Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive chronic hepatitis B patients with lamivudine-resistant disease

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http://www3.interscience.wiley.com/journal/123194731/abstract?CRETRY=1 & SRETRY=0

Hepatology

Early View (Articles online in advance of print)

Published Online: 30 Nov 2009

American Association for the Study of Liver Diseases

Viral Hepatitis

Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive

chronic hepatitis B patients with lamivudine-resistant disease§

Man-Fung Yuen 1¶, Kwang-Hyub Han 2¶, Soon-Ho Um 3, Seung Kew Yoon 4, Hye-Ryon

Kim 5, Kim 5, Chung Ryeol Kim 5, Ching-Lung Lai 1 *||

1Department of Medicine, Queen Hospital, The University of Hong Kong, Hong

Kong

2Department of Internal Medicine, Yonsei University College of Medicine, Seoul,

Korea

3Department of Internal Medicine, Korea University College of Medicine, Seoul,

Korea

4Department of Internal Medicine, College of Medicine, The Catholic University

of Korea, Seoul, Korea

5LG Life Sciences, Seoul, Korea

email: Ching-Lung Lai (hrmelcl@...)

*Correspondence to Ching-Lung Lai, Department of Medicine, Queen Hospital,

The University of Hong Kong, Pokfulam Road, Hong Kong

This study has been registered (registration number NCT00895596) in

ClinicalTrials.gov (URL

http://clinicaltrials.gov/ct2/show/NCT00895596?term=LB80380 & rank=1).

This study was supported by LG Life Sciences which also provided the drug

LB80380. The data collection and data report were carried out by an independent

data management company, Covance Pty Limited, Australia. The analysis and the

writing of the manuscript were mainly performed by the first two authors as well

as the corresponding author. The drug company employees read and commented on

the manuscript, and gave their approval.

§Potential conflicts of interest: M. F. Y. and C. L. L. have received speakers'

honoraria from LG Life Sciences. H. R. K. and C. R. K. are full-time employees

of LG Life Sciences. J. K. is a former employee of LG Life Sciences.

¶These authors contributed equally to this work.

||fax: (852)-28162863.

Funded by:

LG Life Sciences

Korean Ministry for Health, Welfare, and Family Affairs

Anadys Pharmaceuticals, Inc.

Abstract

We aimed to determine the antiviral activity and safety of a new nucleotide

analogue, LB80380, in chronic hepatitis B (CHB) patients with

lamivudine-resistant virus. Sixty-five patients with lamivudine-resistant virus

were randomized to receive five ascending daily doses (30, 60, 90, 150, 240 mg)

of LB80380. LB80380 was given together with lamivudine for the first 4 weeks,

followed by 8 weeks of LB80380 monotherapy. This was then followed by 24 weeks

of adefovir. Hepatitis B virus (HBV) DNA levels, serology, liver biochemistry,

and safety were monitored. The extent of the HBV DNA reduction at week 12 was

dose-dependent. The mean reduction from baseline was 2.81, 3.21, 3.92, 4.16, and

4.00 log10 copies/mL for the five ascending dose groups. The dose-proportionate

effect was statistically significant (P < 0.001) with a decrease of HBV DNA

levels by an average of 1.54 log10 copies/mL for every 1-unit increase in log10

dose of LB80380. In 93.4% of patients, HBV DNA decreased by>2 log10 copies/mL,

and 11.5% of patients had undetectable HBV DNA levels (<300 copies/mL) by week

12. HBV DNA suppression was maintained during the 24 weeks of adefovir

treatment. Hepatitis B e antigen seroconversion and normalization of alanine

aminotransferase were seen in 14.6% and 24.6% of patients, respectively, at week

12; 44.6% of patients experienced mild and self-limiting adverse events, none of

which were attributed to the study drug. Conclusion: LB80380 at doses of up to

240 mg is safe, well tolerated, and effective at reducing viral load in CHB

patients with lamivudine-resistant virus for a period of 12 weeks. (HEPATOLOGY

2010.)

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Received: 15 June 2009; Accepted: 24 October 2009

Digital Object Identifier (DOI)

10.1002/hep.23462