EPIVIR HBV (Page 5 of 6)

12.4 Microbiology

Mechanism of Action

Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of the RNA- and DNA-dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

Activity of lamivudine against HBV in cell culture was assessed in HBV DNA‑transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 microM (2.3 ng per mL) to 5.6 microM (1.3 mcg per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the prescribing information for EPIVIR regarding activity of lamivudine against HIV. The anti-HBV activity of lamivudine in combination with adefovir or tenofovir in cell culture was not antagonistic.

Resistance

Lamivudine‑resistant isolates have been identified in subjects with virologic breakthrough.

Lamivudine‑resistant HBV isolates develop rtM204V/I substitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory substitutions improving replication efficiency. Other substitutions reported in lamivudine‑resistant HBV isolates include rtH55R, rtL80I/V, rtV173M, rtA181T/V, rtT184S, rtF219Y, rtL229F/M/V/W, and rtQ267H.

In 4 controlled clinical trials evaluating EPIVIR-HBV in adults with HBeAg‑positive chronic hepatitis B virus infection (CHB), YMDD‑mutant HBV was detected in 81 of 335 subjects receiving EPIVIR-HBV 100 mg once daily for 52 weeks. The prevalence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in 4 trials: 16% to 32%) at 52 weeks. A similar prevalence of YMDD substitutions has been reported in large controlled Phase 3 clinical trials utilizing EPIVIR-HBV as a comparator arm in adults with HBeAg-positive CHB for 48 weeks (range in 4 trials: 11% to 27%) and in adults with HBeAg-negative CHB for 48 weeks (range in 3 clinical trials: 6% to 18%).

Long-term follow up in subjects who continued 100 mg per day of EPIVIR-HBV demonstrated that the prevalence of YMDD substitutions further increased from 23% (211 of 998) in Year 1, to 46% (368 of 796), 55% (378 of 688), 71% (421 of 592), and 65% (103 of 159) in Years 2, 3, 4, and 5, respectively.

In a controlled trial, treatment‑naive subjects with HBeAg‑positive CHB were treated with EPIVIR-HBV or EPIVIR-HBV plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD‑mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only EPIVIR-HBV. In 2 controlled clinical trials, treatment-naive subjects who received 48 weeks of therapy with EPIVIR-HBV in combination with pegylated interferon developed YMDD substitutions less frequently than subjects treated with EPIVIR-HBV alone (1 of 173 [1%] versus 32 of 179 [18%] in HBeAg-negative subjects; 9 of 256 [4%] versus 69 of 254 [27%] in HBeAg-positive subjects).

Several clinical studies have evaluated alternative regimens in subjects who failed EPIVIR-HBV due to development of lamivudine resistance. These studies demonstrated a higher rate of viral suppression and decreased development of viral resistance compared with continuation of monotherapy with EPIVIR-HBV.

Pediatric Subjects: In a controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving EPIVIR-HBV for 52 weeks. For a subgroup that remained on therapy with EPIVIR-HBV in a follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with EPIVIR-HBV.

Cross-Resistance

HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (greater than 30-fold) and telbivudine (greater than 100-fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (rtI169T and rtM250V, rtT184G and rtS202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice), and 113 and 187 times (male and female rats, respectively) those observed in humans at the recommended therapeutic dose for chronic hepatitis B.

Mutagenesis

Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Impairment of Fertility

Lamivudine did not affect male or female fertility in rats at oral doses up to 4,000 mg per kg per day, associated with concentrations approximately 70 times (male) or 104 times (females) higher than the concentrations (Cmax ) in humans at the dose of 100 mg [see Use in Specific Populations (8.1)].

14 CLINICAL STUDIES

14.1 Adult Subjects

The safety and efficacy of EPIVIR-HBV 100 mg once daily versus placebo were evaluated in 3 controlled trials in subjects with compensated chronic hepatitis B virus infection. All subjects were aged 16 years or older and had chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of HBV replication (serum HBeAg-positive and positive for serum HBV DNA) and persistently elevated ALT levels and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The results of these trials are summarized below.

Trial 1 was a randomized, double-blind trial of EPIVIR-HBV 100 mg once daily versus placebo for 52 weeks followed by a 16-week no-treatment period in 141 treatment-naive U.S. subjects.
Trial 2 was a randomized, double-blind, 3-arm trial that compared EPIVIR-HBV 25 mg once daily versus EPIVIR-HBV 100 mg once daily versus placebo for 52 weeks in 358 Asian subjects.
Trial 3 was a randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis B despite previous treatment with interferon alfa. The trial compared EPIVIR-HBV 100 mg once daily for 52 weeks, followed by either EPIVIR-HBV 100 mg or matching placebo once daily for 16 weeks (Arm 1), versus placebo once daily for 68 weeks (Arm 2).

Principal endpoint comparisons for the histologic and serologic outcomes in subjects receiving EPIVIR-HBV (100 mg daily) or placebo in these trials are shown in the following tables.

Table 7. Histologic Response at Week 52 among Adult Subjects Receiving EPIVIR-HBV 100 mg Once Daily or Placebo
a Improvement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded.

Assessment

Trial 1

Trial 2

Trial 3

EPIVIR

HBV

(n = 62)

Placebo

(n = 63)

EPIVIRHBV

(n = 131)

Placebo

(n = 68)

EPIVIRHBV

(n = 110)

Placebo

(n = 54)

Improvementa

55%

25%

56%

26%

56%

26%

No Improvement

27%

59%

36%

62%

25%

54%

Missing Data

18%

16%

8%

12%

19%

20%

Table 8. HBeAg Seroconvertersa at Week 52 among Adult Subjects Receiving EPIVIR-HBV 100 mg Once Daily or Placebo
a Three-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis.

Seroconversion

Trial 1

Trial 2

Trial 3

EPIVIR

HBV

(n = 63)

Placebo

(n = 69)

EPIVIR

HBV

(n = 140)

Placebo

(n = 70)

EPIVIR

HBV

(n = 108)

Placebo

(n = 53)

Seroconverters

17%

6%

16%

4%

15%

13%

Normalization of serum ALT levels was more frequent with treatment of EPIVIR-HBV compared with placebo in Trials 1, 2, and 3.

The majority of subjects treated with EPIVIR-HBV showed a decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assay-detectable HBV DNA during treatment with EPIVIR-HBV was observed in approximately one-third of subjects after this initial response.

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