of hepatology (J Hepatol) Vol. 79 Issue 4 Pg. 924-932 (10 2023) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 37290591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Hepatitis B Surface Antigens
• Antiviral Agents
• DNA, Viral
• Hepatitis B e Antigens

Topics

• Humans
• Animals
• Mice
• Hepatitis B, Chronic (drug therapy)
• Hepatitis B virus
• Hepatitis B Surface Antigens
• RNAi Therapeutics
• Randomized Controlled Trials as Topic
• Antiviral Agents
• DNA, Viral
• Hepatitis B e Antigens
• Hepatitis B (drug therapy)