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Antiviral Therapy 11:977–983
A randomized placebo-controlled, dose-finding study of oral LB80380 in HBeAg-positive patients with chronic hepatitis B Man-Fung Yuen1*, John Kim2, Chung Ryeol Kim2, Vincent Ngai1, John Chi-Hang Yuen1, Changhee Min2, Hyang Mi Kang 2 , Beom Soo Shin3, Sun Dong Yoo3 and Ching-Lung Lai1* 1
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong LG Life Sciences Ltd, Seoul, Korea 3 College of Pharmacy, Sungkyunkwan University, Seoul, Korea 2
*Corresponding authors: Tel: +852 2855 4252; Fax: +852 2816 2863: E-mail:
[email protected];
[email protected]
Background: LB80380 is potent antiviral agent against hepatitis B virus (HBV) in vitro and in the woodchuck model. It has an excellent preclinical safety profile including lower potential for renal toxicity than adefovir. It is effective against both wild-type and YMDD mutant HBV. LB80380 is converted to its parent drug, LB80331, after oral absorption, and further metabolized to its active form, LB80317. Aims/Methods: This randomized placebo-controlled Phase I/II clinical study of LB80380 was conducted to assess the safety, antiviral activity and pharmacokinetics of its parent drug LB80331 and its active form LB80317 in 29 Asian adults with chronic hepatitis B positive for hepatitis B e antigen in four escalating dose groups (30, 60, 120 and 240 mg once per day) for 4 weeks with a 12-week follow-up period.
Results: The mean maximum HBV DNA reduction was 3.05, 4.20, 3.67 and 3.68 log10 copies/ml for 30, 60, 120 and 240 mg per day, respectively. Viral dynamic analysis suggested a high degree of inhibition of HBV replication at doses of 60 mg or higher per day. LB80380 was well tolerated at all dose groups, and no dose-related clinical or laboratory adverse event was reported. Conclusion: LB80380 is shown to be a potent and safe antiviral agent for HBV. Marked HBV DNA suppression was observed in all dose groups. The HBV DNA suppression was approximately constant at doses of 60 mg and higher over the 28-day dosing period. The dose response of LB80380 will be evaluated further in large clinical studies.
Introduction It is estimated that 400 million people worldwide have chronic hepatitis B (CHB) infection. Of these, 25–40% will develop hepatocellular carcinoma and cirrhosisrelated complications [1]. Effective antiviral treatment is urgently needed. To date, four drugs have been approved for CHB. These include interferon-α (IFN-α; conventional or pegylated IFN), lamivudine (3TC), adefovir dipivoxil and entecavir (ETV). The latter three drugs are nucleos(t)ide analogues with negligible side effects and convenient daily oral dosing. However, prolonged use of 3TC is associated with increasing chance of emergence of 3TC-resistant hepatitis B virus (HBV) in the YMDD motif, namely, rtM204I and rtM204V [2]. Although adefovir dipivoxil is associated with a lower chance of emergence of adefovir-resistant HBV (rtN236T) [3], there is the potential renal toxicity to consider with prolonged treatment [4]. Of the three nucleo(t)side analogues, ETV is the most potent one. However, ETV © 2006 International Medical Press 1359-6535
has been shown to be carcinogenic in mice at dose exposures 3–40 times higher than those in humans [5]. Several newer nucleos(t)ide analogues are being developed and extensively tested in preclinical and clinical trials. The ideal nucleos(t)ide analogues should possess the following features: (i) marked viral suppression, preferably down to levels undetectable by PCR assays; (ii) lowest rate of emergence of drug-resistant HBV; (iii) effective action against all known forms of resistant HBV; (iv) no or low toxicity profile on long-term treatment; and (v) pharmacokinetics that allow once-daily dosing. Since more effective HBV DNA reduction is associated with a significantly lower chance of emergence of drug-resistant HBV [6], highly potent and safe nucleos(t)ide analogues that are effective against both wild-type HBV and 3TC resistant HBV are required. LB80380 is an oral nucleotide prodrug and is chemically comparable with adefovir dipivoxil and tenofovir 977
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disoproxil fumarate. LB80380 is rapidly converted to the parent drug LB80331 in the liver and intestine, probably by esterases. LB80331 is further metabolized to LB80317, a nucleotide analogue of guanosine monophosphate (Figure 1), by oxidases such as aldehyde oxidase or xanthine oxidase, a nucleotide analogue of guanosine monophosphate (Figure 1). After phosphorylation to the di- and tri-phosphate forms, the molecule inhibits viral replication following incorporation into viral DNA. We report the safety, antiviral activity and pharmacokinetics of 4-week, escalating doses of LB80380 in a Phase I/II, double-blind, randomized, placebocontrolled study in patients with CHB.
Patients and methods Study centre and approval The trial BVCL002 was approved by the Ethics Committee, Institutional Review Board, The University Hong Kong, Queen Mary Hospital, Hong Kong, and conducted under Good Clinical Practice standards with local regulatory authorization and an Investigational New Drug application approved by the US Food and Drug Administration. All screened and recruited patients gave written informed consent.
Study design Four escalating doses of LB80380 (30, 60, 120 and 240 mg once daily) were tested in consecutive cohorts. Each cohort comprised seven patients of whom six were
randomized to receive LB80380 of the respective dose and one to receive placebo. The randomization was performed by computer allocation. Treatment was given for 4 weeks. Recruitment of each cohort was performed in a dose-escalating manner. Initiation of the next higher dose cohort was only allowed under two conditions: (i) Not more than one out of the six patients receiving the 4-week treatment in the preceding lower-dose cohort experienced dose-limiting toxicity, or (ii) if two out of the six patients developed dose-limiting toxicity during the 4-week treatment, two additional patients should complete the 4-week treatment at the same dose without dose-limiting toxicity. Dose-limiting toxicity was defined as a prothrombin time of more than 3 s above control; a serum albumin level less than 30 g/l; grade 3 or greater elevation of total bilirubin, creatinine or amylase; grade 4 alanine aminotransferase (ALT) elevation (>10 times baseline) with any evidence of hepatic insufficiency; or any other grade 4 clinical or laboratory toxicity considered by the investigators to be at least reasonably or possibly related to the study drug. Pharmacokinetics study was performed in all patients at baseline and during the apparent steady state between weeks 2 and 4 at the time points of pre-dose and 0.5, 1, 2, 3, 6, 8 and 24 h post-dose. Plasma concentrations of LB80331 and LB8017 were measured with a validated liquid chromatographic assay with tandem mass spectrometric detection (LC/MS/MS). The lower limits of quantitation were 5 and 10 ng/ml for LB80331 and LB80317, respectively. Intra- and inter-assay precision and accuracy variations were less than 10%. Blood samples for viral
Figure 1. The chemical structure of LB80380 (the prodrug), LB80331 (the parent drug) and LB80317 (the active moiety)
N
N H 2N
N
O
N
O
P
O
O
O
O
O
N
N H 2N
N
N
OH O
P
OH
O
O
LB803 31 (parent drug)
LB80380 (prodrug)
OH N
N Further phosphorylation
H 2N
N
N
OH O
P
OH
O LB80 317 (active moeity) 978
© 2006 International Medical Press
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load measurement were obtained at baseline and weekly through to week 8 and thereafter every other week through to week 16. Serum HBV DNA was quantified using the COBAS AmplicorTM PCR assay for HBV DNA (Roche Diagnostics, Branchburg, NJ, USA) with a lower limit of detection of 300 genome copies/ml.
Patients Patients were recruited under the following inclusion criteria: adults of 18–65 years of age; hepatitis B surface antigen (HBsAg)-positive for at least 6 months; hepatitis B e antigen (HBeAg) positive for at least 1 month; HBV DNA level ≥1×107 copies/ml measured by the COBAS AmplicorTM HBV Monitor test; and serum ALT level 20 ng/ml with evidence of hepatocellular carcinoma by imaging; or history of severe allergic disease or illicit drug or alcohol abuse. A total of 66 patients were screened and 28 patients were recruited (all completed the 4-week dosing and fulfilled the whole study protocol). The remaining 38 were not enrolled because of the following reasons: patient withdrawal of consent (n=21); HBV DNA levels 5×ULN (n=2); HBeAg negativity (n=1); HBV DNA levels
