2.7.3 summary of clinical efficacy...2.7.3 Summary of Clinical Efficacy - 7 - 1.1. Clinical...

CONFIDENTIAL CM2003/00031/002.7.3 Summary of Clinical Efficacy

- 1 -

Module 2.7.3

Summary of Clinical Efficacy

Copyright 2003 the GlaxoSmithKline group of companies. All rights reserved.Unauthorized copying or use of this information is prohibited.


- 2 -

TABLE OF CONTENTS

PAGE

MODULE 2.7.3 ................................................................................................................1

1. BACKGROUND AND OVERVIEW OF CLINICAL EFFICACY ..................................51.1. Clinical Pharmacology and Biopharmaceutics Studies ..................................7

1.1.1. CNA10905 � Intracellular Carbovir Triphosphate Study .................71.1.2. CAL10001 � ABC/3TC Fixed Dose Combination

Bioequivalence Study.....................................................................71.2. Pivotal Study CNA30021...............................................................................8

1.2.1. Study Design..................................................................................81.2.2. Statistical Analysis .........................................................................8

1.2.2.1. Primary efficacy endpoints............................................81.2.2.2. Secondary efficacy endpoints .....................................10

1.3. Ongoing GSK-Sponsored Studies...............................................................10

2. SUMMARY OF RESULTS OF INDIVIDUAL STUDIES...........................................122.1. Clinical Pharmacology and Biopharmaceutics Studies ................................12

2.1.1. CNA10905 � Intracellular Carbovir Triphosphate Study ...............122.1.2. CAL10001 � ABC/3TC Fixed Dose Combination

Bioequivalence Study...................................................................122.2. Pivotal Clinical Study CNA30021 ................................................................14

2.2.1. Study Population..........................................................................142.2.1.1. Subject accountability .................................................142.2.1.2. Demographics and baseline characteristics ................15

2.2.2. Primary and Selected Secondary Efficacy Results.......................172.2.2.1. Virologic response/plasma HIV-1 RNA <50

copies/mL at Week 48 in CNA30021 ..........................172.2.3. Other Secondary Efficacy Results................................................21

2.2.3.1. Treatment outcomes based on time to loss ofvirologic response.......................................................21

2.2.3.2. Cumulative antiviral efficacy........................................232.2.3.3. Immunologic efficacy ..................................................242.2.3.4. Other efficacy results ..................................................25

2.3. Ongoing GSK-Sponsored Studies...............................................................25

3. COMPARISON AND ANALYSES OF RESULTS ACROSS STUDIES....................263.1. Study Populations .......................................................................................273.2. Comparison of Efficacy Results of All Studies .............................................273.3. Comparison of Results in Sub-Populations .................................................27

3.3.1. Pivotal Study CNA30021..............................................................273.3.1.1. Gender analysis..........................................................273.3.1.2. Age analysis ...............................................................283.3.1.3. Race analysis .............................................................293.3.1.4. CD4+ cell count analysis.............................................293.3.1.5. Country analysis .........................................................30

4. ANALYSIS OF CLINICAL INFORMATION RELEVANT TO DOSINGRECOMMENDATIONS ..........................................................................................30

5. PERSISTENCE OF EFFICACY AND/OR TOLERANCE EFFECTS........................31


- 3 -

6. ANALYSIS OF VIROLOGIC GENOTYPE AND PHENOTYPE INABACAVIR CLINICAL TRIALS ...............................................................................316.1. Pivotal Study CNA30021.............................................................................31

6.1.1. Genotypic Results........................................................................326.1.2. Phenotypic Results ......................................................................336.1.3. Relationship of On-Therapy Genotype to Plasma HIV-1

RNA Response ............................................................................336.1.4. Predictors of Virologic Failure ......................................................33

7. APPENDIX .............................................................................................................35


- 4 -

Abbreviations

3TC Lamivudine (EPIVIR�)AAUCMB Average area under curve minus baselineABC Abacavir (ZIAGEN�)AIDS Acquired Immune Deficiency SyndromeART Antiretroviral therapyAUC Area Under the CurveAUClast Area Under the Curve to last timepointAUC∞ Area Under the Curve to infinityBID Twice daily (Bis In Die)CBV-TP carbovir triphosphateCD4+ Helper-inducer T-lymphocyte surface antigenCDC Centers for Disease Control and PreventionCI Confidence intervalCmax Maximum Concentration of DrugCSR Clinical study reportd4T stavudine (Zerit�)ddC zalcitabine (Hivid�)dGTP 2-deoxyguanosine-5�-triphosphateEFV Efavirenz (Sustiva�, Stocrin*)FDC Fixed dose combinationGSK GlaxoSmithKlineHIV-1 Human immunodeficiency virus Type 1ITT Intent-to-TreatKi Inhibition ConstantLLOQ Lower Limit of QuantificationλΖ Elimination Rate ConstantNDA New Drug ApplicationNNRTI Non-nucleoside reverse transcriptase inhibitorNRTI Nucleoside reverse transcriptase inhibitorOAD Once dailyPCR Polymerase Chain ReactionPI Protease InhibitorsRNA Ribonucleic acidt1/2 Half-lifeTAMs Thymidine analogue mutationsTLOVR Time to Loss of Virologic Responsetmax Time of peak drug concentration


- 5 -

1. BACKGROUND AND OVERVIEW OF CLINICALEFFICACY

A high rate of adherence to antiretroviral therapy (ART) is recognized as an importantpredictor of treatment success. Poor adherence has been associated with the developmentof drug resistance, increased likelihood of virologic failure, and increased morbidity andmortality [Paterson, 2000; Carmona, 2000; Walsh, 2000]. There is evidence thatsimplified regimens with reduced pill numbers and dose frequencies improve adherence[Bartlett, 2001; Vibhagool, 2001].

Towards the goal of simplifying therapy, GlaxoSmithKline (GSK) undertook adevelopment program to combine abacavir (ZIAGEN�, abacavir sulfate, ABC) andlamivudine (3TC, EPIVIR�) into a fixed dose combination product (FDC) to beadministered once daily. A clinical program was initiated to evaluate the safety andefficacy of ABC administered once daily, and is described in this submission.

The pivotal clinical study CNA30021 provides safety, efficacy, and durability datarelating to the use of once daily ABC and 3TC as a nucleoside backbone. The primaryobjective of CNA30021 was to test the non-inferiority of ABC administered once daily(OAD) relative to ABC twice daily (BID) as measured by the proportion of subjects withplasma human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA)<50 copies/mL at 48 Weeks. In addition to the pivotal clinical study CNA30021, apivotal bioequivalence study CAL10001 and a clinical pharmacology study CNA10905were conducted to support this application. CAL10001 was designed to demonstrate thebioequivalence between the ABC/3TC (600mg/300mg) combination tablet versusZIAGEN (ABC, 2 X 300mg tablets) and EPIVIR (3TC, 2 X 150mg tablets).CNA10905 was designed to characterize the pharmacokinetics of plasma ABC andintracellular carbovir triphosphate (CBV-TP), the active moiety of ABC.

A tabular listing of completed and ongoing studies discussed in this application isprovided in Module 5 (m5, Section 5.2). A synopsis of each study is provided inModule 2 (m2, Section 2.7.6).

� ZIAGEN is a Trade Mark of the GlaxoSmithKline group of companies.

Registered in US Patent and Trademark Office.

� EPIVIR is a Trade Mark of the GlaxoSmithKline group of companies.Registered in US Patent and Trademark Office.


- 6 -

Conventions for Reporting Treatment Groups

Table 1 presents the conventions for reporting treatment groups in the clinicalpharmacology study and the pivotal biopharmaceutics study.

Table 1 Conventions for Describing Treatment Groups for ClinicalPharmacology and Biopharmaceutics Studies

Protocol Number Treatment GroupAbbreviation Treatment Regimen

CNA10905 ABC + ART ABC 300mg BID + ART

ABC/3TC/ZDV ± ART ABC 300mg BID / 3TC 150mg BID /ZDV 300mg BID ± ART

CAL10001 ABC/3TC ABC 600mg/3TC 300mg single dose FDC(fasted)

ABC/3TC ABC 600mg/3TC 300mg single dose FDC(fed)

ABC + 3TC ABC 600mg single dose + 3TC 300mg singledose (fasted)

Note: ABC=abacavir; ART=antiretroviral therapy; BID=twice daily; FDC=fixed dose combination; 3TC=lamivudine,ZDV=zidovudine (RETROVIR�).

Table 2 shows the convention for reporting the treatment groups in pivotal clinical studyCNA30021:

Table 2 Conventions for Describing Treatment Groups for Pivotal StudyCNA30021

ProtocolNumber

Treatment GroupAbbreviation

Treatment Regimen

ABC once daily ABC 600mg OAD + ABC placebo BID +3TC 300mg OAD + EFV 600mg OAD

CNA30021

ABC twice daily ABC placebo OAD + ABC 300mg BID +3TC 300mg OAD + EFV 600mg OAD

ABC=abacavir; BID=twice daily; EFV=efavirenz (Sustiva�, Stocrin*); OAD=once daily; 3TC=lamivudine

� RETROVIR is a Trade Mark of the GlaxoSmithKline group of companies.


� Sustiva is a Trade Mark of the Bristol Myers Squibb Company.Registered in US Patent and Trademark Office.


- 7 -

1.1. Clinical Pharmacology and Biopharmaceutics Studies

1.1.1. CNA10905 � Intracellular Carbovir Triphosphate Study

CNA10905 was an open-label, single arm, pharmacokinetic, pilot study in HIV-1infected subjects who were on a stable ABC-containing regimen. The study wasdesigned to characterize the pharmacokinetics of plasma ABC and intracellular CBV-TPat steady-state following administration of an ABC 300mg twice daily containingregimen (ZIAGEN or TRIZIVIR�) in HIV-1 infected subjects.

Study subjects were selected for participation if they were on a ZIAGEN(ABC 300mg)-containing antiviral regimen or TRIZIVIR [ABC (300mg), 3TC (150mg),and ZDV (300mg)]-containing regimen for ≥6 weeks. Subjects (n=20) withheld theevening dose on the pharmacokinetic study day. Pharmacokinetic samples were collectedover 24 hours for ABC in plasma and CBV-TP in peripheral blood mononuclear cells.

1.1.2. CAL10001 � ABC/3TC Fixed Dose Combination BioequivalenceStudy

CAL10001 was designed to demonstrate the bioequivalence between the ABC/3TC(600mg/300mg) combination tablet versus ZIAGEN (ABC, 2 X 300mg tablets) andEPIVIR (3TC, 2 X 150mg tablets) in healthy volunteers. The study also evaluated theeffect of food on the bioavailability of the new combination tablet. Study treatments inCAL10001 were:

• ABC/3TC FDC tablet (600mg/300mg) following an overnight fast;

• ZIAGEN (2 X 300mg) + EPIVIR (2 X 150mg) sequentially following an overnightfast; and

• ABC/3TC FDC tablet (600mg/300mg) five minutes following a standardizedbreakfast.

* Sustiva is a Trade Mark of the Merck Company.

� TRIZIVIR is a Trade Mark of the GlaxoSmithKline group of companies.Registered in US Patent and Trademark Office.


- 8 -

The primary endpoints were:

• Serum ABC and 3TC area under the curve to infinity (AUC∞ ), maximumconcentration of drug (Cmax), and area under the curve to last timepoint (AUClast)following single dose oral administration of the combination tablet of ABC/3TCcompared to ZIAGEN 2 X 300mg tablets and EPIVIR 2 X 150mg tablets takensequentially without food.

• Serum ABC and 3TC AUC∞, Cmax, and AUClast following single dose oraladministration of the combination tablet of ABC/3TC with food compared to serumABC and 3TC AUC∞, Cmax, and AUClast following single dose oral administration ofthe combination tablet of ABC/3TC without food.

Secondary endpoints were serum ABC and 3TC tmax (time of peak drug concentration),elimination rate constant (λz) and t½ following administration of the ABC/3TCcombination tablet with or without food compared to a single dose of ZIAGEN(2 X 300mg) and EPIVIR (2 X 150mg) taken sequentially without food.

1.2. Pivotal Study CNA30021

CNA30021 � Use of ABC once daily compared with twice daily in combination with3TC and EFV once daily in treatment-naïve HIV-1 infected adults

1.2.1. Study Design

Clinical study CNA30021 was a Phase III, randomized, double-blind, multicenter,international study designed to evaluate the antiretroviral efficacy (as measured byplasma HIV-1 RNA) and safety of ABC 600mg once daily versus ABC 300mg twicedaily as a component of triple drug therapy including 3TC 300mg once daily plus EFV600mg once daily over at least 48 weeks duration. Subjects were centrally randomized1:1 to one of the following treatment groups:

• ABC (600mg once daily) + ABC (0mg twice daily) + 3TC (300mg once daily) + EFV(600mg once daily); or

• ABC (0mg once daily) + ABC (300mg twice daily once daily) + 3TC (300mg oncedaily) + EFV (600mg once daily).

Randomization was stratified by screening plasma HIV-1 RNA (≤100,000 and>100,000 copies/mL) in order to ensure balance of the treatment groups within the strata.

1.2.2. Statistical Analysis

1.2.2.1. Primary efficacy endpoints

The primary efficacy measure to test the non-inferiority of ABC once daily versus ABCtwice daily was the comparison of the proportion of subjects with plasma HIV-1 RNAlevels <50 copies/mL through Week 48. Data were summarized and plotted by week on


- 9 -

the Intent-to-Treat (ITT)-Exposed Population, which included all subjects randomizedand exposed to at least one dose of study drug. The test of the hypothesis ofnon-inferiority was based on the calculation of a two-sided 95% confidence interval (CI)on the point estimate of the treatment difference in the proportion of subjects with plasmaHIV-1 RNA <50 copies/mL at Week 48 using the Cochran Mantel Haenszel methodstratified by baseline plasma HIV-1 RNA (≤100,000 copies/mL; >100,000 copies/mL).

The sample size in the pivotal study CNA30021 was based on 90% power to assess anon-inferiority margin of 12% at the 0.05 level of significance. The non-inferioritymargin of 12% was pre-selected as the appropriate measure for distinguishing the clinicaleffectiveness of two study treatments. The choice of delta was based largely on expertclinical judgement and discussion with independent HIV physicians, with 12%representing the largest difference that would be clinically acceptable. Furthermore, toexclude 12% from the CI with this sample size and this assumed success rate, theobserved virologic response rates would need to differ by no more than 4% to 5%, adifference considered to be clinically unimportant. The active control in this study ofABC twice daily + 3TC + EFV was established in the previously submitted studyCNA30024 as non-inferior to a widely used and widely recommended first-line treatmentof ZDV + 3TC + EFV [GSK Document Number RM2002/0025/00] in Module 5 (m5,Section 5.2).

The durability of treatment response over time was measured by Time to Loss ofVirologic Response (TLOVR), where the event time was calculated according to thefollowing algorithm which was applied to all plasma HIV-1 RNA data while onrandomized treatment, including off-scheduled visits and post Week-48 visits:

a) For a subject who never achieved a confirmed plasma HIV-1 RNA level below50 copies/mL (i.e., two consecutive visits below 50 copies/mL) before thefollowing events, this subject was considered a failure at time 0:

• Death;

• Premature discontinuation of randomized study drugs or matched placebo;

• Introduction of a new ART, except changes to background drugs (i.e., 3TC andEFV); and

• Last available visit.b) For a subject who achieved a confirmed plasma HIV-1 RNA below 50 copies/mL,

the failure was the earliest time of:

• Death;

• Premature discontinuation of randomized study drugs or matched placebo;

• Introduction of a new ART, except changes to background drugs (i.e., 3TC andEFV);

• Loss to follow up; and

• Confirmed plasma HIV-1 RNA ≥50 copies/mL (i.e., two consecutive visits≥50 copies/mL or one visit ≥50 copies/mL followed by lost to follow-up).


- 10 -

c) If the time of failure defined above was immediately preceded by a single missingscheduled visit or multiple consecutive missing scheduled visits, then the time offailure was replaced by the first time of such missing visits.

d) For all subjects who remained in the trial without experiencing a loss of virologicresponse as defined above by the study termination, the subjects were rightcensored at the time of the last study visit.

1.2.2.2. Secondary efficacy endpoints

The secondary efficacy measures in CNA30021 included:

• Comparison of the proportion of subjects with plasma HIV-1 RNA <50 copies/mL atWeek 48, stratified by baseline plasma HIV-1 RNA;

• Comparison of the proportion of subjects with plasma HIV-1 RNA <50 copies/mL atWeek 48 � As Treated Population;

• Comparison of time to treatment failure using the TLOVR algorithm;

• Comparison of cumulative antiviral efficacy as measured by the integrated decreasein plasma HIV-1 RNA defined as the average area under the plasma HIV-1 RNAcurve minus baseline (AAUCMB) stratified by time on treatment.

• Comparison of immunological effects of treatment via measurement of absolute andcumulative changes (AAUCMB stratified by time on treatment) from baseline inCD4+ cell counts through Week 48; and

• Comparison of disease progression rates via clinical endpoints of HIV-related deathon new Centers for Disease Control and Prevention (CDC) Class C Acquired ImmuneDeficiency Syndrome (AIDS) disease progressions.

For genotype and phenotype analysis in this Summary of Clinical Efficacy described inSection 6, subjects were selected as virologic failure based on the TLOVR algorithm,according to at least one of the following:

• Rebound: Confirmed (two consecutive) plasma HIV-1 RNA values greater than orequal to the lower limit of quantification (LLOQ = 50 copies/mL) after achieving aconfirmed level below the LLOQ during the treatment phase;

• Never Suppressed: Plasma HIV-1 RNA levels never achieved confirmedsuppression with at least 48 weeks of randomized treatment; or

• Insufficient Viral Response: Plasma HIV-1 RNA levels never achieved confirmedsuppression and investigator identified the reason for treatment discontinuation priorto Week 48 due to insufficient plasma HIV-1 RNA response.

1.3. Ongoing GSK-Sponsored Studies

Although not included in this Summary of Clinical Efficacy, there are three ongoingefficacy and safety trials that evaluate ABC 600mg once daily as part of a FDC with


- 11 -

3TC: CAL30001, ESS30008, and ESS30009. Study descriptions and synopses from theongoing GSK-sponsored studies CAL30001, ESS30008, and ESS30009 are provided inthe Tabular Listing of All Clinical Studies in Module 5 (m5, Section 5.2) and Module 2(m2, Section 2.7.6), respectively.

CAL30001 - Use of ABC/3TC FDC once daily compared with ABC twice daily + 3TConce daily in combination with TDF and a new PI or NNRTI, in treatment-experienced HIV-1 infected adults

CAL30001 is a randomized, open-label, parallel group, multicenter study to evaluatetreatment with the ABC/3TC FDC once daily versus ABC (300mg) twice daily and 3TC(300mg) once daily in combination with tenofovir disoproxil fumarate (TDF, Viread�)once daily and a new protease inhibitor (PI) or non-nucleoside reverse transcriptaseinhibitor (NNRTI) for 48 weeks in ART-experienced HIV-1 infected subjects withvirologic failure.

ESS30008 � Use of ABC/3TC FDC once daily compared with ABC + 3TC twice dailyas a component of a triple combination regimen in treatment-experienced HIV-1infected adults

ESS30008 is a 48-week, open-label, randomized, multicenter study of the safety andefficacy of the ABC/3TC FDC administered once daily versus ABC + 3TC administeredtwice daily in combination with a PI or NNRTI in ART-experienced subjects withvirologic suppression and currently receiving ABC and 3TC as single entities. Subjectswere stratified according to PI or NNRTI use and randomized 1:1 to one of two treatmentregimens:

• ABC 300mg twice daily + 3TC 150mg twice daily + baseline PI or NNRTI; or

• ABC 600mg/3TC 300mg FDC once daily + baseline PI or NNRTI.

ESS30009 - Use of ABC/3TC FDC once daily as a component of a triplecombination regimen in treatment-naïve HIV-1 infected adults

ESS30009 is a randomized, open-label, multicenter study of the safety and efficacy ofEFV versus TDF when administered in combination with the ABC/3TC FDC tablet as aonce daily regimen in ART-naïve HIV-1 infected subjects.

Eligible subjects were stratified at entry according to screening plasma HIV-1 RNA level<100,000 copies/mL and ≥100,000 copies/mL, and randomized 1:1 to receive one of thefollowing ART regimens for 48 weeks:

• EFV 600mg once daily + ABC 600mg/3TC 300mg FDC once daily; or

• TDF 300mg once daily + ABC 600mg/3TC 300mg FDC once daily (discontinuedafter interim analyses due to virologic non-response).

� Viread is a Trade Mark of the Gilead.



- 12 -

Shortly after initiation of this study, GSK received reports from investigators of poorvirologic response in patients receiving TDF + ABC/3TC. An unplanned interimanalysis was conducted to assess virologic non-response. These results are presented inthis Summary of Clinical Efficacy, Section 2.3.

2. SUMMARY OF RESULTS OF INDIVIDUAL STUDIES

A tabular listing of studies discussed in this application is provided in Module 5(m5, Section 5.2). A synopsis for each study that contributed data to this submission isprovided in Module 2 (m2, Section 2.7.6). Brief descriptions of study population,demography and efficacy results for studies in this Summary of Clinical Efficacy areshown in Table 4, Table 5, and Table 17.

2.1. Clinical Pharmacology and Biopharmaceutics Studies

2.1.1. CNA10905 � Intracellular Carbovir Triphosphate Study

CNA10905 was an open-label, single arm, pharmacokinetic, pilot study in 20 HIV-1infected subjects who were on a stable 300mg twice daily ABC-containing regimen. Theobserved intracellular CBV-TP concentrations and corresponding pharmacokineticparameters including a geometric mean terminal half-life of 20.64 hours, 95% CI(16.39-25.99h), support the clinical investigation of the use of ABC 600mg once daily forthe treatment of HIV-1 infected patients. The half-life (t1/2) range of CBV-TP forsubjects receiving ABC as ZIAGEN (n=9) was 6.28h-35.42h and for subjects receivingABC as TRIZIVIR (n=11) was 9.56h-48.1h. The intracellular CBV-TP concentrationsaveraged about 2-fold greater than the reported inhibition constant (Ki) value [Daluge,1997] for inhibiting 2-deoxyguanosine-5`-triphosphate (dGTP) incorporation into DNAby HIV-1 reverse transcriptase.

Detailed results of study CNA10905 can be found in the Summary of ClinicalPharmacology in Module 2 (m2, Section 2.7.2).

2.1.2. CAL10001 � ABC/3TC Fixed Dose Combination BioequivalenceStudy

CAL10001 was a single-center, open-label, randomized, single-dose, three-way crossoverstudy conducted with 30 healthy subjects. The ABC/3TC FDC tablet was administeredin the fasted state (Treatment A) and after a high fat, high calorie meal (Treatment C).Treatment B consisted of administration of ABC 600mg as marketed ZIAGEN tablets(2 x 300mg) and of 3TC 300mg as marketed EPIVIR tablets (2 x 150mg) in the fastedstate. Twenty-five of the 30 subjects completed all treatment periods and were includedin the bioequivalence and food effect analyses. Detailed results of biopharmaceuticsstudy CAL10001 can be found in the Summary of Biopharmaceutics Studies in Module 2(m2, Section 2.7.1).


- 13 -

Summary results from the bioequivalence assessment of the ABC/3TC FDC tablet andABC and 3TC given as the marketed ZIAGEN and EPIVIR formulations are providedin Table 3.

Table 3 Summary ABC and 3TC Pharmacokinetic Parameters FollowingSingle-Dose Administration of the ABC/3TC FDC Tablet (600mgABC; 300mg 3TC) Compared to Administration of ZIAGEN (2 x300mg) and EPIVIR (2 x 150mg) (Study CAL10001)

Geometric LS Mean1

PK Parameter Treatment AN=25

Treatment BN=25

Ratio ofGeometricLS Means

(Trt A / Trt B)

90% CIfor Ratio

ABCAUClast (µg●h/mL) 14.12 14.12 1.000 0.955, 1.048AUC∞ (µg●h/mL) 14.15 14.15 1.000 0.954, 1.048Cmax (µg/mL) 4.68 4.94 0.946 0.855, 1.048

3TCAUClast (µg●h/mL) 12.36 13.00 0.951 0.910, 0.995AUC∞ (µg●h/mL) 12.60 13.23 0.952 0.912, 0.994Cmax (µg/mL) 2.64 2.84 0.930 0.865, 0.999LS=least squares, Trt=treatment group.Source Data: Table 13.8, Table 13.9, Table 13.12, and Table 13.13 of CAL10001 Clinical Study Report (CSR).1. Based on log-transformed data.Treatment A = fixed dose combination of abacavir/lamivudine, fasted.Treatment B = ZIAGEN (2 x 300mg) + EPIVIR (2 x 150mg), fasted.

Bioequivalence was established for the ABC/3TC FDC tablet for both ABC and 3TC, asindicated by the 90% CIs for the geometric least square ratios for AUClast, AUC∞, andCmax all being well within the 0.80 to 1.25 equivalence interval. When the ABC/3TCFDC tablet was administered with food, ABC AUClast and AUC∞ were unchangedcompared to administration in the fasted state, but ABC Cmax was reduced byapproximately 24%. For 3TC, the parameters AUClast, AUC∞ and Cmax were not affectedby coadministration with food. The food effects observed on ABC and 3TCpharmacokinetics with the ABC/3TC FDC tablet were consistent with effects seenhistorically with ZIAGEN and EPIVIR, both of which may be administered with orwithout food. Accordingly, the ABC/3TC FDC tablet may be given without regard tomeals.


- 14 -

2.2. Pivotal Clinical Study CNA30021


Additional details of the study results are provided in the CNA30021 Clinical StudyReport [GSK Document Number RM2002/00296/00] in Module 5 (m5, Section 5.3.5.1).

2.2.1. Study Population

2.2.1.1. Subject accountability

Subject disposition for pivotal clinical study CNA30021 is presented in Table 4.

Table 4 Subject Disposition (All Randomized Subjects - CNA30021)

ABC OADn (%)

ABC BIDn (%)

Totaln (%)

Total Randomized (N) 392 392 784 Not treated 8 6 14Treated 384 386 770

Completed 290 (76%) 294 (76%) 584 (76%)Discontinued 94 (24%) 92 (24%) 186 (24%)

<48 weeks of treatment 58 (15%) 63 (16%) 121 (16%) >48 weeks of treatment1 36 (9%) 29 (8%) 65 (8%)Reason for Discontinuation

Number discontinued 94 92 186Adverse event 22 (23%) 25 (27%) 47 (25%)Consent withdrawn 12 (13%) 9 (10%) 21 (11%)Lost to follow-up 32 (34%) 35 (38%) 67 (36%)Clinical progression 1 (1%) 1 (1%) 2 (1%)Protocol violation 4 (4%) 2 (2%) 6 (3%)Insufficient plasma HIV-1RNA response 6 (6%) 5 (5%) 11 (6%)Other 17 (18%) 15 (16%) 32 (17%)

Source Data: Table 12.3 and Table 12.5 of CNA30021 CSR.1. Subjects who discontinued after 48 weeks of treatment may have been counted as responders at the 48-

Week analysis.

A total of 784 adult subjects were randomized to receive either ABC 600mg once daily(N=392) or ABC 300mg twice daily (N=392) in combination with 3TC and EFV. Of allsubjects randomized, 14 (2%) never initiated treatment; eight of these subjects wererandomized to the ABC once daily group and six subjects to the ABC twice daily group.A total of 584 (76%) subjects completed at least 48 weeks of study treatment (defined as295 days of study treatment); the total included 290 (76%) subjects in the ABC oncedaily group and 294 (76%) subjects in the ABC twice daily group. Reasons forpremature discontinuation were captured on the end of study record and were comparablewith 24% discontinued from the study in each group.


- 15 -

Further information on subject accountability can be found in the CNA30021 ClinicalStudy Report in Module 5 (m5, Section 5.3.5.1).

2.2.1.2. Demographics and baseline characteristics

Key baseline and demographic characteristics for the ITT-Exposed Population for studyCNA30021 are presented in Table 5.


- 16 -

Table 5 Key Baseline & Demographic Characteristics(ITT-Exposed Population - CNA30021)

CharacteristicABC OAD

N=384ABC BID

N=386Total

N=770Age in Years, median (min, max) 36 (18, 71) 36 (18, 71) 36 (18, 71)Gender, n (%)

FemaleMale

61 (16%)323 (84%)

82 (21%)304 (79%)

143 (19%)627 (81%)

Race, n (%)WhiteBlackAmerican HispanicAsianOther

207 (54%)99 (26%)60 (16%)10 (3%)8 (2%)

207 (54%)111 (29%)55 (14%)

8 (2%)5 (1%)

414 (54%)210 (27%)115 (15%)18 (2%)13 (2%)

Randomization Strata, n (%)HIV-1 RNA ≤100,000 copies/mLHIV-1 RNA >100,000 copies/mL

217 (57%)167 (43%)

217 (56%)169 (44%)

434 (56%)336 (44%)

Baseline CD4+ Cell Count, n (%) <200 cells/mm3 130 (34%) 109 (29%) 239 (31%) 200 � 350 cells/mm3 144 (38%) 171 (44%) 315 (41%) >350 cells/mm3 109 (28%) 105 (27%) 214 (28%)Baseline Values, median (range)

HIV-1 RNA PCR (log10 copies/mL)HIV-1 RNA PCR (copies/mL) (range)CD4+ cell count (cells/mm3)

4.91 (3.05�6.99)81,684

(1,127-9,872,576)264 (21.0-918)

4.87 (2.60-6.59)74,894

(399-3,893,696)259 (37.0-886)

4.89 (2.60-6.99)78,521

(399-9,872,576)262 (21.0-918)

CDC Classification of HIV, n (%) Class A � asymptomatic 298 (78%) 285 (74%) 583 (76%) Class B � symptomatic, no AIDS 63 (16%) 70 (18%) 133 (17%) Class C � AIDS 23 (6%) 30 (8%) 53 (7%) Missing 0 1 (<1%) 1 (<1%)Confirmed Hepatitis, n (%) Hepatitis B surface antigen 18 (5%) 16 (4%) 34 (4%) Hepatitis C antibody 55 (14%) 47 (12%) 102 (13%) Hepatitis B & C co-infected 2 (<1%) 1 (<1%) 3 (<1%)Other Non-CDC HIV-1 AssociatedCondition, n (%) Yes 9 (2%) 21 (5%) 30 (4%)Source Data: Table 12.9, Table 12.10, Table 12.12, Table 12.13, and Table 12.14 of CNA30021 CSR.PCR=polymerase chain reaction

In the ITT-Exposed Population, 81% of subjects were male and the overall age range was18 to 71 years. At baseline, the median plasma HIV-1 RNA was 4.89 log10 copies/mL(range 2.60 to 6.99 log10 copies/mL) and median CD4+ cell count was 262 cells/mm3

(range 21 to 918 cells/mm3). Demographic and baseline characteristics were


- 17 -

well-balanced across the treatment groups, with a slight majority of Whites (54%) andsubjects with plasma HIV-1 RNA ≤100,000 copies/mL (56%) enrolling in the study.

2.2.2. Primary and Selected Secondary Efficacy Results

2.2.2.1. Virologic response/plasma HIV-1 RNA <50 copies/mL at Week 48 inCNA30021

The statistical evaluation of non-inferiority of virologic response at Week 48 based onplasma HIV-1 RNA <50 copies/mL for the ITT-Exposed Population is presented in Table6.

Table 6 Statistical Evaluation of Non-inferiority of Virologic Response atWeek 48 Based on Plasma HIV-1 RNA <50 copies/mL using theTLOVR Algorithm (ITT-Exposed Population - CNA30021)

StrataABC OAD

N=384n/N (%)

ABC BIDN=386n/N (%)

PointEstimate (%)

95%Confidence

IntervalStratified -1.7 -8.4, 4.9 ≤100,000 copies/mL 141/217 (65%) 145/217 (67%) -1.8 -10.8, 7.1 >100,000 copies/mL 112/167 (67%) 116/169 (69%) -1.6 -11.6, 8.4Unstratified -1.7 -8.4, 4.9 Total 253/384 (66%) 261/386 (68%)Source Data: Table 13.1 of CNA30021 CSR.

For the ITT-Exposed Population, 66% of subjects in the ABC once daily group,compared to 68% of subjects in the ABC twice daily group, achieved a virologicresponse of plasma HIV-1 RNA <50 copies/mL by Week 48. Subjects were stratified atbaseline based on plasma HIV-1 RNA ≤100,000 copies/mL or >100,000 copies/mL. Asshown in Table 6, the stratified two-sided 95% CI (-8.4%, 4.9%) demonstrates the non-inferiority of the ABC once daily treatment group as compared to the ABC twice dailytreatment group irrespective of baseline plasma HIV-1 RNA, because it excludes thepredefined non-inferiority margin of �12%. A total of 67% (112/167) and 69% (116/169)of subjects with high viral load (≥100,000 copies/mL) achieved a virologic response atWeek 48 in the ABC once daily and ABC twice daily groups, respectively (ITT-ExposedPopulation). The two-sided 95% CI (-11.6%, 8.4%) in this subgroup supports the non-inferiority of the ABC once daily treatment group as compared to the ABC twice dailytreatment group. The reduced number of subjects in the high plasma HIV-1 RNA stratasub-group accounts for the wider CI.

As with the primary analysis, similar proportions of ITT-Exposed subjects had plasmaHIV-1 RNA <400 copies/mL throughout the study when comparing once daily dosing ofABC to twice daily dosing in the ITT-Exposed, TLOVR analysis. A total of 72% ofsubjects in each treatment arm achieved virologic responses based on plasma HIV-1RNA <400 copies/mL by Week 48 (Table 13.50 of CNA30021 CSR).


- 18 -

The statistical evaluation of non-inferiority of the proportion of subjects with plasmaHIV-1 RNA <50 copies/mL at Week 48 for the As-Treated Population is shown inTable 13.7 and presented in Table 7.

Table 7 Statistical Evaluation of Non-inferiority Based on the Proportion ofSubjects with Plasma HIV-1 RNA <50 copies/mL at Week 48(As-Treated Population - CNA30021)

StrataABC OAD

N=266n/N (%)

ABC BIDN=265n/N (%)

PointEstimate

(%)

95%Confidence

IntervalStratified 0.4 -5.3, 6.2 ≤100,000 copies/mL 132/145 (91%) 126/145 (87%) >100,000 copies/mL 99/121 (82%) 103/120 (86%)Unstratified 0.4 -5.4, 6.2 Total 231/266 (87%) 229/265 (86%)Source Data: Table 13.7 of CNA30021 CSR.

As-Treated subjects were stratified based on plasma HIV-1 RNA ≤100,000 copies/mL or>100,000 copies/mL at screening. The stratified two-sided 95% CI (-5.3%, 6.2%) atWeek 48 supports the non-inferiority of the ABC once daily group compared to the ABCtwice daily group (Table 13.7 of CNA30021 CSR).


- 19 -

The proportion of subjects with plasma HIV-1 RNA <50 copies/mL by study week usingthe TLOVR Algorithm (ITT-Exposed Population) is presented in Figure 1.

Figure 1 Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL byStudy Week using the TLOVR Algorithm(ITT-Exposed Population - CNA30021)

Source Data: Figure 13.3 of CNA30021 CSRNote: q.d. = once daily.Responders at each visit were subjects who had achieved and maintained plasma HIV-1 RNA <50 copies/mL withouttreatment discontinuation by that visit.

The proportion of subjects with plasma HIV-1 RNA <50 copies/mL by study week usingthe TLOVR Algorithm (As-Treated Population) is presented in Figure 2.


- 20 -

Figure 2 Proportions of Subjects with Plasma HIV-1 RNA <50 copies/mL byStudy Week (As Treated Population - CNA30021)

Study Week

BL W2 W4 W8 W12 W24 W36 W48 W60 W72ABC OAD 384 341 326 317 314 300 288 266 136 45ABC BID 386 340 339 333 326 311 294 265 144 36

0102030405060708090

100

BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

% R

espo

nder

ABC once daily ABC twice daily

Source Data: Figure 13.5 of CNA30021 CSR.

Similar proportions of subjects had plasma HIV-1 RNA <50 copies/mL throughout thestudy when comparing once daily dosing of ABC to twice daily dosing in theITT-Exposed, TLOVR analysis and the As-Treated analysis (Figure 1 and Figure 2,respectively).


- 21 -

2.2.3. Other Secondary Efficacy Results

2.2.3.1. Treatment outcomes based on time to loss of virologic response

Kaplan-Meier estimates for plasma HIV-1 RNA response <50 copies/mL based onTLOVR are shown in Figure 3.

Figure 3 Time to Loss of Virologic Response(ITT-Exposed Population � CNA30021)

Source Data: Figure 13.1 of CNA30021 CSR.Note: q.d. = once daily.Numbers represent the total number of subjects remaining on randomized treatment at a specified timepoint, plusnumber of subjects who previously reached a failure endpoint.

The time to loss of virologic response was comparable in each treatment group over72 weeks.


- 22 -

Treatment outcomes at Week 48

Treatment outcomes (TLOVR analysis) at Week 48 are summarized in Table 8 for theITT-Exposed Population with plasma HIV-1 RNA <50 copies/mL and <400 copies/mL.

Table 8 Summary of Treatment Outcomes at Week 48 (based on TLOVR) forPlasma HIV-1 RNA <50 copies/mL and <400 copies/mL(ITT-Exposed Population - CNA30021)

ABC OADN=384n (%)

ABC BIDN=386n (%)Outcome

<50copies/mL,

n (%)

<400copies/mL,

n (%)

<50copies/mL,

n (%)

<400copies/mL,

n (%)Responder 253 (66%) 276 (72%) 261 (68%) 279 (72%)Virologic Failure 38 (10%) 15 (4%) 32 (8%) 16 (4%)

Rebound 9 (2%) 10 (3%) 8 (2%) 12 (3%)Never suppressed through Week48

27 (7%) 3 (<1%) 21 (5%) 2 (<1%)

Insufficient plasma HIV-1 RNAresponse1

2 (<1%) 2 (<1%) 3 (<1%) 2 (<1%)

Discontinued or changed therapydue to AE 50 (13%) 50 (13%) 42 (11%) 42 (11%)Discontinued or changed therapydue to other reasons

43 (11%) 43 (11%) 51 (13%) 49 (13%)

Consent withdrawn 10 (3%) 10 (3%) 10 (3%) 10 (3%)Lost to follow-up 20 (5%) 20 (5%) 23 (6%) 22 (6%)Protocol violation 1 (<1%) 1 (<1%) 2 (<1%) 2 (<1%)Insufficient CD4+ Response 0 0 0 0Clinical progression 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%)Change of ART2 2 (<1%) 2 (<1%) 1 (<1%) 1 (<1%)Other 9 (2%) 9 (2%) 14 (4%) 13 (3%)

Source Data: Table 13.5 and Table 13.50 of CNA30021 CSR.1. As recorded on the treatment discontinuation CRF page.2. Excluding changes to background medications (3TC and EFV).

Virologic failure rates were low and similar in both treatment groups.Withdrawals/discontinuations, when they occurred, were most likely due to an AE amongsubjects in either treatment group (13% ABC once daily, 11% ABC twice daily). Elevenpercent (43/384) of subjects in the ABC once daily group and 13% (51/386) of subjectsin the ABC twice daily group discontinued treatment due to other reasons. Overall, therewere no apparent treatment-related trends in reasons for treatment discontinuation.


- 23 -

2.2.3.2. Cumulative antiviral efficacy

Median plasma HIV-1 RNA and change from baseline

The observed plasma HIV-1 RNA values and change from baseline in plasma HIV-1RNA values over 48 weeks for the ITT-Exposed Population are presented in Table 9.

Table 9 Summary of Median Plasma HIV-1 RNA (log10 copies/mL)and Change from Baseline(ITT-Exposed Population, Observed - CNA30021)

StudyABC OAD

N=384ABC BID

N=386Week N Median

(log10copies/mL)

Changefrom

Baseline

N Median(log10

copies/mL)

Changefrom

BaselineBaseline 384 4.91 386 4.87Week 2 366 2.84 -2.06 356 2.81 -2.04Week 4 361 2.51 -2.33 362 2.48 -2.33Week 8 358 2.04 -2.75 362 2.01 -2.65Week 12 352 1.691 -3.01 357 1.69 -2.91Week 24 335 1.69 -3.15 342 1.69 -3.13Week 36 323 1.69 -3.18 321 1.69 -3.16Week 48 315 1.69 -3.13 314 1.69 -3.15Source Data: Table 13.11 and Table 13.12 of CNA30021 CSR.1. The lower limit of quantification (LLOQ) of the assay was 50 copies/mL or 1.69 log10 copies/mL.

In the ITT-Exposed Population, there was a median reduction of approximately2 log10 copies/mL in plasma HIV-1 RNA by Week 2 in both treatment groups(Table 13.11 of CNA30021 CSR). By Week 12, median plasma HIV-1 RNAconcentrations had decreased to the lower limit of detection of the assay (50 copies/mL or1.69 log10 copies/mL) in both treatment groups and this was maintained throughWeek 48.

Median changes from baseline in plasma HIV-1 RNA were comparable betweentreatment groups at each time point (Table 13.12 of CNA30021 CSR).

Plasma HIV-1 RNA AAUCMB at Week 48

The 95% CI on median difference of plasma HIV-1 RNA AAUCMB at Week 48 arepresented by strata for the ITT-Exposed Population in Table 10.


- 24 -

Table 10 Median Plasma HIV-1 RNA (log10 copies/mL) AAUCMB at Week 48(ITT-Exposed Population, Observed - CNA30021)

Strata ABC OADN=384

ABC BIDN=386

MedianDifference(ABC OAD-ABC BID)

95% CI

n Median n Median≤100,000 copies/mL 216 -2.49 213 -2.47 -0.03 -0.14, 0.09>100,000 copies/mL 166 -3.21 168 -3.18 -0.02 -0.13, 0.09Total 382 -2.84 381 -2.76 -0.03 -0.13, 0.07Source Data: Table 13.15 and Table 13.16 of CNA30021 CSR.

Median plasma HIV-1 RNA AAUCMB values were comparable between treatmentgroups through Week 48 (ABC once daily: -2.84 log10 copies/mL; ABC twice daily:-2.76 log10 copies/mL).

2.2.3.3. Immunologic efficacy

Median CD4+ cell count and change from baseline

The median changes in CD4+ cell counts by study week through Week 48 are shown inFigure 4.

Figure 4 Median CD4+ Cell Count Change from Baseline (cells/mm3) throughWeek 48 (ITT-Exposed Population, Observed - CNA30021)

0

50

100

150

200

BL 4 8 12 16 20 24 28 32 36 40 44 48

Study Week

Med

ian

CD

4+ C

ell C

ount

C

hang

e fr

om B

L

ABC once daily ABC twice daily

Source Data: Table 13.21 of CNA30021 CSR.


- 25 -

Median CD4+ cell counts at Week 48 were comparable in both treatment groups, being468 cells/mm3 in the ABC once daily group and 471 cells/mm3 in the ABC twice dailygroup. Median change from baseline in CD4+ cell counts at Week 48 was+188 cells/mm3 in the ABC once daily group and +200 cells/mm3 in the ABC twice dailygroup (Table 13.20 and Table 13.21 of CNA30021 CSR).

2.2.3.4. Other efficacy results

Virologic genotypic and phenotypic data for pivotal clinical study CNA30021 aresummarized in Section 6 of this Summary of Clinical Efficacy and presented in detail inModule 5 (m5, Section 5.3.5.4).

Clinical disease progression

The majority of subjects did not progress in their disease status (98% in the ABC oncedaily group and 97% in the ABC twice daily group). A low proportion of subjects inboth groups progressed from Class A or B to death (ABC once daily, two subjects; ABCtwice daily, three subjects).

2.3. Ongoing GSK-Sponsored Studies

Studies CAL30001 and ESS30008 are currently ongoing; there are no efficacy data toreport for these studies at this time.

Shortly after initiation of study ESS30009, GSK received reports from investigators ofpoor virologic response in patients receiving TDF + ABC/3TC. An unplanned interimanalysis was conducted to assess virologic non-response, defined as either:

a) Failure to achieve a 2 log10 copies/mL decrease from baseline by treatmentWeek 8; or

b) A 1 log10 copies/mL increase above nadir on any subsequent treatment visit.

The primary objectives of the ESS30009 study are:

• To compare the efficacy of EFV once daily versus TDF once daily whenadministered in combination with ABC/3TC FDC once daily over 48 weeks inART-naïve HIV-1 infected subjects; and

• To compare the safety and tolerability of EFV once daily versus TDF once dailywhen administered in combination with ABC/3TC FDC once daily over 48 weeksin ART-naïve HIV-1 infected subjects.


- 26 -

Interim analysis

Results of the ESS30009 interim analysis are shown in Table 11.

Table 11 Proportion of Subjects Meeting the Definition of VirologicNon-Response (ESS30009)

Number (%) of Subjects Meeting the Definitionof Virologic Non-Response

TDF + ABC/3TCn/N (%)

EFV + ABC/3TCn/N (%)

Plasma HIV-1 RNA data forsubjects on therapy for ≥8 weeks

50/102 (49%) 5/92 (5%)

Plasma HIV-1 RNA data forsubjects on therapy for ≥12 weeks

30/63 (48%) 3/62 (5%)

Preliminary genotypes of viral isolates among some subjects with non-response takingthe TDF + ABC/3TC regimen have shown the K65R mutation in addition to the M184Vmutation in HIV reverse transcriptase in 8 of 14 (57%) isolates genotyped to date.

On review of these results, the TDF + ABC/3TC group in this study was terminated andthe protocol was amended. Patients changed therapy based on genotype and clinicalacumen. The once daily EFV + ABC/3TC group performed well and continuesunchanged.

Data from study ESS30009 relates to the use of TDF + ABC/3TC as triple antiretroviraltherapy and the nature of any interaction between the components of this regimen isbeing investigated. This study indicates that ABC/3TC should not be used with TDF aspart of triple anti-retroviral therapy. Other studies included in this and previoussubmissions (ZIAGEN NDA 20-977; EPIVIR NDA 20-564) indicate that ABC/3TC canbe effectively used as a nucleoside backbone with other third agents from the PI,nucleoside reverse transcriptase inhibitor (NRTI) (ZDV, stavudine [d4T, Zerit�]), andNNRTI class of drugs.

3. COMPARISON AND ANALYSES OF RESULTS ACROSSSTUDIES

No formal comparisons and analyses of results across studies were completed for thisSummary of Clinical Efficacy. However, results of subgroup analyses are provided fromthe pivotal study CNA30021 in Section 3.3, �Comparison of Results in Sub-Populations.�

� Zerit is a Trade Mark of Bristol-Myers Squibb Company.



- 27 -

3.1. Study Populations

Since one pivotal study (CNA30021) is included in this submission, no comparison ofstudy populations is provided. Information on individual study populations can be foundin Section 2.2.1 for the pivotal study CNA30021.

3.2. Comparison of Efficacy Results of All Studies

Since the only efficacy study included in this submission is CNA30021, no information isprovided.

3.3. Comparison of Results in Sub-Populations

Subgroup analyses of efficacy results by gender, age, race, baseline CD4+ cell countcategories (<200, 200-350, >350 cells/mm3), and country are provided from the pivotalstudy CNA30021. No differences in efficacy were seen when analyzing sub-populationsby gender, age, race, baseline CD4+ cell count and country for the pivotal studyCNA30021.

3.3.1. Pivotal Study CNA30021

CNA30021 - Use of ABC once daily compared with twice daily in combination with3TC and EFV once daily in treatment-naïve HIV-1 infected adults

3.3.1.1. Gender analysis

An analysis by gender of the proportion of subjects with plasma HIV-1 RNA<50 copies/mL at Week 48 is summarized in Table 12.

Table 12 Summary of Proportion of Subjects with Plasma HIV-1 RNA<50 copies/mL by Gender at Week 48 (Based on TLOVR)(ITT-Exposed Population - CNA30021)

Treatment Group All Subjectsn/N (%)

Malen/N (%)

Femalen/N (%)

ABC OAD 253/384 (66%) 216/323 (67%) 37/61 (61%)ABC BID 261/386 (68%) 215/304 (71%) 46/82 (56%)Source Data: Table 13.57 of CNA30021 CSR.

Odds ratios comparing response rates at Week 48 for the two treatment groups whilecontrolling for gender were computed based on Mantel-Haenszel methods. These oddsratios for gender were consistent with the overall study results (Table 13.59 ofCNA30021 CSR). Based on the Breslow-Day test results, there was no evidence of atreatment difference with respect to gender.

Gender analysis was conducted for plasma HIV-1 RNA AAUCMB and CD4+ cell countAAUCMB in CNA30021. Results are summarized in Table 13.


- 28 -

Table 13 Plasma HIV-1 RNA (log10 copies/mL) and CD4+ Cell Count(cells/mm3) AAUCMB at Week 48 by Gender(ITT-Exposed Population, Observed - CNA30021)

ABC OADN=384

ABC BIDN=386

Measure/ Gender N Median Range N Median RangePlasma HIV-1 RNAAAUCMB, log10 copies/mL Male 322 -2.86 -4.74, 0.07 302 -2.79 -4.39, 0.15 Female 60 -2.72 -3.71, -0.12 79 -2.65 -4.10, -0.18 Total 382 -2.84 -4.74, 0.07 381 -2.76 -4.39, 0.15CD4+ AAUCMB, cells/mm3

Male 320 137.8 -122.9, 602.9 301 145.6 -148.6, 493.5 Female 60 135.6 6.9, 499.6 79 126.6 -243.1, 527.5 Total 380 137.4 -122.9, 602.9 380 141.6 -243.1, 527.5Source Data: Table 13.17 and Table 13.30 of CNA30021 CSR.

There were no clinically significant differences between treatment groups within gendercategories for median plasma HIV-1 RNA or CD4+ cell count AAUCMB values throughWeek 48.

3.3.1.2. Age analysis

An analysis by age (≤35 years, >35 years) of the proportion of subjects with plasmaHIV-1 RNA <50 copies/mL at Week 48 is summarized in Table 14.

Table 14 Summary of Proportion of Subjects with Plasma HIV-1 RNA<50 copies/mL by Age at Week 48 (Based on TLOVR)(ITT-Exposed Population � CNA30021)

Age Group(years)

ABC OADn/N (%)

ABC BIDn/N (%)

Breslow-Day Testp value

≤30 59/102 (58%) 73/111 (66%) 0.290>30 194/282 (69%) 188/275 (68%)≤35 102/181 (56%) 120/180 (67%) 0.018>35 151/203 (74%) 141/206 (68%)≤40 159/260 (61%) 173/258 (67%) 0.070>40 94/124 (76%) 88/128 (69%)

Source Data: Table 18 in Appendix

The results of the Breslow-Day test in the age subgroups indicate lack of homogeneity ofresponse between subjects 35 and those >35 years of age. The response rate was morefavorable for subjects 35 years of age taking ABC twice daily, while it was morefavorable for subjects >35 years of age taking ABC once daily. These differences inresponse rates were driven by reasons other than virologic failure (Table 19 inAppendix). For age categories above and below 30 and 40 years, no significantdifferences were seen. Furthermore, when the analyses described above were performed


- 29 -

for the As-Treated Population, no significant Breslow-Day results were found (Table 20in Appendix). Overall, findings from the sub-analyses by age groups are unlikely to beclinically relevant.

3.3.1.3. Race analysis

An analysis by race of the proportion of subjects with plasma HIV-1 RNA<50 copies/mL at Week 48 is summarized in Table 15.

Table 15 Summary of Proportion of Subjects with Plasma HIV-1 RNA<50 copies/mL by Race at Week 48 Based on TLOVR Algorithm(ITT-Exposed Population - CNA30021)

TreatmentGroup

All Subjectsn/N (%)

Whiten/N (%)

Blackn/N (%)

Hispanicn/N (%)

Othern/N (%)

ABC OAD 253/384 (66%) 135/207 (65%) 61/99 (62%) 47/60 (78%) 10/18 (56%)ABC BID 261/386 (68%) 146/207 (71%) 66/111 (59%) 39/55 (71%) 10/13 (77%)Source Data: Table 13.56 of CNA30021 CSR.

A total of 46% of subjects were non-White. Odds ratios comparing response rates atWeek 48 for the two treatment groups while controlling for race were computed based onMantel Haenszel methods. These odds ratios for race were consistent with the overallstudy results (Table 13.59 of CNA30021 CSR). Based on the Breslow-Day test results,there was no evidence of a treatment difference with respect to race.

3.3.1.4. CD4+ cell count analysis

An analysis of the proportion of subjects with plasma HIV-1 RNA <50 copies/mL atWeek 48 by baseline CD4+ cell count categories (<200, 200-350, >350 cells/mm3) issummarized in Table 16 for CNA30021.

Table 16 Summary of Proportion of Subjects with Plasma HIV-1 RNA<50 copies/mL by Baseline CD4+ Cell Count (cells/mm3) at Week 48Based on TLOVR Algorithm (ITT-Exposed Population - CNA30021)

TreatmentGroup

All Subjectsn/N (%)

<200n/N (%)

200-350n/N (%)

>350n/N (%)

Missingn/N (%)

ABC OAD 253/384 (66%) 80/130 (62%) 102/144 (71%) 71/109 (65%) 0/1 (0%)ABC BID 261/386 (68%) 70/109 (64%) 114/171 (67%) 76/105 (72%) 1/1 (100%)

Source Data: Table 13.3 and Table 13.4 of CNA30021 CSR.

When summarized by CD4+ cell count groups (<200 cells/mm3, 200-350 cells/mm3, and>350 cells/mm3), the proportion of subjects with virologic response based on plasmaHIV-1 RNA <50 copies/mL through Week 48 for the ITT-Exposed Population wascomparable between the two treatment groups (Table 13.4 of CNA30021 CSR).


- 30 -

3.3.1.5. Country analysis

The proportion of subjects with virologic response based on plasma HIV-1 RNA<50 copies/mL through Week 48 for the ITT-Exposed Population is summarized bycountry in Table 13.58 of CNA30021 CSR. The statistical test results are provided inTable 13.59 of CNA30021 CSR.

Odds ratios comparing response rates at Week 48 for the two treatment groups whilecontrolling for country were computed based on Mantel Haenszel methods. These oddsratios for country were consistent with the overall study results (Table 13.59 ofCNA30021 CSR). Based on the Breslow-Day test results, there was no evidence of atreatment difference with respect to country.

4. ANALYSIS OF CLINICAL INFORMATION RELEVANT TODOSING RECOMMENDATIONS

The ABC/3TC FDC tablet is indicated for the treatment of HIV-1 infection incombination with other ART. The recommended oral dose for the ABC/3TC FDC tabletsfor adults and adolescents weighing ≥40kg is one tablet administered once a day.

EPIVIR is indicated for the treatment of HIV infection, in combination with other ART,at a dose of 300mg daily, administered as either 150mg twice daily or 300mg once daily.Dosage reductions are recommended for patients with impaired renal function (creatinineclearance <50 mL/min). 3TC can be administered with or without food. Therecommended oral dose for adolescents and pediatric patients from 3 months up to16 years of age is 4mg/kg (150mg maximum) twice daily, administered as EPIVIR OralSolution. Because of potential phosphorylation interactions, coadministration of 3TC andzalcitabine (ddC, Hivid�) is not recommended.

Currently approved ZIAGEN dosing recommendations for the treatment of HIVinfection in adults are for administration of 300mg twice daily, with or without food, incombination with other ART. The recommended oral dose for pediatric and adolescentpatients from 3 months up to 16 years of age is 8mg/kg (300mg maximum) twice daily,administered as ZIAGEN Oral Solution. ZIAGEN is contraindicated in patients withmoderate or severe liver impairment, and dose reduction to 200mg twice daily viaZIAGEN Oral Solution administration is recommended in patients with mild hepaticimpairment (Child-Pugh score 5-6).

Clinical information presented in this submission supports the administration of theABC/3TC FDC tablet once daily for use in the treatment of HIV infection. This supportis primarily provided by the clinical pharmacology study CNA10905, the bioequivalencestudy CAL10001, and the pivotal efficacy study CNA30021.

� Hivid is a Trade Mark of Roche Company.



- 31 -

Clinical pharmacology study CNA10905 demonstrated a prolonged intracellular half-life(>20 hours) of CBV-TP, the active anabolite of ABC, which supports once daily dosingof ABC.

Study CAL10001 established the bioequivalence of the ABC/3TC FDC tablet and themarketed ZIAGEN and EPIVIR formulations. The effect of food on the bioavailabilityof ABC and 3TC from administration of the ABC/3TC FDC tablet was consistent withhistorical results for ZIAGEN and EPIVIR tablets; indicating that, as with the marketedformulations, the ABC/3TC FDC tablet may be taken with or without food.

The efficacy of ABC 600mg once daily dosing was demonstrated in the pivotal efficacystudy CNA30021, which confirmed the non-inferiority of the ABC 600mg once dailyregimen versus the ABC 300mg twice daily regimen.

Because of the fixed dose nature of the ABC/3TC tablet, the separate marketedformulations of ZIAGEN and EPIVIR should be used when weight-based dosing isrequired (e.g., pediatrics) or when dosage adjustments are required.

5. PERSISTENCE OF EFFICACY AND/OR TOLERANCEEFFECTS

For the pivotal study, CNA30021, conducted in ART-naïve subjects, results are presentedin this Summary of Clinical Efficacy through 48 weeks of treatment, and in somesubjects up to 72 weeks. There was no evidence of the need for dose escalation overtime. The data presented in this summary reflect the long-term efficacy of ABC + 3TC +EFV once daily in this patient population.

The durability of ABC in combination with 3TC + EFV is further supported by the dataFigure 3 shown in , which presents a Kaplan-Meier plot of the time to loss of virologicresponse (≥50 copies/mL) for the ITT-Exposed Population. Subjects receiving ABConce daily had a favorable antiviral response that was sustained throughout the durationof the study and beyond Week 48 and was comparable to that of subjects receiving ABCtwice daily.

ART drugs are not associated with pharmacological tolerance.

6. ANALYSIS OF VIROLOGIC GENOTYPE ANDPHENOTYPE IN ABACAVIR CLINICAL TRIALS

6.1. Pivotal Study CNA30021


The virology sub-study population from clinical study CNA30021 consisted of twooverlapping subsets from the ITT-Exposed population. A random sample of 196 subjects(ABC once daily, n=97/384; ABC twice daily, n=99/386) representative of the


- 32 -

ITT-Exposed Population was selected for a baseline survey of genotypes. The secondpopulation consisted of 70 subjects who met the definition of virologic failure (ABC oncedaily, n=38; ABC twice daily, n=32). The virologic failure population was evaluated atbaseline and, whenever possible, at the point of virologic failure for viral genotype andphenotypic susceptibility to NRTIs and NNRTIs.

Genotypes and most phenotypes (phenotyping failed for two subjects) were successfullyobtained at baseline for the 70 subjects in the virologic failure population. For technicalreasons, genotyping and phenotyping were restricted to those samples with >500 copiesplasma HIV-1 RNA/mL. Only 31/70 subjects had >500 copies/mL of plasma HIV-1RNA at time of failure (n=29) or at a later time point (n=2), split equally between thegroups (ABC once daily: 16; ABC twice daily: 15). Genotypes were obtained for all ofthese subjects both at baseline and post-baseline.

Further details are provided in the CNA30021 Virology Report (GSK Document NumberSM2003/00014/00 in Module 5 [m5, Section 5.3.5.4]).

6.1.1. Genotypic Results

Comparison of baseline genotype distributions

The number of subjects with NRTI and/or NNRTI mutations at baseline in the RandomSample was low in both groups (ABC once daily: n=6; ABC twice daily: n=9), and wascomprised of single mutations (n=13) or double mutations (n=2). Notably six sampleshad detectable K103N virus and one had detectable M184V at baseline, yet none of thesesubjects were virologic failures (5 responded, 2 discontinued for non-virologic reasons).

For the virologic failure population with on-therapy genotypes, baseline mutations weredetected in plasma from 5 of 16 subjects receiving ABC once daily and in 2 of15 subjects receiving ABC twice daily. Furthermore, three subjects in the ABC oncedaily group and one in the ABC twice daily group had virus with three or moremutations.

Comparisons of on-therapy genotype distributions

The most prevalent mutations to emerge during therapy were M184V (n=15), K103N(n=14), and L74V (n=8). Selection for other NRTI resistance-associated mutations wasinfrequent (K65R: n=1, Y115F: n=2, thymidine analogue mutations [TAMs]: n=2).Other NNRTI resistance-associated mutations selected included L100I (n=2), V108I(n=1), Y181C (n=2), Y188H (n=1), Y188L (n=1), G190A/S (n=2) and P225H (n=2).

Overall, post-baseline in the virologic failure population, there were 14 of 16 subjects inthe ABC once daily group with NRTI or NNRTI resistance-associated mutations versus10 of 15 subjects in the ABC twice daily group. There was a low overall incidence ofvirologic failure in both the once daily and twice daily treatment groups. This togetherwith the low plasma HIV-1 RNA at time of virologic failure resulted in a small samplesize in the virology analysis. Due to the small number of evaluable subjects and lack ofapparent treatment differences, no firm conclusions can be drawn regarding differencesbetween the two treatment groups. Selection of NRTI-associated resistance during


- 33 -

therapy with ABC once daily is characterized mainly by the M184V mutation, selectionof which might be influenced by the additional presence of 3TC.

6.1.2. Phenotypic Results

Phenotypic data were obtained from 68/70 subjects at baseline and from a total of29/32 subjects on-therapy (ABC once daily: 16/16; ABC twice daily: 13/16). In general,the phenotypic data were consistent with the genotypic data. Resistance against studydrugs was most prevalent against EFV in both groups (resistance to EFV: ABC oncedaily: 12/16; ABC twice daily: 8/13). Resistance to 3TC and ABC was also observed(resistance to 3TC: ABC once daily: 10/16; ABC twice daily: 4/13; resistance to ABC:ABC once daily: 3/16; ABC twice daily: 2/13). Despite the selection of M184V in amajority of subjects, resistance to ABC was observed in relatively few subjects;additional mutations appeared to be required. All subjects in the virologic failurepopulation retained activity against TDF, ZDV and d4T.

6.1.3. Relationship of On-Therapy Genotype to Plasma HIV-1 RNAResponse

On-therapy genotypes could not be obtained from the majority (56%) of subjects withvirologic failure due to low plasma HIV-1 RNA. Most subjects failing with mutations inboth groups showed some level of plasma HIV-1 RNA reduction relative to baseline atthe point of failure.

6.1.4. Predictors of Virologic Failure

Logistic regression modeling found that the treatment group (ABC once daily vs.ABC twice daily) was not predictive of virologic failure, but for the group of all virologicfailures and for the non-responder group, high baseline plasma HIV-1 RNA(i.e., ≥100,000 copies/mL) was predictive of failure.

EFFICACY CONCLUSIONS

The results of study CNA10905, which investigated the intracellular pharmacokinetics ofCBV-TP, were consistent with two published studies and showed that the terminalhalf-life of CBV-TP was sufficiently long to support the clinical use of ABC 600mg oncedaily in treatment regimens (geometric mean t1/2 = 20.64 hours, 95% CI: 16.39, 25.99h).Bioequivalence study CAL10001 demonstrated that the ABC/3TC FDC tablet wasbioequivalent to the separate components (ZIAGEN and EPIVIR tablets) and can begiven with or without food.

The pivotal study CNA30021 provides robust clinical data to support the efficacy ofABC once daily in combination with 3TC and EFV once daily. For the ITT-ExposedPopulation, 66% of subjects in the ABC once daily group, compared to 68% of subjectsin the ABC twice daily group, achieved a virologic response of plasma HIV-1 RNA<50 copies/mL by Week 48 using the TLOVR algorithm. Both the unstratified andstratified analysis (≤100,000 copies/mL or >100,000 copies/mL) demonstrated the non-


- 34 -

inferiority of the ABC once daily treatment group as compared to the ABC twice dailytreatment group; the responses were comparable irrespective of baseline plasma HIV-1RNA or CD4+ cell count.

The incidence of virologic failure was low and comparable between the treatment groups(ABC once daily, 10%; ABC twice daily, 8%) throughout 48 weeks of study. The mostfrequently selected NRTI mutation was the M184V mutation. The L74V mutation wasthe next most frequently selected. The K65R and Y115F mutations were selectedinfrequently. Subjects with virologic failure typically retained susceptibility to mostother NRTIs, consistent with the emergence of M184V as the most common NRTIassociated mutation on-therapy.

Overall, the efficacy data in this submission support the following conclusions:

• ABC once daily is non-inferior to ABC twice daily when used in combination with3TC plus EFV;

• ABC once or twice daily is effective in subjects irrespective of baseline plasmaHIV-1 RNA levels or CD4+ cell counts;

• ABC + 3TC once or twice daily is an efficacious NRTI combination which may helppreserve future treatment options;

• ABC/3TC FDC comprises a convenient and effective once daily NRTI backbone.

• ABC resistance profile appears to be unaltered by once daily dosing relative to twicedaily dosing.

In conclusion, ABC/3TC is an efficacious combination that can be delivered once daily.


- 35 -

7. APPENDIX

Table 17 Results of Pivotal Efficacy Studies

Clinical Study TreatmentGroups

NumberCompleted1/

Exposed (%)

Proportion ofSubjects withPlasma HIV-1RNA <50copies/mL atWeek 48

Point Estimate(95%ConfidenceInterval)

StatisticalTest/P Value

Proportion ofSubjects withPlasma HIV-1RNA <400copies/mL atWeek 48

Point Estimate(95%ConfidenceInterval)

CNA30021(pivotal)

ABC OADABC BID

290/384 (76%)294/386 (76%)

253/384 (66%)261/386 (68%)

-1.7%(-8.4%,4.9%)

Two-sidedstratified 95% CI

276/384 (72%)279/386 (72%)

-0.4%(6.7%, 5.9%)

Source Data: Table 12.3 of CNA30021 CSR, Table 12.5 of CNA30021 CSR, Table 13.1 of CNA30021 CSR, Table 13.46 of CNA30021 CSR.1. Completed 48 weeks of study.ABC=abacavir; BID=twice daily; HIV=human immunodeficiency virus type 1; OAD=once daily; RNA=ribonucleic acid.

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Intent to Treat - Exposed (Data as of: June 27, 2003) Table 18 Summary of Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Age at Week 48 (ITT Exposed, Based on TLOVR Algorithm) ABC OAD+3TC+EFV ABC BID+3TC+EFV Age Group (N=384) (N=386) p-value [1] --------------------------------------------------------------------------------------- <=30 Yrs n 102 111 0.2898 <50 copies/mL 59 (58%) 73 (66%) >=50 copies/mL 43 (42%) 38 (34%) > 30 Yrs n 282 275 <50 copies/mL 194 (69%) 188 (68%) >=50 copies/mL 88 (31%) 87 (32%) Total n 384 386 <50 copies/mL 253 (66%) 261 (68%) >=50 copies/mL 131 (34%) 125 (32%) [1] p value from Breslow-Day test for homogeneity of the odds ratios w.r.t age.

CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

36


CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

37


CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

38

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Intent to Treat - Exposed (Data as of: June 27, 2003) Table 19 Summary of Outcomes of Time to Loss of Virologic Response at Week 48 by Age Group ITT Exposed Population, <50 copies/mL Age: <=35 years ABC OAD+3TC+EFV ABC BID+3TC+EFV Outcome (N=384) (N=386) ----------------------------------------------------------------------------- Responder 102 (56%) 120 (67%) Virologic failure 20 (11%) 16 (9%) Rebound 6 (3%) 6 (3%) Never suppressed through Week 48 12 (7%) 8 (4%) Insufficent viral load response [1] 2 (1%) 2 (1%) D/C or chg therapy due to AE 28 (15%) 19 (11%) D/C or chg therapy due to other reasons 31 (17%) 25 (14%) Consent withdrawn 7 (4%) 5 (3%) Lost to follow up 17 (9%) 13 (7%) Protocol violation 0 0 Insufficient CD4 response 0 0 Clinical Progression 0 0 Other 5 (3%) 6 (3%) Change of ART [2] 2 (1%) 1 (<1%) [1] As indicated on the treatment discontinuation CRF page.[2] Excludes changes to background medications (3TC and EFV).NOTE: Outcomes are based on the results of the TLOVR algorithm through study day 379.hz39798:US/cna2/a30021/programs/fda/outcome_age.sas 05SEP03 11:29 Page 1 of 2

CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

39

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Intent to Treat - Exposed (Data as of: June 27, 2003) Table 19 Summary of Outcomes of Time to Loss of Virologic Response at Week 48 by Age Group ITT Exposed Population, <50 copies/mL Age: > 35 years ABC OAD+3TC+EFV ABC BID+3TC+EFV Outcome (N=384) (N=386) ----------------------------------------------------------------------------- Responder 151 (74%) 141 (68%) Virologic failure 18 (9%) 16 (8%) Rebound 3 (1%) 2 (<1%) Never suppressed through Week 48 15 (7%) 13 (6%) Insufficent viral load response [1] 0 1 (<1%) D/C or chg therapy due to AE 22 (11%) 23 (11%) D/C or chg therapy due to other reasons 12 (6%) 26 (13%) Consent withdrawn 3 (1%) 5 (2%) Lost to follow up 3 (1%) 10 (5%) Protocol violation 1 (<1%) 2 (<1%) Insufficient CD4 response 0 0 Clinical Progression 1 (<1%) 1 (<1%) Other 4 (2%) 8 (4%) Change of ART [2] 0 0 [1] As indicated on the treatment discontinuation CRF page.[2] Excludes changes to background medications (3TC and EFV).NOTE: Outcomes are based on the results of the TLOVR algorithm through study day 379.hz39798:US/cna2/a30021/programs/fda/outcome_age.sas 05SEP03 11:29 Page 2 of 2

CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

40

Protocol: CNA30021 -- ABC+3TC FDCPopulation: As Treated (Data as of: June 27, 2003) Table 20 Summary of Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Age at Week 48 (As Treated) ABC OAD+3TC+EFV ABC BID+3TC+EFV Age Group (N=266) (N=265) p-value [1] --------------------------------------------------------------------------------------- <=30 Yrs n 64 70 0.7897 <50 copies/mL 56 (88%) 60 (86%) >=50 copies/mL 8 (13%) 10 (14%) > 30 Yrs n 202 195 <50 copies/mL 175 (87%) 169 (87%) >=50 copies/mL 27 (13%) 26 (13%) Total n 266 265 <50 copies/mL 231 (87%) 229 (86%) >=50 copies/mL 35 (13%) 36 (14%) [1] p value from Breslow-Day test for homogeneity of the odds ratios w.r.t age.

CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

41


CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

42


CO

NF

IDE

NT

IAL

CM

2003/00031/002.7.3 S

umm

ary of Clinical E

fficacy

43

2.7.3 summary of clinical efficacy...2.7.3 Summary of Clinical Efficacy - 7 - 1.1. Clinical...

Documents

Transcript of 2.7.3 summary of clinical efficacy...2.7.3 Summary of Clinical Efficacy - 7 - 1.1. Clinical...