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Clevudine, new HBV drug, 3 studies
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Reported by Jules Levin
"A PHASE II, RANDOMIZED TRIAL EVALUATING THE SAFETY, PHARMACOKINETICS AND ANTIVIRAL ACTIVITY OF CLEVUDINE FOR 12 WEEKS IN PATIENTS WITH CHRONIC HEPATITIS B"
Patrick Marcellin, Hosp. Beaujon, Clichy, France; Nancy Leung, Prince of Wales Hosp. , Chinese Univ. of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China; Hie-Won L Hann, Thomas Jefferson Univ. Hosp, Philadelphia, PA; George Kk Lau, Queen Mary Hospital, University of Hong Kong, Hong kong, Hong Kong Special Administrative Region of China; Christian Trepo, Hotel Dieu, Lyon, France; Stephen Sacks, Viridae, Vancouver, BC, Canada; Herve Mommeja-Marin, Cary Moxham, Andrea Snow, Franck Rousseau, Gilead Sciences, Inc., Durham, NC; Seng Gee Lim, National Univ. Hosp, Singapore, Singapore
Clevudine (CLV, L-FMAU) is a potent inhibitor of Hepatitis B virus (HBV) replication in vitro. In woodchucks and in a Phase I/II clinical study, CLV produced a potent and sustained viral suppression following a 4-week dosing period.
A multicenter, international, randomized, double-blind study comparing 10, 30 and 50 mg CLV once daily (QD) for 12 weeks. Patients were followed post-treatment for at least 24 weeks. Eligible patients had chronic HBV infection with Baseline serum HBV DNA levels (VL) >= 3x106 copies/mL (c/mL) as measured by the Chiron Quantiplex™ assay, and were nucleoside treatment-naïve without HIV, HDV or HCV co-infection. VL was assayed using Digene Hybrid Capture II (lower limit of detection of 4700 c/mL) and genotypic analysis of Baseline, Week 12 and Week 26 samples was performed using di-deoxy sequencing.
Results
Thirty-one patients were enrolled (10, 11 and 10 in the 10, 30 and 50 mg cohorts, respectively) of whom 55% were male, 84% Asian, and 81% HBeAg positive. At Baseline, median VL was 8.7, 7.9, and 8.7 log10 c/mL and median alanine aminotransferase (ALT) level was 53, 63, and 80 IU/L in the 10, 30 and 50 mg CLV cohorts, respectively.
After 12 weeks of dosing, the median log10 VL change from Baseline was -3.2, -3.7 and -4.2 log10 c/mL in the 10, 30, and 50 mg cohorts, respectively (P=0.012 for trend).
One out of 10, 5/11 and 2/10 patients had VL below the assay LOD at Week 12 in the 10, 30, and 50 mg cohorts, respectively. Only 2 patients seroconverted to anti-HBe (both in the 30mg cohort).
CLV was generally well tolerated without dose related adverse events, and no severe or serious adverse events. One patient reported a transient Grade 3 increase in ALT and another a transient Grade 3 creatine phosphokinase increase, both while on study drug.
The pharmacokinetics of CLV were dose proportional with a mean plasma half-life of 70 hours. Pharmacodynamic modeling shows that 97% of the maximal treatment effect was reached with a dose of 30 mg QD.
These preliminary results confirm the potent antiviral activity of once daily clevudine and further demonstrate the tolerability of the drug over 12 weeks of dosing. Based on these results, the optimal dose of clevudine appears to be >10 mg QD.
'A 12-WEEK CLEVUDINE THERAPY SHOWED DURABLE ANTIVIRAL ACTIVITY AND NORMALIZATION OF ALANINE TRANSMINASE LEVELS FOR 6 MONTHS AFTER DISCONTINUATION OF TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS B"
Hyo-Suk Lee, Seoul National University Hospital, Seoul, Republic of Korea; Young-Hwa Chung, Asan Medical Center, Seoul, Republic of Korea; Kwan Sik Lee, Yongdong Severance Hospital, Seoul, Republic of Korea; Kwan Soo Byun, Korea University Medical Center Guro Hospital, Seoul, Republic of Korea; Seung Woon Paik, Samsung Medical Center, Seoul, Republic of Korea; Joon-Yeol Han, The Catholic University of Korea, St. Mary's Hospital, Seoul, Republic of Korea; Kwon Yoo, Ewha Woman's University Mokdong Hospital, Seoul, Republic of Korea; Soo Geum Hwang, Bukwang Pharm. Co. , Ltd., Seoul, Republic of Korea; Byung Chul Yoo, Samsung Medical Center, Seoul, Republic of Korea; Jin Heon Lee, Hallym University Hospital, Seoul, Republic of Korea
Clevudine is a pyrimidine analogue that is a potent inhibitor of HBV replication in vitro. In woodchucks, clevudine caused potent and durable post-treatment viral suppression. In a preliminary clinical trial of 4-week clevudine treatment, potent antiviral activity was demonstrated along with the marked post-treatment antiviral effect.
The primary objectives of the study were to evaluate the tolerability, safety and antiviral activity of clevudine in a 12-week, double-blind, randomized, multicenter, phase II clinical trial and to assess the durable antiviral response at week 24 off therapy.
The safety and efficacy of clevudine (30mg/day or 50mg/day orally) were compared with those of placebo, and then each group was observed for 24 weeks off therapy (a total period of 36 weeks). The study was conducted at a total of 8 sites in South Korea. Eligible patients were female or male with HBeAg-positive chronic hepatitis B with HBV DNA levels greater than or equal to 3 million copies/mL.
Among a total of 99 patients (33, 32 and 34 in the placebo, 30mg and 50mg cohorts, respectively) enrolled, 88 patients (25, 31 and 32 in the placebo, 30mg and 50mg cohorts, respectively) have completed 36-week study period, the data of whom were analyzed.
RESULTS
Median HBV DNA level at baseline was 8.4, 8.4 and 8.2 log10 copies/mL, and the median change in HBV DNA levels from baseline at week 12 was -0.12, -4.47 and -4.45 log10 copies/mL in the placebo, 30mg and 50mg cohorts, respectively.
Post-treatment antiviral activities were sustained with 3.32 and 2.99 log10 reduction at week 12 off therapy and 2.28 and 1.40 log10 reduction at week 24 off therapy in 30mg and 50mg cohorts, respectively. In the placebo, 30mg and 50mg cohorts, 0 and 63 and 52% had HBV DNA levels below the lower limit of detection assay (4.7 thousand copies/mL) at the end of 12-week treatment, and 4, 16 and 9% at week 36, respectively.
Serum ALT levels declined from average of about 160 IU/L at week 0 to about 40 IU/L at week 12 and remained at about this level at weeks 24 and 36. Normalization of alanine transminase levels was observed in 7, 53 and 55% at week 12 and 12, 71 and 63% at week 36 in the placebo, 30mg and 50mg cohorts, respectively. Clevudine was well tolerated and most adverse events were comparable in all study groups.
A 12-week clevudine therapy showed potent antiviral activity against HBV with durable viral suppression and normalization of aminotransferase levels at week 24 off therapy and was well tolerated.
"CLEVUDINE THERAPY FOR 24 WEEKS FURTHER REDUCED SERUM HEPATITIS B VIRUS DNA LEVELS AND INCREASED ALT NORMALIZATION RATES WITHOUT EMERGENCE OF VIRAL BREAKTHROUGH THAN 12-WEEK CLEVUDINE THERAPY"
Kwan Sik Lee, Yongdong Severance Hospital, Seoul, Republic of Korea; Kwan Soo Byun, Korea University Medical Center Guro Hospital, Seoul, Republic of Korea; Young-Hwa Chung, Asan Medical Center, Seoul, Republic of Korea; Seung Woon Paik, Samsung Medical Center, Seoul, Republic of Korea; Joon-Yeol Han, The Catholic University of Korea, St. Mary's Hospital, Seoul, Republic of Korea; Kwon Yoo, Ewha Woman's University Mokdong Hospital, Seoul, Republic of Korea; Soo Geum Hwang, Bukwang Pharm. Co. , Ltd., Seoul, Republic of Korea; Byung Chul Yoo, Samsung Medical Center, Seoul, Republic of Korea; Hyo-Suk Lee, Seoul National University Hospital, Seoul, Republic of Korea
Clevudine(CLV, L-FMAU) is a pyrimidine analogue that is a potent inhibitor of HBV replication in vitro. In woodchucks and in a phase I/II clinical study (L-FMAU-102), CLV produced a potent and durable post-treatment viral suppression. In a phase II clinical study (L-FMAU-201), CLV showed potent antiviral activities during 12-week dosing period and prolonged antiviral activities after discontinuation of treatment, which was associated with sustained normalization of ALT.
The primary objectives of this study were to evaluate the safety and antiviral activity of CLV during longer treatment period of 24 weeks.
The safety and efficacy of CLV (30mg/day, orally) for 24 weeks was evaluated. The study was conducted at a total of 7 sites in South Korea. Eligible patients were chronic hepatitis B patients previously included in the placebo group of L-FMAU-201 study, whose HBeAgs were not seroconverted to anti-HBe. A total of 21 patients were enrolled and among them, 17 patients have completed 24-week treatment period, the data of which were analyzed for this interim report.
RESULTS
Median HBV DNA level at baseline was 7.53 log10 copies/mL, and the median changes in HBV DNA levels from baseline were -4.05, 4.64 log10 copies/mL at week 12 and week 24, respectively.
59 % of patients had HBV DNA levels below the lower limit of detection of Supersensitive Digene II assay (LOD, 4.7 × 103 copies/mL) at week 12, and 82 % at the end of 24-week treatment. 24 % of patients had HBV DNA levels below LOD in Amplicor PCR assay (400 copies/mL) at week 12, and 59 % at the end of 24-week treatment.
Viral breakthrough was not observed during the entire dosing period.
Normalization of alanine transaminase level was observed in 47 % and 76% at week 12 and 24, respectively. HBeAg loss occurred in 12 % and 24% at week 12 and 24, respectively.
No serious or severe adverse events relevant to CLV were reported during the study and no adverse events led to treatment discontinuation.
The authors concluded that CLV treatment for 24 weeks showed more potent antiviral activity against HBV without the emergence of viral breakthrough and higher rates of HBeAg loss as well as ALT normalization rates than 12-week treatment of CLV with an excellent safety profile.
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