Similar Efficacy and Tolerability of Atazanavir ATV Compared to AtazanavirRitonavir ATVr, each with

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Similar Efficacy and Tolerability of Atazanavir
(ATV) Compared to Atazanavir/Ritonavir
(ATV/r), each with Abacavir/Lamivudine (ABC/3TC)
after InitialSuppression with ABC/3TC ATV/r
84 Week Results of the ARIES Trial
Kathleen Squires, MD Professor of Medicine,
Thomas Jefferson University Philadelphia, PA
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Acknowledgements
Study Participants Study Coordinators GlaxoSmith
Kline E Blackmon M Bomar D Sutherland-Phillips N
Figliola V Garay S LaBelle T Lai Q Liao L Patel P
Patel D Percival D Raimonde L Ross M Schultz M
Shaefer M Vourvahis P Wannamaker B Wine H
Zhao GSK Monitors Bristol Myers Squibb for
generously donating study medication
Investigators
United States B Akil J Applebaum N Bellos D
Berger I Brar C Brinson F Carpio-Cedraro P Cook M
Cuenca E DeJesus R Dretler J Duggan R Elion T
File J Gathe E Godofsky R Greenberg R Hao K
Henry A M Khalsa J Kort P Kumar P Lackey A
LaMarca C Lucasti
C McDonald P McLeroth I Melendez-Rivera A
Mestre J Morales-Ramirez R Nahass C Newman W
OBrien E Oldfield P OKeefe H Olivet T Overton D
Pearce M Ramgopal B Rashbaum F Rhame G Richmond J
Rodriguez P Salvato A Sanchez P Sax J Sarria L
Santiago K Sathasivam S Schneider R Scott
A Scribner G Sepulveda-Arzola G Simon J Slim L
Sloan C Small D Siraj K Squires K Tashima P
Tebas M Thompson J Torres V Trivedi T Vanig D
Ward W Weinberg M Weinert B Young Canada J G
Baril D Murphy M Potter A Rachlis G Smith S
Walmsley
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Study Design
Phase IIIb, randomized (11), open-label,
non-inferiority study
ATV (400mg) QD ABC/3TC FDC (600/300mg) QD
ATV/r (300/100mg) QD ABC/3TC FDC (600/300mg)
QD N515
ATV/r (300/100mg) QD ABC/3TC FDC (600/300mg)
QD
Results presented at ICAAC 2008
Entry criteria HIV-1 RNA ?1000 c/mL No CD4
cell count restrictions Appropriate
genotype HLA-B5701 negative Stratified at
randomization by baseline
HIV-1 RNA lt or ?100,000 c/mL
Day 1
Week 84
Week 36 Randomization
48 weeks
Optional treatment extension to Week 144
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Study Design
Phase IIIb, randomized (11), open-label,
non-inferiority study
Randomized N419
ATV (400mg) QD ABC/3TC FDC (600/300mg)
QD n210
ATV/r (300/100mg) QD ABC/3TC FDC (600/300mg)
QD N515
ATV/r (300/100mg) QD ABC/3TC FDC (600/300mg)
QD n209
Results presented at ICAAC 2008
Day 1
Week 84
Week 36 Randomization

• Randomization criteria
• Confirmed RNA lt50 c/mL prior to Week 36
• RNA lt50 c/mL immediately preceding Week 36
• No protocol defined virologic failure

48 weeks
Optional treatment extension to Week 144
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Objectives/ Endpoints

• Primary Objective
• Evaluate compare efficacy, safety,
  tolerability, and durability of antiviral
  response between the randomized treatment groups
  over 48 weeks
• Endpoints
• Primary
• Proportion of subjects with HIV RNA lt50 c/mL
  (TLOVR) at Week 84
• Secondary/Exploratory
• Proportion of subjects with HIV RNA lt50 c/mL and
  lt400 c/mL
• Change from baseline in HIV RNA and CD4 cell
  count
• Resistance in subjects with virologic failure
• Safety

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Baseline Demographics, Randomized Population
(ITT-E)
ATV ATV/r
Total n210 n209
n419
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Baseline Characteristics, Randomized Population
(ITT-E)
ATV ATV/r
Total n210 n209
n419
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Study Outcomes, Randomized Population
(ITT-E)
ATV ATV/r
Total n210 n209
n419
as noted on the CRF
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HIV RNA lt50 copies/mL, Randomized
Population (ITT-E, TLOVR)
Induction Phase Non-Randomized Results
Simplification Phase Randomized Results
86
81

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HIV RNA lt50 copies/mL at Week 84,
Randomized Population (ITT-E, TLOVR)
Stratified 95 CI (-1.75, 12.48) p 0.140
HIV RNA lt400 c/mL at Week 84 (TLOVR) ATV 92
vs. ATV/r 86, 95 CI (0.44, 12.22) p 0.036
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HIV RNA lt50 copies/mL at Week 84,
Randomized Population (ITT-E, TLOVR)
BL HIV RNA 100,000 c/mL
BL HIV RNA lt100,000 c/mL
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Change in CD4 Cell Count from Baseline,
Randomized Population (ITT-E, Observed)
259
240
Median 197 434 CD4 204 469
n (ATV) 210 208
204 203 208
201 194 193 n
(ATV/r) 209 209 207
203 204 200
191 187
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Protocol Defined Virologic Failure,
Randomized Population (ITT-E)
Subject with M184M/I/V did have reduced
susceptibility to 3TC at time of failure. Two PI
polymorphisms, G16G/E and K20K/R, were detected
at failure HIV from these subjects remained
susceptible to all PIs.

• Definition of Virologic Failure
• Baseline to Week 36
• Failure to achieve HIV RNA lt400 c/mL by Week 30
• Confirmed HIV RNA ?400 c/mL after achieving lt400
  c/mL
• After Week 36
• Confirmed HIV RNA ?400 c/mL

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Treatment-Related Adverse Events (5),
Randomized Population (ITT-E)
Note No MIs reported to date
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Fasting Lipids
TotalCholesterol
200 mg/dL
FastingTriglycerides
150 mg/dL
FastingLDL-C
130 mg/dL
Fasting HDL-C
40 mg/dL
Lipid lowering medication usage ATV 13 vs.
ATV/r 16 through 84 weeks
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Fasting Lipids
TotalCholesterol
200 mg/dL
FastingTriglycerides
150 mg/dL
FastingLDL-C
130 mg/dL
Fasting HDL-C
40 mg/dL
Lipid lowering medication usage ATV 13 vs.
ATV/r 16 through 84 weeks
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Fasting Lipids
TotalCholesterol
200 mg/dL
FastingTriglycerides
150 mg/dL
FastingLDL-C
130 mg/dL
Fasting HDL-C
40 mg/dL
Lipid lowering medication usage ATV 13 vs.
ATV/r 16 through 84 weeks
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Conclusions

• ATV demonstrated similar efficacy to ATV/r
  (non-inferior TLOVR lt 50 c/mL), each in
  combination with ABC/3TC, regardless of baseline
  viral load
• Both treatment regimens were generally well
  tolerated over 84 weeks
• Subjects in the simplification arm demonstrated a
  more favorable lipid profile and decreased
  bilirubin levels compared to those in the
  continuation arm
• Protocol-defined virologic failure was infrequent
  (2) from Week 36 to 84
• There were no major treatment-emergent PI
  mutations

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Backup Slides
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Study Outcomes at Week 36
As noted on the CRF page.
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Baseline Characteristics Comparison
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Baseline Characteristics Comparison
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Study Outcomes for Randomized Population (lt50
c/mL TLOVR)
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Study Outcomes for Randomized Population (lt400
c/mL TLOVR)
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HIV RNA lt 50 c/mL, Randomized Population (ITT-E,
Observed Analysis)
92
92

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HIV RNA lt 50 c/mL by Baseline Viral Load Strata,
Randomized Population (ITT-E, MDF Analysis)
lt100,000 c/mL
100,000 c/mL
Overall
n 210 209 111
113 99 96
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HIV RNA lt 50 c/mL by Baseline Viral Load Strata,
Randomized Population (ITT-E, Observed Analysis)
Overall
lt100,000 c/mL
100,000 c/mL
n 194 187 106
104 88 83
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HIV RNA lt 400 c/mL, Randomized Population (ITT-E,
TLOVR Analysis)
92
86
Induction Phase
Simplification Phase

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HIV RNA lt 400 c/mL, Randomized Population (ITT-E,
Observed Analysis)
99
98

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HIV RNA lt 400 c/mL at Week 84, Randomized
Population (ITT-E)
Stratified by baseline HIV RNA
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HIV RNA lt 400 c/mL by Baseline Viral Load Strata,
Randomized Population (ITT-E, TLOVR Analysis)
lt100,000 c/mL
100,000 c/mL
Overall
n 210 109 111
113 99 96
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HIV RNA lt 400 c/mL by Baseline Viral Load Strata,
Randomized Population (ITT-E, MDF Analysis)
lt100,000 c/mL
100,000 c/mL
Overall
n 210 209 111
113 99 96
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HIV RNA lt 400 c/mL by Baseline Viral Load Strata,
Randomized Population (ITT-E, Observed Analysis)
lt100,000 c/mL
100,000 c/mL
Overall
n 194 187 106
104 88 83
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Summary of Virologic Response at Week 36 (50
copies/mL)
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Summary of Virologic Response at Week 36 (400
copies/mL)
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Virologic Failures by Week 36
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All Grade 2-4 AEs from BL to Week 84 (5),
Regardless of Causality, (N419)
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Treatment-Related Grade 2-4 AEs from BL to Week
84 (3), (N419)
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Treatment-Related SAEs from BL to Week 84, (N419)
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Treatment-Related AEs by Baseline vRNA
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Summary of Median Total Bilirubin Values (mg/dL)
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Framingham Risk Stratification, Randomized
Population (ITT-E, Observed Analysis)
ATV ATV/r
lt5
5-10
10-20
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CHD Risk Categories
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Biomarker Data for Randomized Population (ITT-E,
Observed Analysis
ATV ATV/r
hsCRP(mg/L)
IL6(pg/mL)
Lp-pLA2(log 10) (nmol/min/mL)
n (obs) ATV 200 183 209
192 207 179 ATV/r 202
175 206 185 205 179
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Median Percent Compliance from Baseline to Week
84
Percent compliance total number of pills
taken/total number of pills prescribed.