A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B

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A phase II dose-escalating trial of clevudine in patients with chronic

hepatitis B

Marcellin 1 *, Herve Mommeja-Marin 2, L. Sacks 3, K.

K. Lau 4, Sereni 5, Jean-Pierre Bronowicki 6, Conway 7,

Christian Trepo 8, M. Blum 2, Byung Chul Yoo 9, Elsa Mondou 2, Jeff

Sorbel 2, Snow 2, Franck Rousseau 2, Hyo-Suk Lee 10

1Hopital Beaujon, Clichy, France

2Triangle Pharmaceuticals, Inc./Gilead Sciences Inc., Durham, NC

3Viridiae, Vancouver, British Columbia, Canada (deceased)

4Queen Hospital, University of Hong Kong, Hong Kong SAR, China

5Centre d'Investigation Clinique, Hôpital Saint Louis, Paris, France

6Hôpital Brabois, , France

7University of British Columbia, British Columbia, Canada

8Hotel Dieu, Lyon, France

9Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,

South Korea

10Seoul National University Hospital, Seoul, South Korea

email: Marcellin (marcellin@...)

*Correspondence to Marcellin, Service d'Hépatologie, Hpital Beaujon,

100 Bd. du Général Leclerc, 92110 Clichy, France

fax: 33 1 47 30 94 40

Funded by:

Triangle Pharmaceuticals, Inc.

Bukwang Pharmaceuticals Ltd.

Abstract

Current therapies available for the treatment of chronic hepatitis B are

limited in their ability to result in a cure. Clevudine is a new pyrimidine

analog with potent anti-hepatitis B virus (HBV) activity in vitro. A

multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and

200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 ×

106 copies/mL or more, had not undergone nucleoside treatment, and were

without human immunodeficiency or hepatitis C virus coinfection. Thirty-two

patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and

200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were

hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum

HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL. After 28 days, the

median HBV DNA log10 change from baseline was -2.5, -2.7, -3.0, and -2.6

log10. Six months after dosing, median changes from baseline

were -1.2, -1.4, -2.7 and -1.7 log10 in the 10-, 50-, 100-, and 200-mg

cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients

seroconverted to HBe antibody. Clevudine was well tolerated, with no

dose-limiting toxicities. A transient increase in alanine aminotransferase

of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186

IU/L) was observed in six patients in the 100-mg cohort, without signs of

liver failure. These increases were associated with improved viral

suppression. The pharmacokinetic profile of clevudine was proportional to

the dose. In conclusion, these results demonstrate the tolerability and

potent activity of clevudine in HBV-infected patients and support further

clinical study. (HEPATOLOGY 2004;40:140-148.)

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Received: 19 August 2003; Accepted: 4 April 2004

Digital Object Identifier (DOI)

10.1002/hep.20257 About DOI