Dose Ranging Study of Pegylated Interferon Lambda in Patients With Hepatitis B and Positive for the Hepatitis B e Antigen (LIRA-B)

• Part A: Proportion of subjects who achieve Hepatitis B e antigen (HBeAg) seroconversion [ Time Frame: 24 weeks post-dosing (Week 72) ] [ Designated as safety issue: No ]
• Part A: Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
• Part A: Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events [ Time Frame: 24 weeks post-dosing (Week 72) ] [ Designated as safety issue: Yes ]
• Part B: Safety and tolerability of Lambda/ETV regimen as measured by the frequency of SAEs and discontinuations due to AEs [ Time Frame: Up to 84 Weeks ] [ Designated as safety issue: Yes ]

• Proportion of subjects who achieve HBeAg seroconversion [ Time Frame: 24 weeks post-dosing (Week 72) ] [ Designated as safety issue: No ]
• Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
• Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events [ Time Frame: 24 weeks post-dosing (Week 72) ] [ Designated as safety issue: Yes ]

• Part A: Proportion of subjects who achieve an hepatitis B virus Deoxyribonucleic acid levels (HBV DNA) < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - High Pure System (HPS) assay [ Time Frame: Weeks 24, 48, 72, 96, 120, 144, 168 and 192 ] [ Designated as safety issue: No ]
• Part A: Mean change from baseline in log10 HBV DNA levels over time (Proportion of subjects with Alanine amino transferase (ALT) normalization (≤ 1 x upper limit of normal (ULN)) [ Time Frame: Baseline (Day 1), Weeks 24, 48, 72, 96, 120, 144, 168 and 192 ] [ Designated as safety issue: No ]
• Part A: Proportion of subjects with ALT normalization (≤ 1 x ULN) [ Time Frame: Weeks 24, 48, 72, 96, 120, 144, 168 and 192 ] [ Designated as safety issue: No ]
• Part A: Hepatitis E antigen (HBeAg) loss [ Time Frame: Weeks 24, 48, 72, 96, 120, 144, 168 and 192 ] [ Designated as safety issue: No ]
• Part A: HBeAg seroconversion [ Time Frame: Weeks 24, 48, 96, 120, 144, 168 and 192 ] [ Designated as safety issue: No ]
• Part A: Mean change from baseline in log10 quantitative HBeAg levels over time [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96, 120, 144, 168 and 192 ] [ Designated as safety issue: No ]
• Part A: Number and percent of subjects with adverse events (AEs) or laboratory abnormalities [ Time Frame: Up to Week 24 ] [ Designated as safety issue: Yes ]
• Part A: Number and percent of subjects with adverse events (AEs) or laboratory abnormalities [ Time Frame: Up to Week 72 ] [ Designated as safety issue: Yes ]
• Part A: Pharmacokinetic (PK) parameter Maximum observed concentration (Cmax) of Pegylated interferon lambda (pegIFNλ) will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]
• Part A: Pharmacokinetic (PK) parameter Time of maximum observed concentration (Tmax) of Pegylated interferon lambda (pegIFNλ) will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]
• Part A: Pharmacokinetic (PK) parameter Trough serum concentration pre-dose (C0) of Pegylated interferon lambda (pegIFNλ) will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]
• Part A: PK parameter serum concentration 168 hours post observed dose [Cmin] (C0 will be used as an estimate of Cmin if sample is not collected) of pegIFNλ will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]
• Part A: PK parameter Area under the concentration-time curve in 1 dosing interval from time 0 to 168 hours post observed dose [AUC(TAU)] of pegIFNλ will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]
• Part A: PK parameter Accumulation index (AI) ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose (only conducted if data warrant) of pegIFNλ will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]
• Part B: HBeAg seroconversion rate at 24 weeks off treatment [ Time Frame: Week 84 ] [ Designated as safety issue: No ]
• Part B: Antiviral activity of Lambda/ETV regimen, as determined by the proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - HPS assay [ Time Frame: Weeks 4, 8, 12, 24, 36, 60, and 84 ] [ Designated as safety issue: No ]
• Part B: Mean change from baseline in HBV DNA over time in subjects treated with Lambda/ETV [ Time Frame: Weeks 4, 8, 12, 24, 36, 60, and 84 ] [ Designated as safety issue: No ]
• Part B: HBeAg loss and seroconversion in subjects treated with Lambda/ETV regimen [ Time Frame: Weeks 12, 24, 36, 60 and 84 ] [ Designated as safety issue: No ]
• Part B: HBeAg levels over time in subjects treated with Lambda/ETV regimen [ Time Frame: Weeks 4, 8, 12, 24, 36, 60, and 84 ] [ Designated as safety issue: No ]
• Part B: biochemical response rates in subjects treated with Lambda/ETV regimen [ Time Frame: Weeks 4, 8, 12, 24, 36, 60, and 84 ] [ Designated as safety issue: No ]
• Part B: Pharmacokinetic (PK) parameter Maximum observed concentration (Cmax) of Lambda/ETV regimen will be derived from serum concentration versus time data [ Time Frame: Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 ] [ Designated as safety issue: No ]
• Part B: Pharmacokinetic (PK) parameter Time of maximum observed concentration (Tmax) of Lambda/ETV regimen will be derived from serum concentration versus time data [ Time Frame: Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 ] [ Designated as safety issue: No ]
• Part B: Pharmacokinetic (PK) parameter Trough serum concentration pre-dose (C0) of Lambda/ETV regimen will be derived from serum concentration versus time data [ Time Frame: Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 ] [ Designated as safety issue: No ]
• Part B: PK parameter Area under the concentration-time curve in 1 dosing interval from time 0 to 168 hours post observed dose [AUC(TAU)] of Lambda/ETV regimen will be derived from serum concentration versus time data [ Time Frame: Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 ] [ Designated as safety issue: No ]
• Part B: PK parameter serum concentration 168 hours post observed dose [Cmin] (C0 will be used as an estimate of Cmin if sample is not collected) of Lambda/ETV regimen will be derived from serum concentration versus time data [ Time Frame: Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 ] [ Designated as safety issue: No ]
• Part B: PK parameter Accumulation index (AI) ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose (only conducted if data warrant) of Lambda/ETV regimen will be derived from serum concentration versus time data [ Time Frame: Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 ] [ Designated as safety issue: No ]
• Part B: Rate of resistance to ETV during treatment with the Lambda/ETV regimen [ Time Frame: Up to Week 84 ] [ Designated as safety issue: No ]

• Proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - HPS assay [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
• Proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - HPS assay [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
• Proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - HPS assay [ Time Frame: Week 72 ] [ Designated as safety issue: No ]
• Proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) at Weeks 48 using the Roche COBAS® TaqMan - HPS assay [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
• Mean change from baseline in log10 HBV DNA levels over time (Proportion of subjects with ALT normalization (≤ 1 x ULN) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
• Mean change from baseline in log10 HBV DNA levels over time (Proportion of subjects with ALT normalization (≤ 1 x ULN) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
• Mean change from baseline in log10 HBV DNA levels over time (Proportion of subjects with ALT normalization (≤ 1 x ULN) [ Time Frame: Week 72 ] [ Designated as safety issue: No ]
• HBeAg loss [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
• HBeAg loss [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
• HBeAg loss [ Time Frame: Week 72 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
• Mean change from baseline in log10 quantitative HBeAg levels [ Time Frame: Duration of trial (Week 24) ] [ Designated as safety issue: No ]
• Mean change from baseline in log10 quantitative HBeAg levels [ Time Frame: Duration of trial (Week 72) ] [ Designated as safety issue: No ]
• Number and percent of subjects with adverse events (AEs) or laboratory abnormalities [ Time Frame: Duration of trial (Week 24) ] [ Designated as safety issue: Yes ]
• Number and percent of subjects with adverse events (AEs) or laboratory abnormalities [ Time Frame: Duration of trial (Week 72) and upon occurrence ] [ Designated as safety issue: Yes ]
• Pharmacokinetic parameters of pegIFNλ will be derived from serum concentration versus time data [ Time Frame: Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 ] [ Designated as safety issue: No ]

At least 1 dose of pegIFNλ will be identified which is safe, well tolerated, and efficacious for the treatment of chronic hepatitis B virus infection (CHB)

Amendment 7, Part B Sub Study: The primary purpose of this amendment is to obtain preliminary data on the safety of pegylated interferon Lambda (Lambda) when administered in combination with Entecavir(ETV) to patients with hepatitis E antigen-positive (HBeAg-positive) chronic hepatitis B(CHB) infection employing a sequential therapy approach

Part B sub study is Open Label

• Drug: pegIFN
  Syringe, Subcutaneous, 180 μg, Once Weekly, 48 weeks
• Drug: pegIFNα-2a
  Syringe, Subcutaneous 180 μg, Once Weekly, 48 Weeks
  Other Name: Pegasys
• Drug: PegIFN lambda
  Syringe, Subcutaneous, 180 µg, Once weekly, 48 weeks
  Other Name: BMS-914143
• Drug: Entecavir
  Tablet, Oral, 0.5 mg, Once daily, 12 weeks initial monotherapy followed by 48 weeks of combination therapy with PegIFN lambda
  Other Name: Baraclude

• Experimental: Part A Arm 1: pegIFN (180 μg)
  Intervention: Drug: pegIFN
• Active Comparator: Part A Arm 2: pegIFNα-2a
  Intervention: Drug: pegIFNα-2a
• Experimental: Part B: pegIFN lambda + Entecavir
  Interventions:

  • Drug: PegIFN lambda
  • Drug: Entecavir

Inclusion Criteria:

• Infection with the hepatitis B virus (HBV) and positive for the hepatitis B e antigen
• Between the ages of 18 and 70
• Have not been previously treated with an interferon
• HBV nucleos(t)ide-naive

Exclusion Criteria:

• Not infected with the hepatitis C virus (HCV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV)
• Do not have a serious liver, psychiatric, blood, thyroid, lung, heart or eye disease
• Able to tolerate oral medication