Entecavir (Page 5 of 7)

14 CLINICAL STUDIES

The safety and efficacy of Entecavir were evaluated in three Phase 3 active-controlled trials [see Clinical Studies (14.1, 14.2)]. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Subjects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of Entecavir were also evaluated in a study of 191 HBV-infected subjects with decompensated liver disease and in a study of 68 subjects co-infected with HBV and HIV [see Clinical Studies (14.1)].

14.1 Outcomes in Adults

At 48 Weeks

The safety and efficacy of Entecavir in adults were evaluated in three Phase 3 active-controlled trials. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Subjects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of entecavir were also evaluated in a study of 191 HBV-infected subjects with decompensated liver disease and in a study of 68 subjects co-infected with HBV and HIV.

Nucleoside-inhibitor-naïve Subjects with Compensated Liver Disease

HBeAg-positive: Study AI463022 was a multinational, randomized, double-blind study of Entecavir 0.5mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715 randomized) nucleoside-inhibitor-naïve subjects with chronic hepatitis B virus infection, compensated liver disease, and detectable HBeAg. The mean age of subjects was 35 years, 75% were male, 57% were Asian, 40% were Caucasian and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.66 log copies/mL, and mean serum ALT level was 143 U/L. Paired, adequate liver biopsy samples were available for 89% of subjects.

HBeAg-negative (anti-HBe-positive/HBV DNA-positive): Study AI463027 was a multinational, randomized, double-blind study of entecavir 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648 randomized) nucleoside-inhibitor-naïve subjects with HBeAg-negative (HBeAb-positive) chronic hepatitis B virus infection and compensated liver disease. The mean age of subjects was 44 years, 76% were male, 39% were Asian, 58% were Caucasian and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log copies/mL, and mean serum ALT level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of subjects.

In Studies AI463022 and AI463027, entecavir was superior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as a 2-point or greater reduction in Knodell Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. Histologic Improvement and change in Ishak Fibrosis Score are shown in Table 8.

Table 8: His tologic Improvement and Change in Is hak Fibros is Score at Week 48, Nucleos ide- Inhibitor-Naïve Subjects in Studies AI463022 and AI463027
Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative)
Entecavir 0.5 mg N=314 a Lamivudine 100 mg N=314 a Entecavir 0.5 mg N=296 a Lamivudine 100 mg N=287 a
Histologic Improvement (Knodell Scores) Improvementb No improvement 72%21% 62%24% 70%19% 61%26%
Ishak Fibrosis Score Improvementc No ChangeWorsening 39%46%8% 35%40%10% 36%41%12% 38%34%15%
Missing Week 48 biopsy 7% 14% 10% 13%

a Subjects with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2).

b ≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.

c For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥1-point increase from baseline

Selected virologic, biochemical and serologic outcome measures are shown in Table 9.

Table 9: Selected Virologic, Biochemical and Serologic Endpoints at Week 48, Nucleos ide- Inhibitor-Naïve Subjects in Studies AI463022 and AI463027
Study AI463022 (HBeAG-Positive) Study AI463027 (HBeAg-Negative)
Entecavir 0.5 mg N=354 Lamivudine 100 mg N=355 Entecavir 0.5 mg N=325 Lamivudine 100 mg N=313
HBV DNAa Proportion undetectable (<300 Copies/mL)Mean change from baseline(log10 copies/mL)ALT normalization (<1 x ULN)HBeAg seroconversion 67%-6.8668%21% 36%-5.3960%18% 90%-5.0478%NA 72%-4.5371%NA

a Roche COBAS Amplicor PCR assay [lower limit of quantification (LLOQ) = 300 copies/mL]

Histologic Improvement was independent of baseline levels of HBV DNA or ALT.

Lamivudine-r efractory Subjects with Compensated Liver Diseas e

Study AI463026 was a multinational, randomized, double-blind study of Entecavir in 286 (of 293 randomized) subjects with lamivudine-refractory chronic hepatitis B virus infection and compensated liver disease. Subjects receiving lamivudine at study entry either switched to Entecavir 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of 52 weeks. The mean age of subjects was 39 years, 76% were male, 37% were Asian, 62% were Caucasian and 52% had previously received interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance substitutions at baseline by an investigational line probe assay. At baseline, subjects had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of subjects.

Entecavir was superior to lamivudine on a primary endpoint of Histologic Improvement (using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in Table 10.

Table 10: His tologic Improvement and Change in Is hak Fibrosis Score at Week 48, Lamivudine-Refractory Subjects in Study AI463026
Entecavir 1 mg N=124 a Lamivudine 100 mg N=116 a
Histologic Improvement (Knodell Scores) Improvementb No Improvement 55%34% 28%57%
Ishak Fibrosis Score Improvementc No changeWorseningc Missing Week 48 biopsy 34%44%11%11% 16%42%26%16%

a Subjects with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥2).

b ≥2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.

c For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥1-point increase from baseline.

Table 11 shows selected virologic, biochemical and serologic endpoints.

Table 11: Selected Virologic, Biochemical and Serologic Endpoints at Week 48, Lamivudine-Refractory Subjects in StudyAI463026
Entecavir 1 mg N=141 Lamivudine 100 mg N=145
HBV DNAa ProportionUndetectable (<300 copies/mL)Mean change from baseline (log10 copies/mL)ALT normalization (<1 x ULN)HBeAg seroconversion 19%-5.1161%8% 1%-0.4815%3%

a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

Histologic Improvement was independent of baseline levels of HBV DNA or ALT.

Subjects with Decompensated Liver Disease

Study AI463048 was a randomized, open-label study of entecavir 1 mg once daily versus adefovir dipivoxil 10 mg once daily in 191 (of 195 randomized) adult subjects with HBeAg-positive or –negative chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Subjects were either HBV-treatment-naïve or previously treated, predominantly with lamivudine or interferon-α.

In Study AI463048, 100 subjects were randomized to treatment with entecavir and 91 subjects to treatment with adefovir dipivoxil. Two subjects randomized to treatment with adefovir dipivoxil actually received treatment with entecavir for the duration of the study. The mean age of subjects was 52 years, 74% were male, 54% were Asian, 33% were Caucasian and 5% were Black/African American. At baseline, subjects had a mean serum HBV DNA by PCR of 7.83 log copies/mL and mean ALT level of 100 U/L; 54% of subjects were HBeAg-positive; 35% had genotypic evidence of lamivudine resistance. The baseline mean CTP score was 8.6. Results for selected study endpoints at Week 48 are shown in Table 10.

Table 12: Selected Endpoints at Week 48, Subjects with Decompensated Liver Disease, Study AI463048
Entecavir 1 mg N=100 a Adefovir Dipivoxil 10 mg N=91 a
HBV DNAb Proportion undetectable (<300 copies/mL)Stable or improved CTP scorec HBsAg lossNormalization of ALT (<1 x ULN)d 57%61%5%49/78 (63%) 20%67%033/71 (46%)

a Endpoints were analyzed using intention-to-treat (ITT) method, treated subjects as randomized.

b Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

c Defined as decrease or no change from baseline in CTP score.

d Denominator is subjects with abnormal values at baseline.

Subjects Co-infected with HIV and HBV

Study AI463038 was a randomized, double-blind, placebo-controlled study of entecavir versus placebo in 68 subjects co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Subjects continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either entecavir 1 mg once daily (51 subjects) or placebo (17 subjects) for 24 weeks followed by an open-label phase for an additional 24 weeks where all subjects received entecavir. At baseline, subjects had a mean serum HBV DNA level by PCR of 9.13 log copies/mL. Ninety-nine percent of subjects were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at Week 24 are shown in Table 13. There are no data in patients with HIV/HBV co-infection who have not received prior lamivudine therapy. Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment [see Warnings and Precautions (5.2)].

Table 13: Virologic and Biochemical Endpoints at Week 24, Study AI463038
Entecavir 1 mg a N=51 Placebo a N=17
HBV DNAb Proportion undetectable (<300 copies/mL) Mean change from the baseline (log10 copies/mL)ALT normalization (<1 x ULN) 6%-3.6534%c 0+0.118%c

a All subjects also received a lamivudine-containing HAART regimen.

b Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

c Percentage of subjects with abnormal ALT (>1 x ULN) at baseline who achieved ALT normalization (n=35 for entecavir and n=12 for placebo).

For subjects originally assigned to entecavir, at the end of the open-label phase (Week 48), 8% of subjects had HBV DNA <300 copies/mL by PCR, the mean change from baseline HBV DNA by PCR was −4.20 log copies/mL, and 37% of subjects with abnormal ALT at baseline had ALT normalization (≤1 x ULN).

Beyond 48 Weeks

The optimal duration of therapy with entecavir is unknown. According to protocol-mandated criteria in

the Phase 3 clinical trials, subjects discontinued entecavir or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression (<0.7 MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive subjects) or ALT <1.25 x ULN (in HBeAg-negative subjects) at Week 48. Subjects who achieved virologic suppression but did not have serologic response (HBeAg-positive) or did not achieve ALT <1.25 x ULN (HBeAg-negative) continued blinded dosing through 96 weeks or until the response criteria were met. These protocol-specified subject management guidelines are not intended as guidance for clinical practice.

Nucleoside-inhibitor-naïve Subjects

Among nucleoside-inhibitor-naïve, HBeAg-positive subjects (Study AI463022), 243 (69%) entecavir-treated subjects and 164 (46%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. Of those continuing blinded treatment in Year 2, 180 (74%) Entecavir subjects and 60 (37%) lamivudine subjects achieved HBV DNA <300 copies/mL by PCR at the end of dosing (up to 96 weeks). 193 (79%) Entecavir subjects achieved ALT ≤1 x ULN compared to 112 (68%) lamivudine subjects, and HBeAg seroconversion occurred in 26 (11%) Entecavir subjects and 20 (12%) lamivudine subjects.

Among nucleoside-inhibitor-naïve, HBeAg-positive subjects, 74 (21%) entecavir subjects and 67 (19%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. Among Entecavir responders, 26 (35%) subjects had HBV DNA <300 copies/mL, 55 (74%) subjects had ALT ≤1 x ULN, and 56 (76%) subjects sustained HBeAg seroconversion at the end of follow-up. Among lamivudine responders, 20 (30%) subjects had HBV DNA <300 copies/mL, 41 (61%) subjects had ALT ≤1 x ULN, and 47 (70%) subjects sustained HBeAg seroconversion at the end of follow-up.

Among nucleoside-inhibitor-naïve, HBeAg-negative subjects (Study AI463027), 26 (8%) entecavir-treated subjects and 28 (9%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. In this small cohort continuing treatment in Year 2, 22 Entecavir and 16 lamivudine subjects had HBV DNA <300 copies/mL by PCR, and 7 and 6 subjects, respectively, had ALT ≤1 x ULN at the end of dosing (up to 96 weeks).

Among nucleoside-inhibitor-naïve, HBeAg-negative subjects, 275 (85%) Entecavir subjects and 245 (78%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. In this cohort, very few subjects in each treatment arm had HBV DNA <300 copies/mL by PCR at the end of follow-up. At the end of follow-up, 126 (46%) entecavir subjects and 84 (34%) lamivudine subjects had ALT ≤1 x ULN.

Lamivudine-refractory Subjects

Among lamivudine-refractory subjects (Study AI463026), 77 (55%) entecavir-treated subjects and 3 (2%) lamivudine subjects continued blinded treatment for up to 96 weeks. In this cohort of entecavir subjects, 31 (40%) subjects achieved HBV DNA <300 copies/mL, 62 (81%) subjects had ALT ≤1 x ULN, and 8 (10%) subjects demonstrated HBeAg seroconversion at the end of dosing.

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