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BRISTOL-MYERS SQUIBB COMPANY

Peginterferon Lambda-1a

Final Clinical Study Report for Study AI452008

A Phase 2B, randomized study to evaluate the safety and efficacy of Pegylated

Interferon Lambda (BMS-914143) administered with Ribavirin plus a single

direct antiviral agent (BMS-790052 or BMS-650032) versus Pegasys

administered with Ribavirin (Part A) and of Pegylated Interferon Lambda

(BMS-914143) administered with or without Ribavirin plus 2 direct antiviral

agents (BMS-790052 and BMS-650032) (Part B) in chronic hepatitis C

genotype-1 treatment naïve subjects

Indication: Chronic Hepatitis B Virus Infection

Phase: 2

Study Initiation Date: 31-Mar-2011

Last Subject Last Visit for this Clinical Study Report:

08-Jan-2013

Report Date: 13-Jan-2014

Document Control Number: 930075980

Previous Version(s) of this Report:

None

THIS STUDY WAS CONDUCTED IN ACCORDANCE WITH GOOD CLINICAL PRACTICE

Sponsor’s Responsible Medical Officer:

This document is a confidential communication of Bristol-Myers Squibb Company. Acceptance of this document constitutes an agreement by the recipient that no unpublished information contained herein will be published or disclosed without Bristol-Myers Squibb Company's prior written approval.

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Peginterferon Lambda-1a AI452008BMS-914143 Final Clinical Study Report

Name of Sponsor/Company: Individual Study Table Referring to the Dossier

(For National Authority Use Only)

Bristol-Myers Squibb

Name of Finished Product:

Name of Active Ingredient:

Peginterferon Lambda-1a

(BMS-914143)

SYNOPSIS

Final Clinical Study Report for Study AI452008

TITLE OF STUDY: A Phase 2B, randomized study to evaluate the safety and efficacy of Pegylated Interferon Lambda (BMS-914143) administered with Ribavirin plus a single direct antiviral agent (BMS-790052 or BMS-650032) versus Pegasys administered with Ribavirin (Part A) and of Pegylated Interferon Lambda (BMS-914143) administered with or without Ribavirin plus 2 direct antiviral agents (BMS-790052 and BMS-650032) (Part B) in chronic hepatitis C genotype-1 treatment naïve subjects

INVESTIGATORS/STUDY CENTERS: 141 subjects were randomized at 40 investigational sites in 9 countries

PUBLICATIONS: None

STUDY PERIOD: Study Initiation Date: 31-Mar-2011 CLINICAL PHASE: 2

Last subject last visit for this Clinical Study Report: 08-Jan-2013

INTRODUCTION:

This the clinical study report (CSR) presents results for the primary efficacy endpoint (sustained virologic response at post treatment Week 24 [SVR24]) and safety through post-treatment Week 24 in AI452008 Part A. Completeresults for pharmacokinetic (PK) endpoints, and available resistance data through Week 48 of post-treatment follow up are also presented. Results for HCV RNA status through Week 48 of post-treatment follow-up, persistence of resistant mutants, and complete immunogenicity are presented in an addendum to the CSR.

OBJECTIVES:

Primary (Part A):

To evaluate the safety and tolerability (as measured by the frequency of serious adverse events [SAEs], dose reductions and discontinuations due to AEs) of Lambda administered with ribavirin (RBV) plus either of 2 investigational direct acting antivirals (DAAs): asunaprevir (ASV) (BMS-650032, a HCV NS3/4A protease inhibitor) or daclatasvir (DCV) (BMS-790052, a HCV NS5A replication complex inhibitor).

To describe the antiviral activity as determined by the proportion of HCV genotype (GT)-1 subjects with SVR24

Secondary (Part A):

To describe the antiviral activity as determined by the proportion of HCV GT-1 subjects with protocol defined response (PDR)

To assess serum HCV RNA levels, as measured by the Roche COBAS Taqman test version 2

To describe the antiviral activity as determined by the proportion of HCV GT-1 subjects with SVR4 and SVR12

To assess the population PK of Lambda and ASV or DCV in combination regimens and the relationship between Lambda exposure and antiviral effect

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To investigate the relationship between Lambda and ASV or DCV exposure and antiviral responses

To describe DAA-resistant variants associated with virologic failure

METHODOLOGY: Part A comprised a global study and a Japan substudy. Part A was randomized, double dummy, site and subject blinded, and active controlled (Figure 1). Subjects were randomized 1:1:1 to 3 treatment groups: Lambda/RBV/ASV; Lambda/RBV/DCV; and peginterferon alfa-2a (alfa-2a)/RBV. Randomization wasstratified by IL28B rs12979860 SNP genotype and HCV GT-1 subtype (in the Japan substudy, stratification was by IL28B rs12979860 single nucleotide polymorphism [SNP] genotype only).

An objective of the study was to determine whether subjects receiving Lambda/RBV+DAA who achieved PDR(HCV RNA < lower limit of quantitation [LLOQ] at Week 4 and < LLOQ, target not detected [TND] at Week 12)could safely discontinue their treatment at Week 24. Accordingly, PDR responders discontinued all treatment at Week 24 and thereafter were followed off treatment for 48 weeks to be monitored for HCV relapse.

Subjects randomized to Lambda/RBV+DAA who did not achieve PDR continued the study regimen with the DAA component through Week 24, continued on Lambda/RBV without the DAA component for an additional 24 weeks, and thereafter were followed off-treatment for 24 weeks or 48 weeks depending on end of treatment virologic response (undetectable or detectable HCV RNA).

Subjects randomized to alfa/RBV discontinued the DAA placebo component of the study regimen at Week 24,continued on alfa/RBV up to Week 48, and thereafter were followed off treatment for 24 or 48 weeks, depending on end-of-treatment virologic response.

Figure 1: AI458008 Part A Study Design

L =Lambda; R = Ribavirin1:1:1 RandomizationN = 120

n =

40

n =

40

n =

40

Wk 4 Wk 24 Wk 72Wk 48Wk 12

Lambda + RBV +BMS-790052 +(LR/NS5A 24) Lambda/RBV

(LR 24)

PDR?

Yes

No

Lambda + RBV +BMS-650032 +(LR/NS3 24) Lambda/RBV

(LR 24)

PDR?

Yes

No

24 Weeks*

24 Weeks*

pegIFN-2a + RBV

Wk 4RNA

Wk 12RNA

Wk 24EoT

Wk 48EoT

Wk 72End of Follow-up*Detectable RNA at

EOT or later requires 48 wks of total follow-up, therefore maximum

of 96 wks on study

Part A Protocol Defined Response (PDR):Wk 4 < Lower Limit of Quantitation(LLOQ) + Wk 12 undetectable

24 Weeks*

48 Weeks

48 Weeks

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NUMBER OF SUBJECTS (Planned and Analyzed): The planned number of subjects to be randomized was 200 subjects (approximately 80 subjects in prior non-responder, maximum 120 subjects in IFN-based therapy ineligible-naive/intolerant subjects). Approximately 120 subjects were to be randomized equally to the 3 treatment groups. A total of 141 subjects (119 in the global study and 22 subjects in the Japan substudy) were randomized.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: The study population was composed of chronic HCV GT-1 treatment-naïve subjects who had HCV RNA > 100,000 IU/mL at screening, were seronegative for HIV and HBsAg, and had a liver biopsy within the previous 2 years. Subjects with compensated cirrhosis could enroll and were capped at approximately 10%.

TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT, BATCH NUMBERS: In this study, investigational products were BMS-914143 (Lambda), Pegasys (alfa-2a), BMS-790052 and matching placebo, BMS-650032 and matching placebo, and Ribasphere (RBV). Investigational product information appears in Table 1. Container numbers are listed by subject in an appendix to the CSR.

Table 1: Investigational Product Identification

Treatment FormulationMode of

Administration Potency

BMS-914143 (Lambda) Solution Subcutaneous (SC) injection

0.2 mg/mL

Peginterferon alfa-2a

(Pegasys

)

Solution SC injection 180 g/mL

Daclatasvir (BMS-790052)

Film-coated tablet Oral 30 mg

Placebo for daclatasvir Film-coated tablet Oral Not applicable

Asunaprevir (BMS-650032)

Film Coated Tablet Oral 200 mg

Placebo for asunaprevir Film Coated Tablet Oral Not applicable

Ribavirin (Ribasphere

) Tablet Oral 200 mg

CRITERIA FOR EVALUATION:

Efficacy: Primary efficacy assessment: Proportion of subjects with 24-week sustained virologic response (SVR24),

defined as HCV RNA undetectable at end of treatment (EOT) (maximum of 48 weeks) and HCV RNA undetectable

at follow-up Week 24.

Key secondary efficacy assessments included antiviral activity as determined by the proportion of subjects with PDR, serum HCV RNA levels, antiviral activity as determined by the proportion of subjects with SVR4 and SVR12.

Safety: Key safety endpoints included deaths, SAEs, AEs leading to discontinuation, Grade 3 or 4 AEs, and Grade 3 or 4 laboratory abnormalities.

Other: Resistance testing of variants associated with virologic failure; population PK of Lambda and ASV or DCV, and the relationship between Lambda exposure and antiviral effect; the relationship between Lambda and ASV or DCV exposure and antiviral responses; immunogenicity of Lambda.

STATISTICAL CONSIDERATIONS: The primary efficacy analysis for SVR24 used modified intent to treat (mITT). The numerator was based on subjects meeting the response criteria. The denominator was based on all treated subjects. The difference in the proportion of subjects with SVR24 between each Lambda/RBV/DAA regimen and alfa/RBV regimen was presented with a difference estimate and 80% confidence interval (CI). The CI wasbased on a normal approximation and was stratified by SNP genotype and HCV GT-1 subtype. The SVR24 rate for

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a Lambda/RBV/DAA treatment regimen was inferred to be superior to alfa/RBV if the lower bound of the 80% CI for the difference was > 0%.

For all binary antiviral activity endpoints, the response rates and 80% CIs were presented by treatment regimen using mITT and using observed values.

Deaths were listed for enrolled subjects. Other safety analyses were based on treated subjects, including SAEs, AEs leading to discontinuation of study therapy, and AEs by intensity and relationship to study medication. Treatment-emergent laboratory abnormalities were summarized using The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS) grades.

SUMMARY OF RESULTS:

Global Study

Disposition and Baseline/Demographic Characteristics:

Disposition

119 subjects randomized in the global study received study treatment and most subjects completed the treatment period (Table 2). AE was the most common reasons for not completing the full treatment period in the Lambda/RBV/ASV group (15.8%). Lack of efficacy was the most common reason for not completing the full treatment period in the alfa/RBV group (27.5%).

Most subjects in the Lambda/RBV/DAA groups who entered the follow-up period completed the follow-up period (Lambda/RBV/ASV 88.9%; Lambda/RBV/DCV 84.6%), while 58.8% in the alfa/RBV group who entered follow-up completed the follow-up period.

Baseline/Demographic Characteristics:

Baseline demographics were balanced across treatment groups (Table 3). The majority of subjects were male

(60.5%) and White (89.9%), with a mean age of 46.7 years. A total of 9 (7.6%) subjects were Black/African

American, with 4 subjects each in the Lambda/RBV/DCV and alfa/RBV groups.

Baseline HCV disease characteristics were generally comparable across treatment groups. The majority of subjects

had HCV GT-1a (65.5%). A total of 16 (13.4%) subjects had cirrhosis present at baseline. The majority of subjects

had IL-28 non-CC genotypes (68.1%) and most (76.5%) had BMI < 30. Subjects with IL28b non CC infected with

HCV GT1a constituted 47% of total randomized subjects, and were equally represented across treatment groups.

Dose Reduction of Study Therapy: Nine subjects had Lambda dose reductions, 7 (18.4%) subjects in the Lambda/RBV/ASV group and 2 (4.9%) subjects in the Lambda/RBV/DCV group.

Treatment Adherence: The proportion of subjects who received > 80% of the dose duration for their treatment regimens was similar in the 3 treatment groups (86.8%, 92.7%, and 85.0%, respectively, in the Lambda/RBV/ASV, Lambda RBV/DCV, and alfa/RBV groups).

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Table 2: Subject Disposition: Global Study - Treated Subjects

==================================================================================================================

ASV/L/R DCV/L/R PBO/P/R Total

_________________________________________________________________________________________________________________________________

SUBJECTS 38 41 40 119

SUBJECTS COMPLETING THE PERIOD (%) 29 ( 76.3) 35 ( 85.4) 18 ( 45.0) 82 ( 68.9)

SUBJECTS NOT COMPLETING THE PERIOD (%) 9 ( 23.7) 6 ( 14.6) 22 ( 55.0) 37 ( 31.1)

REASON FOR NOT COMPLETING THE PERIOD (%)

LACK OF EFFICACY 1 ( 2.6) 2 ( 4.9) 11 ( 27.5) 14 ( 11.8) ADVERSE EVENT 6 ( 15.8) 2 ( 4.9) 5 ( 12.5) 13 ( 10.9)

SUBJ REQUEST TO DISCONTINUE STUDY TRT 1 ( 2.6) 1 ( 2.4) 4 ( 10.0) 6 ( 5.0)

SUBJECT WITHDREW CONSENT 0 0 1 ( 2.5) 1 ( 0.8)

POOR/NON-COMPLIANCE 1 ( 2.6) 1 ( 2.4) 0 2 ( 1.7)

SUBJECT NO LONGER MEETS STUDY CRITERIA 0 0 1 ( 2.5) 1 ( 0.8)

SUBJECTS CONTINUING IN THE STUDY (%) 36 ( 94.7) 39 ( 95.1) 34 ( 85.0) 109 ( 91.6)

SUBJECTS NOT CONTINUING IN THE STUDY (%) 2 ( 5.3) 2 ( 4.9) 6 ( 15.0) 10 ( 8.4)

REASON FOR NOT CONTINUING IN THE STUDY (%)

LACK OF EFFICACY 0 1 ( 2.4) 1 ( 2.5) 2 ( 1.7)

SUBJECT WITHDREW CONSENT 1 ( 2.6) 0 5 ( 12.5) 6 ( 5.0) POOR/NON-COMPLIANCE 0 1 ( 2.4) 0 1 ( 0.8)

ADMINISTRATIVE REASON BY SPONSOR 1 ( 2.6) 0 0 1 ( 0.8)

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Table 3: Baseline Demographic and Disease Characteristics - Global Study

===============================================================================================

-------------------------------------------------------------------------------------------------------------- ASV/L/R DCV/L/R PBO/P/R Total N = 38 N = 41 N = 40 N = 119 -------------------------------------------------------------------------------------------------------------- AGE N 38 41 40 119 MEAN 47.9 45.6 46.7 46.7 MEDIAN 49.5 47.0 50.5 49.0 MIN , MAX 26 , 70 24 , 64 21 , 61 21 , 70 Q1 , Q3 40.0 , 55.0 40.0 , 52.0 41.0 , 55.0 40.0 , 55.0 STANDARD DEVIATION 10.70 9.96 10.71 10.41

AGE CATEGORIZATION (%) 21 - < 65 36 ( 94.7) 41 (100.0) 40 (100.0) 117 ( 98.3) >= 65 2 ( 5.3) 0 0 2 ( 1.7) NOT REPORTED 0 0 0 0

GENDER (%) MALE 26 ( 68.4) 20 ( 48.8) 26 ( 65.0) 72 ( 60.5) FEMALE 12 ( 31.6) 21 ( 51.2) 14 ( 35.0) 47 ( 39.5) NOT REPORTED 0 0 0 0

RACE (%) WHITE 35 ( 92.1) 37 ( 90.2) 35 ( 87.5) 107 ( 89.9) BLACK/AFRICAN AMERICAN 1 ( 2.6) 4 ( 9.8) 4 ( 10.0) 9 ( 7.6) ASIAN OTHER 2 ( 5.3) 0 0 2 ( 1.7) OTHER 0 0 1 ( 2.5) 1 ( 0.8) NOT REPORTED 0 0 0 0

ETHNICITY (%) HISPANIC/LATINO 7 ( 18.4) 3 ( 7.3) 5 ( 12.5) 15 ( 12.6) NOT HISPANIC/LATINO 28 ( 73.7) 34 ( 82.9) 31 ( 77.5) 93 ( 78.2) NOT REPORTED 3 ( 7.9) 4 ( 9.8) 4 ( 10.0) 11 ( 9.2)

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Table 3: Baseline Demographic and Disease Characteristics - Global Study

===============================================================================================

ASV/L/R DCV/L/R PBO/P/R Total N = 38 N = 41 N = 40 N = 119 ------------------------------------------------------------------------------------------------------------------

HCV RNA (LOG10 IU/ML) N 38 41 40 119 MEAN 6.3 6.3 6.3 6.3 MEDIAN 6.5 6.3 6.5 6.5 MIN , MAX 4.6 , 7.6 5.0 , 7.5 3.5 , 7.2 3.5 , 7.6 Q1 , Q3 5.9 , 6.8 5.9 , 6.7 6.0 , 6.7 6.0 , 6.8 STANDARD DEVIATION 0.68 0.61 0.68 0.65

HCV RNA DISTRIBUTION (IU/ML)(%) < 800,000 10 ( 26.3) 11 ( 26.8) 8 ( 20.0) 29 ( 24.4) >= 800,000 28 ( 73.7) 30 ( 73.2) 32 ( 80.0) 90 ( 75.6)

RANDOMIZATION STRATA (%) IL28 CC/GENOTYPE 1A 6 ( 15.8) 7 ( 17.1) 7 ( 17.5) 20 ( 16.8) IL28 NONCC/GENOTYPE 1A 18 ( 47.4) 20 ( 48.8) 18 ( 45.0) 56 ( 47.1) IL28 CC/GENOTYPE NON1A 6 ( 15.8) 6 ( 14.6) 6 ( 15.0) 18 ( 15.1) IL28 NONCC/GENOTYPE NON1A 8 ( 21.1) 8 ( 19.5) 9 ( 22.5) 25 ( 21.0)

HCV GENOTYPE FROM CENTRAL LABORATORY (%) HCV GENOTYPE 1 38 (100.0) 41 (100.0) 40 (100.0) 119 (100.0) 1A 25 ( 65.8) 27 ( 65.9) 26 ( 65.0) 78 ( 65.5) 1B 13 ( 34.2) 14 ( 34.1) 14 ( 35.0) 41 ( 34.5)

CIRRHOSIS STATUS (%) ABSENT 32 ( 84.2) 37 ( 90.2) 34 ( 85.0) 103 ( 86.6) PRESENT 6 ( 15.8) 4 ( 9.8) 6 ( 15.0) 16 ( 13.4)

BODY MASS INDEX (KG/M̂ 2)(%) < 25 13 ( 34.2) 20 ( 48.8) 12 ( 30.0) 45 ( 37.8) 25 - < 30 16 ( 42.1) 11 ( 26.8) 19 ( 47.5) 46 ( 38.7) >= 30 9 ( 23.7) 9 ( 22.0) 9 ( 22.5) 27 ( 22.7) NOT REPORTED 0 1 ( 2.4) 0 1 ( 0.8)

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Efficacy Results: HCV RNA levels was measured using the Roche COBAS Taqman test version 2, with a LLOQ

25 IU/mL, and a lower limit of detection 9.3 IU/mL, which is reported as < LLOQ, target not detected (TND).

Of note, practice guideline definitions for SVR were modified during the conduct of this study as HCV RNA

< LLOQ (target detected [TD] or TND) at follow-up Week 24 regardless of end of treatment response. This

endpoint was analyzed in this protocol as a separate measure; however the primary endpoint (SVR24) was analyzed

using the older definition specified in the protocol (HCV RNA < LLOQ, TND at end of treatment and HCV RNA

< LLOQ, TND at post-treatment follow-up).

The following summary points for efficacy are based on the modified ITT analysis (Table 4).

Primary efficacy endpoint:

SVR24 rates were consistently higher in the Lambda RBV/DAA groups (Lambda/RBV/ASV 68.4% and Lambda/RBV/DCV 63.4%) and compared with the alfa/RBV group (SVR24 35.0%).

HCV RNA < LLOQ (updated definition of SVR from current guidelines) rates at follow-up Week 24 showedthe same trend.

Secondary and other efficacy endpoints

High rates of concordance were observed in the rates of SVR12 and SVR24 among subjects with HCV RNA results at follow-up Weeks 12 and 24 for the Lambda groups.

Virologic failure was less frequent in the Lambda/RBV/DAA groups (31.6% and 36.6%, respectively for ASV and DCV) compared with the alfa/RBV group (65.0%).

Robust early virologic response rates were observed in the Lambda/RBV/DAA groups compared to the alfa-2a group. RVR rates in the Lambda/RBV/ASV and Lambda/RBV/DCV groups were 81.6% and 70.7%, respectively, compared with 5.0% in the alfa/RBV group.

A total of 69 of 79 subjects (87.4%) receiving the Lambda/RBV/DAA regimen achieved PDR (32 of 38 subjects [84.2%] in the Lambda/RBV/ASV group; and 37 of 41 subjects [90.2%] in the Lambda/RBV/DCV group) and qualified per protocol for stopping treatment at Week 24. Of these subjects, 25 of the 32 (78.1%) PDR-positive subjects in the Lambda/RBV/ASV group, and 26 of the 37 (70.3%) PDR-positive subjects in the Lambda/RBV/DCV group achieved SVR24.

Ten (10) of 79 subjects receiving the Lambda/RBV/DAA regimens did not achieve PDR. Eight of the 10 subjects were infected with HCV GT-1a. Six of the 10 subjects discontinued before Week 24, while 4 of the 10 subjects continued treatment beyond Week 24, with only 1 completing the 48-week treatment period. None of the 4 subjects treated beyond Week 24 achieved SVR24, suggesting that the benefit of the Lambda/RBV/DAA regimen is to be gained from 24 weeks of treatment, and additional treatment beyond Week 24 is unlikely to improve outcomes.

SVR24 rates were higher among subjects with HCV GT-1b vs. GT-1a. SVR24 rates among subjects with GT-1b were 84.6%, 92.9%, and 50.0% in the Lambda/RBV/ASV, Lambda/RBV/DCV, and alfa/RBV groups, respectively, while rates among subjects with GT-1a were 60.0%, 48.1%, and 26.9%, respectively.

SVR24 rates were higher among subjects with host IL28b CC genotype (75.0%, 69.2%, and 46.2%) compared to non-CC subjects (65.4%, 60.7%, and 29.6%) in the Lambda/RBV/ASV, Lambda/RBV/DCV, and alfa/RBV groups, respectively).

Among the small number of cirrhotics treated (10 in the Lambda/RBV/DAA groups), subjects with GT-1a had a lower rate of SVR24 (0 of 6 GT-1a cirrhotic subjects [0%]) compared to GT-1b (2 of 4 GT-1b cirrhotic subjects [50.0%]).

Virologic failure was less common among subjects with HCV GT-1b compared with HCV GT-1a and was also less common for subjects with the IL28B CC host genotype compared with subjects with the IL28B non-CC genotype in the Lambda/RBV/DAA groups. Subjects who had infection with HCV GT-1a and were IL28B non-CC were the most likely to fail treatment.

Most of the median decline from baseline in HCV RNA in the Lambda groups occurred at Weeks 1 and 4 and

was sustained at Week 24 on treatment.

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Table 4: Key HCV RNA Endpoints - Treated Subjects, Global Study (Modified ITT analysis)

Lambda/RBV/ASVN = 38

Lambda/RBV/DCVN= 41

Alfa-2a/RBVN = 40

HCV RNA

Primary Endpoint

SVR24, n (%)

80% CI

26 (68.4)

(56.9, 78.4)

26 (63.4)

(52.2, 73.6)

14 (35.0)

(24.9, 46.3)

HCV RNA <LLOQ at FU Week 24, n (%)

80% CI

27/38 ( 71.1)

(59.6, 80.7)

27/41 ( 65.9)

(54.7, 75.8)

15/40 ( 37.5)

(27.1, 48.9)

Secondary and Other Efficacy Endpoints

RVR (Week 4), n (%)

80% CI

31 (81.6)

(71.0, 89.4)

29 (70.7)

(59.8, 80.1)

2 (5.0)

(1.3, 12.8)

<LLOQ (Week 4) n (%)

80% CI

36/38 ( 94.7)

(86.6, 98.6)

41/41 (100.0)

(94.5, 100.0)

5/40 ( 12.5)

(6.2, 22.0)

PDR, n (%)

GT-1a

GT-1b

32 ( 84.2)

21/25 (84.0)

11/13 (84.6)

37 ( 90.2)

23/27 (85.2)

14/14 (100)

5 ( 12.5)

3/26 (11.5)

2/14 (14.3)

ETVR (Week 24), n (%)

80% CI

31 (81.6)

(71.0, 89.4)

36 (87.8)

(78.5, 93.9)

21 (52.5)

(41.2, 63.6)

SVR12, n (%)

80% CI

25 (65.8)

(54.2, 76.1)

28 (68.3)

(57.2, 77.9)

15 (37.5)

(27.1, 48.9)

HCV RNA <LLOQ at FU Week 12, n (%)

80% CI

27/38 ( 71.1)

(59.6, 80.7)

28/41 ( 68.3)

(57.2, 77.9)

15/40 ( 37.5)

(27.1, 48.9)

Virologic failure 12 (31.6) 15 (36.6) 26 (65.0)

Virologic breakthrough, n (%) 2 (5.3) 2 (4.9) 2 (5.0)

Relapse, n (%) 4 (10.5) 7 (17.1) 5 (12.5)

Other reason, n (%) 6 (15.8) 6 (14.6) 19 (47.5)

HCV RNA median decline from baseline (log10 IU/mL)

Week 1 -4.48 -4.54 -0.69

Week 4 -5.13 -4.91 -2.05

Week 24 -5.07 -4.78 -4.90

RVR: HCV RNA < LLOQ, TND at Week 4 on treatment

PDR: Week 4 < LLOQ and Week 12 < LLOQ, TND

ETVR: HCV RNA <LLOQ, TND at subject’s last on-treatment visit

SVR12: HCV RNA < LLOQ TND at end of treatment and HCV RNA < LLOQ, TND at post-treatment follow-up Week 12

SVR24: HCV RNA < LLOQ TND at end of treatment and HCV RNA < LLOQ, TND at post-treatment follow-up Week 24HCV RNA <LLOQ at FU Week 12 [and Week 24] and no requirement regarding virologic criteria at end of

treatment

Breakthrough: confirmed > 1 log10 increase in HCV RNA over nadir or confirmed HCV RNA) LLOQ after

confirmed undetectable HCV RNA while on treatment

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Relapse: HCV RNA < LLOQ, TND at the end of treatment followed by HCV RNA ≥ LLOQ at any post-treatment follow-up visit

Safety Results:

An overview of safety results in the global study is provided in Table 5, and summarized as follows:

No deaths were reported.

On-treatment SAEs were reported for 3 (7.9%) subjects in the Lambda/RBV/ASV group, 2 (4.9%) subjects in the Lambda/RBV/DCV group, and no subjects in the alfa/RBV group. The only SAE reported for more than 1 subject was ALT increased (2 subjects, 5.3%) in the Lambda/RBV/ASV group.

AEs leading to discontinuation were reported least frequently in the Lambda/RBV/DCV group (2 subjects, 4.9%). AEs leading to discontinuation were reported for 6 subjects (15.8%) in the Lambda/RBV/ASV group, and 5 subjects (12.5%) in the alfa/RBV group.

Consistent with prior reports on Lambda, AEs such as headache, flu-like symptoms, myalgias, and arthralgias were lower in the Lambda/RBV/DAA groups compared to alfa/RBV.

Rates of Grade 3/4 hematologic laboratory abnormalities, such as reductions in neutrophils and platelets, were also consistently lower in the Lambda/RBV/DAA groups compared to alfa/RBV. No subjects experienced Grade 3/4 reductions in hemoglobin; however, Lambda/RBV/DAA groups had lower rates of Grade 1/2 hemoglobin reduction (Lambda/RBV/ASV: 10.5%, Lambda/RBV/DCV: 24.4%) compared to alfa/RBV (45.0%).

Grade 3/4 increases in ALT or AST were most common in the Lambda/RBV/ASV group (7.9%), while these rates were similar for the Lambda/RBV/DCV group (2.4%) when compared to alfa/RBV (2.5%).

Grade 3/4 increases in total bilirubin were more common in the Lambda-treated groups (Lambda/RBV/ASV: 15.8%, Lambda/RBV/DCV: 4.9%) compared to the alfa/RBV group (0%).

Laboratory criteria for pDILI (potential drug induced liver injury) as defined in the protocol were met by 2 (5.3%) subjects in the Lambda/RBV/ASV group. Neither of these subjects had cirrhosis at baseline.

No subjects with Grade 3/4 increases in ALT/AST or total bilirubin showed evidence of hepatic decompensation.

Table 5: On-treatment Safety - Global Study, Treated Subjects

Number (%) of Subjects

Lambda/RBV/ASV (N = 38)

Lambda/RBV/DCV (N = 41)

Alfa/RBV (N = 40)

Adverse Events

Deaths 0 0 0

SAEs 3 (7.9) 2 (4.9) 0

Discontinuation due to AE 6 (15.8) 2 (4.9) 5 (12.5)

Grade 3/4 AEs 11 (28.9) 7 (17.1) 8 (20.0)

Most Common AEs ( 20% in any group)

Pruritus 7 (18.4) 15 (36.6) 15 (37.5)

Fatigue 12 (31.6) 14 (34.1) 19 (47.5)

Nausea 9 (23.7) 14 (34.1) 8 (20.0)

Headache 6 (15.8) 14 (34.1) 20 (50.0)

Insomnia 9 (23.7) 12 (29.3) 12 (30.0)

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Table 5: On-treatment Safety - Global Study, Treated Subjects

Number (%) of Subjects

Lambda/RBV/ASV (N = 38)


Alfa/RBV (N = 40)

Irritability 7 (18.4) 10 (24.4) 10 (25.0)

Asthenia 7 (18.4) 9 (22.0) 7 (17.5)

Myalgia 4 (10.5) 9 (22.0) 12 (30.0)

Cough 3 (7.9) 7 (17.1) 9 (22.5)

Decreased Appetite 4 (10.5) 6 (14.6) 9 (22.5)

Arthralgia 5 (13.2) 6 (14.6) 11 (27.5)

Diarrhea 8 (21.1) 4 (9.8) 12 (30.0)

Influenza Like Illness 4 (10.5) 0 8 (20.0)

Measured Grade 3/4 Laboratory Abnormalities

Hemoglobin 0 0 0

Leukocytes 0 0 3 (7.5)

Lymphocytes 0 1 (2.4) 6 (15.0)

Neutrophils 0 0 8 (20.0)

Platelet Count 0 0 2 (5.0)

AST 7 (18.4) 3 (7.3) 3 (7.5)

ALT 3 (7.9) 1 (2.4) 1 (2.5)

Total Bilirubin 6 (15.8) 2 (4.9) 0

Lipase 1 (2.7) 0 1 (2.5)

Amylase 1 (2.6) 0 1 (2.5)

Prothrombin Time 0 1 (2.4) 1 (2.5)

Japan Substudy

Disposition and Baseline/Demographic Characteristics:

Disposition:

22 subjects were randomized in the Japan substudy, and 21 subjects received study treatment. One subject

randomized to Lambda/RBV/DCV group was not treated because he withdrew consent.

8 of 8 subjects in the Lambda/RBV/DCV group completed the full treatment period (Table 6). 3 of 6 subjects in the

Lambda/RBV/ASV group and 5 of 7 subjects in the alfa/RBV group completed the full treatment period. All but 1

of these subjects discontinued due to AE. All 6 subjects in the Lambda/RBV/ASV group, all 8 subjects in the

Lambda/RBV/DCV group, and 4 of 6 subjects in the alfa/RBV group who entered follow-up completed the follow-

up period.

Baseline/Demographic Characteristics:

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The majority of Japanese subjects were female (14 subjects, 66.7%), with a mean age of 56.2 years (Table 7). Two

(9.5%) subjects were 65 years of age. The overall mean HCV RNA level was 6.4 log10 IU/mL. Most (90.5%)

subjects had an HCV RNA level 800,000 IU/mL. All subjects were GT-1b. None of the subjects had baseline

cirrhosis. Most subjects (71.4%) had IL-28B CC genotypes. Most subjects (95.2%) had BMI < 25.

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Table 6: Subject Disposition: Japan Substudy - Treated Subjects

==================================================================================================================================== ASV/L/R DCV/L/R PBO/P/R Total _________________________________________________________________________________________________________________________________ SUBJECTS 6 8 7 21 SUBJECTS COMPLETING THE PERIOD (%) 3 ( 50.0) 8 (100.0) 5 ( 71.4) 16 ( 76.2) SUBJECTS NOT COMPLETING THE PERIOD (%) 3 ( 50.0) 0 2 ( 28.6) 5 ( 23.8) REASON FOR NOT COMPLETING THE PERIOD (%) LACK OF EFFICACY 0 0 1 ( 14.3) 1 ( 4.8) ADVERSE EVENT 3 ( 50.0) 0 1 ( 14.3) 4 ( 19.0) SUBJECTS CONTINUING IN THE STUDY (%) 6 (100.0) 8 (100.0) 6 ( 85.7) 20 ( 95.2) SUBJECTS NOT CONTINUING IN THE STUDY (%) 0 0 1 ( 14.3) 1 ( 4.8) REASON FOR NOT CONTINUING IN THE STUDY (%) SUBJ REQUEST TO DISCONTINUE STUDY TRT 0 0 1 ( 14.3) 1 ( 4.8)

====================================================================================================================================

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Table 7: Baseline Demographic and Disease Characteristics - Japan Substudy

===============================================================================================

ASV/L/R DCV/L/R PBO/P/R Total N = 6 N = 8 N = 7 N = 21 ------------------------------------------------------------------------------------------------------------ AGE N 6 8 7 21 MEAN 52.7 58.5 56.6 56.2 MEDIAN 57.0 59.5 54.0 59.0 MIN , MAX 34 , 64 47 , 67 51 , 64 34 , 67 Q1 , Q3 42.0 , 62.0 53.0 , 64.5 52.0 , 61.0 52.0 , 62.0 STANDARD DEVIATION 12.23 7.50 5.26 8.44

AGE CATEGORIZATION (%) 21 - < 65 6 (100.0) 6 ( 75.0) 7 (100.0) 19 ( 90.5) >= 65 0 2 ( 25.0) 0 2 ( 9.5) NOT REPORTED 0 0 0 0

GENDER (%) MALE 2 ( 33.3) 2 ( 25.0) 3 ( 42.9) 7 ( 33.3) FEMALE 4 ( 66.7) 6 ( 75.0) 4 ( 57.1) 14 ( 66.7) NOT REPORTED 0 0 0 0

RACE (%) JAPANESE 6 (100.0) 8 (100.0) 7 (100.0) 21 (100.0) NOT REPORTED 0 0 0 0

ETHNICITY (%) NOT HISPANIC/LATINO 6 (100.0) 8 (100.0) 7 (100.0) 21 (100.0) NOT REPORTED 0 0 0 0

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Table 7: Baseline Demographic and Disease Characteristics - Japan Substudy

===============================================================================================

ASV/L/R DCV/L/R PBO/P/R Total N = 6 N = 8 N = 7 N = 21 ------------------------------------------------------------------------------------------------------------------

HCV RNA (LOG10 IU/ML) N 6 8 7 21 MEAN 6.5 6.2 6.5 6.4 MEDIAN 6.6 6.7 6.5 6.6 MIN , MAX 6.0 , 7.1 4.3 , 7.0 6.0 , 7.1 4.3 , 7.1 Q1 , Q3 6.1 , 6.8 5.7 , 6.9 6.1 , 7.0 6.1 , 6.9 STANDARD DEVIATION 0.44 0.98 0.40 0.67

HCV RNA DISTRIBUTION (IU/ML)(%) < 800,000 0 2 ( 25.0) 0 2 ( 9.5) >= 800,000 6 (100.0) 6 ( 75.0) 7 (100.0) 19 ( 90.5)

RANDOMIZATION STRATA (%) IL28 CC 4 ( 66.7) 6 ( 75.0) 5 ( 71.4) 15 ( 71.4) IL28 NONCC 2 ( 33.3) 2 ( 25.0) 2 ( 28.6) 6 ( 28.6)

HCV GENOTYPE FROM CENTRAL LABORATORY (%) HCV GENOTYPE 1 6 (100.0) 8 (100.0) 7 (100.0) 21 (100.0) 1B 6 (100.0) 8 (100.0) 7 (100.0) 21 (100.0)

CIRRHOSIS STATUS (%) ABSENT 6 (100.0) 8 (100.0) 7 (100.0) 21 (100.0)

BODY MASS INDEX (KG/M̂ 2)(%) < 25 6 (100.0) 7 ( 87.5) 7 (100.0) 20 ( 95.2) 25 - < 30 0 1 ( 12.5) 0 1 ( 4.8)

====================================================================================================================================

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Dose Reduction of Study Therapy: Two subjects (2/6 [33.3%]) in the Lambda/RBV/ASV group had dose

reductions of Lambda. There were no Lambda dose reductions in the Lambda/RBV/DCV group.

Treatment Adherence: Eighty-three percent of subjects in the Lambda/RBV/ASV group and 100% in the Lambda/RBV/DCV group received > 80% of the planned dose of the treatment regimen, vs 28.6% in the alfa/RBV group.

Efficacy Results:

Results in the Japan substudy were consistent overall with results in the global study.

Primary efficacy endpoint

In treatment-naive subjects with GT-1 (all subjects were infected with GT-1b) HCV infection, virologic response rates during treatment and SVR rates during post-treatment follow-up were higher for subjects treated with Lambda/RBV/ASV and Lambda/RBV/DCV compared with alfa/RBV.

The results show the same trend using the updated definition of SVR from current guidance (HCV RNA < LLOQ at follow-up Week 24 (Table 8).

Secondary and other efficacy endpoints

Across all groups, high rates of concordance were observed between SVR12 and SVR24 rates.

Virologic failure was less frequent in the Lambda/RBV/DAA groups compared with the alfa/RBV group.

Response rates were higher in the Lambda/RBV/DAA groups compared with the alfa/RBV group at follow-up Week 4 and follow-up Week 24.

A high number of subjects receiving Lambda/RBV/ASV and Lambda RBV/DCV achieved PDR and were eligible to stop treatment at Week 24, and SVR rates were high among subjects with shorter treatment duration.

All subjects in the Japanese substudy had HCV GT-1b and all were noncirrhotic.

In the IL28B CC subgroups, response rates were higher among subjects with the IL28B CC genotype than the non-CC genotype, and were higher in IL28B CC subjects receiving the Lambda/RBV/DAA regimens compared with the alfa/RBV regimen.

The median decline from baseline in HCV RNA in the Lambda/RBV/DAA groups indicated a robust virologic response at Weeks 1 and 4, which was sustained through Week 24.

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Table 8: Key HCV RNA Endpoints - Japan Substudy, Treated Subjects (Modified ITT analysis)

Lambda/RBV/ASVN = 6

Lambda/RBV/DCVN = 8

Alfa/RBVN = 7

Primary efficacy endpoint

SVR24 5/6 ( 83.3) 8/8 (100.0) 2/7 ( 28.6)

80% CI (49.0, 98.3) (75.0, 100.0) (7.9, 59.6)

HCV RNA <LLOQ at FU Week 24, n (%) 5/6 ( 83.3) 8/8 (100.0) 2/7 ( 28.6)

80% CI (49.0, 98.3) (75.0, 100.0) (7.9, 59.6)

Secondary and Other Efficacy Endpoints

RVR (Week 4) 5/6 ( 83.3) 7/8 ( 87.5) 1/7 ( 14.3)

PDR 5/6 ( 83.3) 7/8 ( 87.5) 1/7 ( 14.3)

EOT (Week 24) 6/6 (100.0) 8/8 (100.0) 6/7 ( 85.7)

SVR12 5/6 ( 83.3) 8/8 (100.0) 2/7 ( 28.6)

Virologic failure, n (%) 1 ( 16.7) 0 5 ( 71.4)

Relapse 1 ( 16.7) 0 3 ( 42.9)

Breakthrough 0 0 0

Other 0 0 1 (14.3)a

HCV RNA median decline from baseline

(log10 IU/mL)

Week 1 -5.18 -5.03 -0.97

Week 4 -5.21 -5.35 -4.32

Week 24 -4.76 -5.31 -5.17

aSubject was a partial responder on treatment (achieved EVR but was detectable at end of treatment)

RVR: HCV RNA < LLOQ TND at Week 4 on treatment

PDR: Week 4 < LLOQ and Week 12 < LLOQ TND

ETVR: HCV RNA <LLOQ, TND at subject’s last on-treatment visit

SVR12: HCV RNA < LLOQ TND at end of treatment and HCV RNA < LLOQ TND at post-treatment follow-up Week 12

SVR24: HCV RNA < LLOQ TND at end of treatment and HCV RNA < LLOQ TND at post-treatment follow-up Week 24

Breakthrough: confirmed > 1 log10 increase in HCV RNA over nadir or confirmed HCV RNA LLOQ after

confirmed undetectable HCV RNA while on treatment

Relapse: HCV RNA < LLOQ TND at the end of treatment followed by HCV RNA ≥ LLOQ at any post-treatment follow-up visit

Safety Results:

An overview of safety results in the Japan substudy is provided in Table 9, and summarized as follows:

No deaths were reported.

On-treatment SAEs were reported for 1 subject (Lambda/RBV/ASV group).

No AEs leading to discontinuation were reported for the Lambda/RBV/DCV group. AEs leading to discontinuation were reported for 3 (50.0%) subjects in the Lambda/RBV/ASV group (all for laboratory abnormalities reported as AEs) and for 1 (14.3%) subject in the alfa/RBV group.

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The most frequently reported AEs in each treatment group were AST increased in the Lambda/RBV/ASV group (5 subjects, 83.3%), diarrhea and nasopharyngitis in the Lambda/RBV/DCV group (each in 3 subjects, 37.5%), and malaise in the alfa/RBV group (6 subjects, 85.7%).

Elevated AST laboratory abnormality of any grade was reported for 6 (100%) subjects in the Lambda/RBV/ASV group, 3 (37.5%) subjects in the Lambda/RBV/DCV group, and 3 (42.9%) subjects in the alfa/RBV group. Elevated ALT was reported for 6 (100%) subjects, 1 (12.5%) subject, and 3 (42.9%) subjects, respectively.

Laboratory criteria for pDILI were met by 1 (16.7%) subject in the Lambda/RBV/ASV group.

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Table 9: On-treatment Safety - Japan Substudy, Treated Subjects

Lambda/RBV/ASV

(N = 6)


Alfa/RBV (N = 7)

Adverse Events

Deaths 0 0 0

SAEs 1 (16.7) 0 0

AEs Leading to Discontinuation 3 (50.0) 0 1 (14.3)

Grade 3/4 AEs 5 (83.3) 1 (12.5) 5 (71.4)

Most Common AEs ( 33.3% in any group)

Diarrhea 0 3 (37.5) 0

Nasopharyngitis 1 (16.7) 3 (37.5) 2 (28.6)

Injection Site Reaction 0 2 (25.0) 3 (42.9)

Malaise 4 (66.7) 1 (12.5) 6 (85.7)

Headache 1 (16.7) 1 (12.5) 4 (57.1)

Decreased Appetite 2 (33.3) 1 (12.5) 2 (28.6)

Weight Decreased 0 1 (12.5) 3 (42.9)

AST Increased 5 (83.3) 0 0

ALT Increased 4 (66.7) 0 0

Nausea 3 (50.0) 0 1 (14.3)

Blood Bilirubin Increased 2 (33.3) 0 0

Pyrexia 1 (16.7) 0 4 (57.1)

Neutropenia 0 0 4 (57.1)

Arthralgia 0 0 3 (42.9)

Alopecia 0 0 3 (42.9)

Measured Grade 3/4 Laboratory Abnormalities

Hemoglobin 1 (16.7) 0 1 (14.3)

Leukocytes 0 1 (12.5) 1 (14.3)

Lymphocytes 0 2 (25.0) 3 (42.9)

Neutrophils 0 0 4 (57.1)

Platelet Count 0 0 0

AST 5 (83.3) 0 0

ALT 3 (50.0) 0 0

Total Bilirubin 1 (16.7) 0 0

Lipase 1 (16.7) 0 0

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Pharmacokinetic Results:

The PK of Lambda were similar between the two Lambda/RBV/DAA treatment groups, with both having high

variability in the parameter estimates. In general, it appeared that minor accumulation was noted in the Ctrough

values, with steady state being achieved by Week 4.

Other Results: HCV Drug Resistance:

For subjects with a defined virologic outcome, the resistance barriers of the Lambda/RBV/DCV and Lambda/RBV/ASV combinations were higher in HCV GT-1b than in GT-1a subjects.

Association between NS5A or NS3 resistance-associated variants (RAVs) at baseline (BL) and virologic outcome was not apparent in these analyses.

Virologic failure to the DCV regimen was associated with the emergence of NS5A RAVs at or close to the time of virologic failure. In GT-1a failures, substitution at NS5A-Q30 was frequently observed either alone or in combination with other NS5A substitutions at M28, L31, or Y93. In GT-1b failures, substitutions at NS5A-L31 and Y93 were observed.

Virologic failure to the ASV regimen was generally associated with the emergence of NS3 RAVs in subjects at or close to the time of virologic failure. Predominant GT-1a NS3 RAVs included R155K and D168E/A/V while NS3-D168V was observed in GT-1b.

The resistance profiles of DCV and ASV in combination with Lambda/RBV are comparable to results described for these agents combined with alfa/RBV.

CONCLUSIONS:

The addition of the investigational DAAs, DCV and ASV to Lambda/RBV improved SVR24 rates for subjects with HCV GT-1 infection compared to alfa/RBV in the global study (68.4% and 63.4% for Lambda/RBV/ASV and Lambda/RBV/DCV vs. 35.0% for alfa) or compared with Lambda 180 μg/RBV in the EMERGE study in GT-1, -4 subjects (37.3%).

The majority of subjects receiving the combination regimen of Lambda/RBV/DAA were able to stop all therapy after 24 weeks of treatment (84.2% in the Lambda/RBV/ASV group and 90.2% in the Lambda/RBV/DCV). Of these subjects, 78.1% PDR-positive subjects in the Lambda/RBV/ASV group, and 70.3% PDR-positive subjects in the Lambda/RBV/DCV group achieved SVR24. No incremental improvement in SVR24 was obtained from continuing therapy beyond Week 24 among non-PDR subjects (4 of 41 subjects in the Lambda/RBV/DCV group, all with GT-1a, and 6 of 38 subjects in the Lambda/RBV/ASV group, 4 with GT-1a and 2 with GT-1b).

Overall, across all treatment groups, GT-1b subjects had higher SVR24 rates than those with GT-1a. In the Lambda/RBV/DCV group, 100% of subjects with GT-1b in the global study were able to stop study therapy after 24 weeks of treatment. The SVR24 rates in GT-1b subjects were 84.6% and 92.9% in the Lambda/RBV/ASV and Lambda/RBV/DCV groups, respectively, vs. 50.0% in the alfa/RBV group. SVR24 rates in GT-1a subjects were 60.0%, 48.1%, and 26.9%, respectively.

Virologic failure to Lambda/RBV/DCV was most common among subjects with GT-1a and the IL28 non-CC host genotype. Virologic failure to the Lambda/RBV/DCV regimen was associated with the emergence of NS5A RAVs at or close to the time of virologic failure. In GT-1a failures, substitution at NS5A-Q30 was frequently observed either alone or in combination with other NS5A substitutions at M28, L31, or Y93. In GT-1b failures, substitutions at NS5A-L31 and Y93 were observed

The safety profile of the Lambda/RBV/ASV regimen was not acceptable in this study. Three cases of pDILI were reported in subjects in the Lambda/RBV/ASV group (2 subjects in the global study and 1 subject in the Japan substudy). Even though Lambda/RBV/ASV showed high efficacy rates, the unfavorable safety profile has resulted in discontinuation of this regimen from further development.

Lambda/RBV/DCV was a well tolerated regimen, with a global safety profile characterized by lower rates of influenza like illness, myalgias, and arthralgias, and lower rates anemia, neutropenia, leukopenia, and thrombocytopenia compared with the alfa/RBV group, similar to the safety profile previously observed with Lambda/RBV alone.

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Overall, the Lambda/RBV/DCV regimen had a good safety profile, with and demonstrated strong efficacy in this study, particularly among subjects with GT-1b HCV infection. Hence this regimen is being studied further, as a 12-week regimen among non cirrhotic GT-1b subjects in substudy C of AI452008, and as a fixed duration 12 + 12-week treatment duration regimen in GT-1b subjects in Phase 3.

The PK of Lambda were similar between the two Lambda/RBV/DAA treatment groups, with both having high variability in the parameter estimates. In general, it appeared that minor accumulation was noted in the Ctrough values, with steady state being achieved by Week 4.

DATE OF REPORT: 13-Jan-2014

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