SYNOPSIS. Clinical Study Report AI Addendum #1. Open-label Dosing Phase

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1 Name of Sponsor/Company: Bristol-Myers Squibb Name of Finished Product: Individual Study Table Referring to the Dossier (For National Authority Use Only) Name of Active Ingredient: Entecavir SYNOPSIS Clinical Study Report Addendum #1 Open-label Dosing Phase TITLE OF STUDY: A Phase II Double-Blind, Randomized, Placebo-controlled Study in China of the Safety and Efficacy of Entecavir in Patients Who Have Failed Lamivudine Treatment INVESTIGATORS: 5 STUDY CENTERS: 5 study sites in China. PUBLICATIONS: None STUDY PERIOD: First subject first dose in open-label dosing phase: 03-Jul-2003 Last subject last dose in open-label dosing phase: 28-Jun-2004 The study is ongoing at the time of this report. CLINICAL PHASE: II INTRODUCTION: Study was a randomized (4:1), double-blind, placebo-controlled study conducted in China comparing the safety and efficacy of entecavir (ETV) 1.0 mg once daily (QD) with placebo administered for 12 weeks to subjects with chronic hepatitis B virus (HBV) infection who had previously failed to respond to lamivudine (LVD). Subjects were initially randomized (4:1) to receive ETV 1.0 mg QD versus placebo for 12 weeks in the double-blind dosing phase of the study. After completing 12 weeks of double-blind dosing, subjects received ETV 1.0 mg QD for up to 36 weeks in the open-label dosing phase of the study. All subjects who completed the 36-week open-label dosing phase were given the opportunity to continue open-label ETV by enrolling in ETV rollover study AI Subjects who prematurely discontinued study treatment and subjects who completed the open-label dosing phase but did not enroll in study AI were to be followed for 24 weeks post dosing. The results for the 12-week double-blind dosing phase were reported in a clinical study report completed in August This addendum presents safety and efficacy results through the completion of 36 weeks of open-label dosing. Results for the 24-week post-dosing follow-up will be presented after the last subject has completed the study. OBJECTIVES: To determine the long-term safety and efficacy of ETV 1.0 mg administered QD in patients who have previously failed LVD.

2 METHODOLOGY: Open-label Dosing Phase - Subjects were evaluated for safety every 4 weeks while on open-label ETV. HBV DNA levels by Roche Amplicor polymerase chain reaction (PCR) assay were evaluated at study Weeks 24, 36 and 48. HBV DNA levels by Quantiplex (bdna) assay and HBV serologies were evaluated at study Week 48. All subjects who completed the 36-week open-label dosing phase were given the opportunity to continue open-label ETV treatment by enrolling in ETV rollover study AI NUMBER OF SUBJECTS: Started open-label dosing phase, 145; Completed open-label dosing phase, 141. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Subjects who completed the 12-week double-blind dosing phase were eligible to receive open-label ETV 1.0 mg once daily for up to 36 weeks (study Week 48) in the open-label dosing phase of the study. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: ETV 1.0 mg administered orally, as 2 x 0.5 mg tablets, once daily. The batch numbers for ETV 0.5 mg tablets were 8MDE145 and 8MFE193. DURATION OF TREATMENT: The study design called for up to 36 weeks in the open-label dosing phase. The mean time on open-label ETV therapy was 40.1 weeks. The mean time on open-label therapy was longer than 36 weeks because subjects were permitted to continue open-label ETV dosing in the present study until rollover study AI was available. REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Not applicable as no comparator was used during the open-label phase. CRITERIA FOR EVALUATION: Efficacy: The following efficacy endpoints were evaluated: the proportion of subjects with HBV DNA levels by PCR assay < 400 copies/ml at study Week 48; the proportion of subjects with HBV DNA levels by bdna assay < 0.7 megagenome equivalents per milliliter (MEq/mL) at study Week 48; the proportion of subjects with normalization of alanine aminotransferase (ALT) at study Week 48 (among subjects with ALT 1.25 x upper limit of normal [ULN] at baseline); the mean change in HBV DNA level at study Week 48 compared to baseline as measured by PCR assay; the proportion of subjects who achieved Hepatitis B e antigen (HBeAg) seroconversion at study Week 48 (among subjects HBeAg-positive at baseline). Safety: The proportion of subjects who had adverse events, laboratory abnormalities, or discontinued study medication due to adverse events. STATISTICAL METHODS: Efficacy parameters were presented by initial treatment group (ETV 1.0 mg or placebo) as assigned during the double-blind phase of the study. Adverse events were summarized by initial treatment group and for the total population. Time on therapy was defined as the number of days between the start date and end date of open-label therapy. The start date of open-label ETV therapy was the date the first dose of open-label study drug was taken and the end date was the date the last dose of open-label study drug was taken. Categorical variables were summarized by counts and percentages. For the analyses of binary outcomes, missing data were handled by two methods: Non-Completer = Failure (NC = F; Modified Intent-to-Treat)

3 and Non-Completer = Missing (NC = M). Continuous variables were summarized by the mean, median, standard deviation, standard error, minimum, and maximum. The mean change in HBV DNA level from baseline at study Week 48 was determined for evaluable subjects (ie, subjects with measurements at baseline and at study Week 48). ETV baseline was the last value up to the start of ETV treatment. For subjects initially treated with ETV in the double-blind phase of the study, ETV baseline was the last value up to the start of double-blind dosing. For subjects initially receiving placebo in the double-blind phase of the study, ETV baseline was the last value up to the start of open-label ETV dosing. RESULTS: Study Population and Baseline Characteristics Of 147 subjects randomized in the study, 145 started open-label ETV treatment and 141 (96%) completed open-label treatment. Table 1 presents subject disposition from the start to the end of open-label treatment. Table 1: Subject Disposition (Start of Open-Label Treatment to End of Open-Label Treatment) - Randomized Subjects STATUS ETV 1.0 mg N = 118 Number (%) of Subjects Placebo N = 29 Total N = 147 Started open-label ETV 116 ( 98) 29 (100) 145 ( 99) Discontinued from open-label phase 3 ( 3) 1 ( 3) 4 ( 3) Death 0 1 ( 3) 1 ( <1) Other - lost to follow-up 1 ( <1) 0 1 ( <1) Protocol Specific Lab Abnormality 1 ( <1) 0 1 ( <1) Subject Withdrew 1 ( <1) 0 1 ( <1) Completed open-label treatment 113 ( 96) 28 ( 97) 141 ( 96) Enrolled in Study AI ( 93) 28 ( 97) 138 ( 94) Started 24-week post-dosing follow-up 4 ( 3) 0 4 ( 3) Entecavir Baseline HBV Disease Characteristics All subjects were positive for hepatitis B surface antigen (HBsAg) at ETV baseline. Most were HBeAg positive (89%, 129/145). The mean ETV baseline HBV DNA level by PCR assay was 8.77 log 10 copies/ml. The proportion of subjects with ALT 1.25 x ULN was 43% (62/145). Extent of Exposure: The mean time on open-label ETV therapy was 40.1 weeks. The mean time on open-label therapy was longer than 36 weeks because subjects were permitted to continue open-label ETV dosing in the present study until rollover study AI was available. The average daily dose of ETV was 1.0 mg.

4 Efficacy: Table 2 presents the key efficacy endpoints at study Week 48. Table 2: Summary of Efficacy At Week 48 (NC = F) Responder / Evaluable (%) Endpoint ETV 1.0 mg Placebo HBV DNA < 400 copies/ml by PCR assay 33/116 (28) 13/29 (45) HBV DNA < 0.7 MEq/mL by bdna assay a 85/115 (74) 22/29 (76) Normalization of ALT b 41/45 (91) 16/17 (94) HBeAg seroconversion c 6/106 (6) 2/23 (9) a Treated subjects with HBV DNA levels by bdna assay 0.7 MEq/mL at ETV baseline b Treated subjects with ALT 1.25 x ULN at ETV baseline. c Treated subjects who were HBeAg positive at ETV baseline. Twenty-eight percent (33/116) of subjects randomized to ETV as the initial treatment regimen in the double-blind dosing phase had achieved HBV DNA levels < 400 copies/ml by PCR at study Week 48 (after 48 weeks of ETV treatment). Forty-five percent (13/29) of subjects initially randomized to placebo had HBV DNA levels < 400 copies/ml by PCR at study Week 48 (after 36 weeks of ETV treatment). Seventy-four percent (85/115) of subjects initially randomized to ETV in the double-blind dosing phase had achieved HBV DNA levels < 0.7 MEq/mL at study Week 48. Seventy-six percent (22/29) of subjects initially randomized to placebo in the double-blind dosing phase had achieved HBV DNA levels < 0.7 MEq/mL at study Week 48 (after 36 weeks of ETV treatment). Among subjects with abnormal ALT at ETV baseline, 91% (41/45) of subjects initially assigned to ETV in the double-blind dosing phase had ALT normalization (ALT < 1.25 x ULN) at study Week 48 (after 48 weeks of ETV treatment) and 94% (16/17) of subjects initially assigned to placebo in the double-blind dosing phase had ALT normalization at study Week 48 (after 36 weeks of ETV treatment). HBeAg seroconversion was achieved in a total of 8 subjects treated with ETV. Table 3: HBV DNA Change from ETV Baseline at Study Week 48 - Evaluable Subjects Change in HBV DNA from ETV Baseline by PCR assay (log 10 copies/ml) at Week 48 ETV 1.0 mg N = 116 Placebo N = 29 Mean (SE) (0.13) (0.25)

5 For subjects initially treated with ETV in the 12-week double-blind phase of the study, the mean change from baseline in HBV DNA by PCR assay (log10 copies/ml) was log 10 copies/ml at study Week 48 (Table 3). Safety: Table 4 presents a summary of adverse events (regardless of severity or relationship to study drug), Grade 3-4 adverse events, deaths, serious adverse events (SAEs), and discontinuations due to adverse event reported in the open-label dosing phase. Adverse events were reported for 54% of subjects during open-label dosing. The most common adverse event was upper respiratory tract infection, which occurred in 17 subjects (12%). There was 1 death (subject ) on open-label ETV treatment. The subject had experienced the serious adverse events of increased ALT, increased aspartate aminotransferase (AST) and increased blood bilirubin on blinded study drug (placebo) and had prematurely discontinued blinded study drug due to these events. An exception to the protocol was granted to permit the subject to begin open-label dosing. The subject developed hepatic failure and hepatorenal syndrome and died due to liver failure. Serious adverse events were reported for 2 subjects (subject , hepatic failure and hepatorenal syndrome; subject , increased ALT and increased AST) on open-label ETV. No subjects discontinued study drug during open-label dosing because of adverse events. Table 4: Summary of Safety - On Open-label ETV Number (%) of Subjects Total Parameter (N = 145) Any adverse event 79 (54) Most common adverse events a Upper respiratory tract infection 17 (12) Nasopharyngitis 11 ( 8) Fatigue 10 ( 7) Hepatic pain 10 ( 7) Any Grade 3-4 adverse event 4 ( 3) Death 1 (<1) Serious adverse events 2 ( 1) Discontinuation of study therapy due to adverse events 0 a Occurring in 5% of subjects Special Safety Considerations No malignant neoplasms or pre-malignant lesions were reported on ETV treatment. ALT flares (ALT > 2 x baseline and > 10 x ULN) were observed in two subjects (2%) on ETV treatment. Both cases occurred during the 12-week double-blind phase of the study and were self-limiting and not associated with hepatic decompensation. At study Week 48, both subjects had achieved HBV DNA levels by PCR assay < 300 copies/ml.

6 CONCLUSIONS: Treatment with ETV 1.0 mg once daily for up to 48 weeks was highly effective in reducing HBV DNA levels in patients who had previously failed LVD therapy. Normalization of ALT levels was observed in more than 90% of patients with abnormal ALT at baseline. HBeAg seroconversion was observed infrequently through 48 weeks of ETV treatment. The benefit of longer durations of therapy in achieving this endpoint will be evaluated in rollover study AI ETV 1.0 mg administered once daily for up to 48 weeks was safe and well tolerated. DATE OF REPORT: 16-Dec-2004