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

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 ma...
Ausführliche Beschreibung

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. Ausführliche Beschreibung

Autor*in:

Gane, Ed [verfasserIn] Lim, Young-Suk [verfasserIn] Kim, Jae B. [verfasserIn] Jadhav, Vasant [verfasserIn] Shen, Ling [verfasserIn] Bakardjiev, Anna I. [verfasserIn] Huang, Stephen A. [verfasserIn] Cathcart, Andrea L. [verfasserIn] Lempp, Florian A. [verfasserIn] Janas, Maja M. [verfasserIn] Cloutier, Daniel J. [verfasserIn] Kaittanis, Charalambos [verfasserIn] Sepp-Lorenzino, Laura [verfasserIn] Hinkle, Gregory [verfasserIn] Taubel, Jorg [verfasserIn] Haslett, Patrick [verfasserIn] Milstein, Stuart [verfasserIn] Anglero-Rodriguez, Yesseinia I. [verfasserIn] Hebner, Christy M. [verfasserIn] Pang, Phillip S. [verfasserIn] Yuen, Man-Fung [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	siRNA HBV virology HBV surface antigen

Übergeordnetes Werk:	Enthalten in: Journal of hepatology - Amsterdam [u.a.] : Elsevier Science, 1985, 79
Übergeordnetes Werk:	volume:79

DOI / URN:	10.1016/j.jhep.2023.05.023

Katalog-ID:	ELV064351521