6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Shionogi-ViiV Healthcare LLC Rapid, Robust and Sustained Antiviral Response with Once-daily (QD) Dolutegravir (DTG, S/GSK ), a Next Generation Integrase Inhibitor (INI) in Combination Therapy in Antiretroviral-naïve Adults 48 Week Results from SPRING-1 (ING112276) Jan van Lunzen 1, Franco Maggiolo 2, Bao Phung 3, Olga Tsybakova 4, Benjamin Young 5,6, Jose Gatell 7, Steve Almond 8, Marty St Clair 9, Cindy Brothers 9 and Sherene Min 9 on behalf of the extended SPRING-1 team 1 University Medical Center, Hamburg-Eppendorf, Germany; 2 Ospedali Riuniti de Bergamo, Bergamo, Italy; 3 Hôpital Bichat-Claude Bernard, Paris, France; 4 AIDS Center, Smolensk, Russian Federation 5 Rocky Mountain CARES/DIDC, Denver, CO, 6 Health Connections International, Amsterdam, Netherlands; 7 University of Barcelona, Barcelona, Spain; 8 GlaxoSmithKline, Missisauga, Canada and 9 RTP, USA

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy ING Study Design ●Phase IIb dose-ranging, partially-blinded, N~200 ART-naïve patients ●All arms include 2 NRTI backbone given once daily ●Primary endpoint: % <50 c/mL at 16 weeks (TLOVR) ●Planned interim analysis: % <50 c/mL at 48 weeks (TLOVR) HIV-1 RNA >1000 c/mL CD4 ≥200 cells/mm 3 1:1:1:1 Randomization HIV-1 RNA >1000 c/mL CD4 ≥200 cells/mm 3 1:1:1:1 Randomization EFV 600 mg DTG 50 mg DTG 25 mg DTG 10 mg 50 mg DTG Selected Dose 50 mg DTG Selected Dose EFV 600 mg Wk 48 interim analysis Stratified by HIV RNA >100,000 or ≤ 100,000 Epzicom/Kivexa or Truvada *Post hoc analysis using bioMONTR HIV-1 EQ SuperLow Assay LLOD=2 c/mL at Weeks 16, 24 and 48 Wk 96

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy DTG 10mg (N=53) DTG 25mg (N=51) DTG 50mg (N=51) EFV 600mg (N=50) Total (N=205) Age (Median and range in years)32 (21 – 61)38 (20-64)37 (22 – 55)40 (20 – 79)37 (20 – 79) Male gender42 (79%)46 (90%)45 (88%)44 (88%)177 (86%) Race African American/African Heritage7 (13%)6 (12%)8 (16%)4 (8%)25 (12%) White41 (77%)42 (82%)38 (75%)43 (86%)164 (80%) Other5 (10%)3 (6%)5 (10%)4 (8%)17 (8%) Baseline HIV-1 RNA Mean (log 10 c/mL) >100,000 c/mL11 (21%)10 (20%)12 (24%)11 (22%)44 (21%) Baseline CD4+ (cells/mm 3 ) Mean <35036 (68%)29 (57%)35 (69%)30 (60%)130 (63%) Investigator-selected NRTIs TDF/FTC36 (68%)34 (67%) 34 (68%)138 (67%) ABC/3TC17 (32%)17 (33%) 16 (32%)67 (33%) Baseline Characteristics

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy DTG: Rapid and Sustained Antiviral Activity Week 48 Efficacy Analysis (%<50 c/mL) Proportion (%) <50 c/mL (TLOVR) 91% 88% 90% 82% DTG 10mg DTG 25mg DTG 50mg EFV 600mg 95% confidence intervals are derived using the normal approximation

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Primary Outcomes: % <50 c/mL (TLOVR) at Week 48 Outcome DTG 10mg (N=53) DTG 25mg (N=51) DTG 50mg (N=51) EFV 600mg (N=50) Responder48 (91%)45 (88%)46 (90%)41 (82%) Reason for non-response (virologic) Rebound or virologic non-response4 (8%)3 (6%) 2 (4%) * 3 (6%) Never suppressed through Week (2%) Reason for non-response (discontinuation or change in ART) Adverse event01 (2%)04 (8%) Protocol deviation1 (2%) 0 Lost to follow-up001 (2%)0 Decision to discontinue study by subject0001 (2%) Non-permitted change in ART01 (2%)00 * Includes one subject discontinued from study drug due to Burkitt’s lymphoma

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Protocol Defined Virologic Failure (>400c/mL) ●SPRING-1 (n=150 on DTG) –Week 48, 3/150 (2%) DTG protocol-defined virologic failures (>400 c/mL HIV-1 RNA)  10 mg DTG, Wk 4: M184V only. No IN mutations or phenotypic changes  25 mg DTG, Wk 24: 404 c/mL. No geno/pheno determined  10 mg DTG, Wk 40: No RT, Pro, or IN mutations or phenotypic changes –No subjects in 50 mg arm had confirmed VL >400 c/mL through Wk 48 –No integrase mutations through week 48 ● Merck P004 (n=160 on RAL) 1 –Week 48, 5/160 (3%) virologic failures (>400 c/mL HIV-1 RNA)  2/5 (40%) had RAL resistance mutations (N155H) 1. Markowitz, M et al. JAIDS 2007: 46.

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Response to 50 mg DTG vs 600 mg EFV <50 c/mL and <2 c/mL Abbott RealTime HIV-1 Assay (lower limit of detection 40 c/mL) and a modified BioMerieux EasyQ HIV-1 SuperLow assay (lower limit of detection 2 c/mL) Percent Weeks 50 mg DTG <50 c/mL 600 mg EFV <50 c/mL 50 mg DTG <2 c/mL 600 mg EFV <2 c/mL

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Median Change from Baseline CD4+ Cell Counts (cells/mm 3 ) Week 24 p=0.008; Week 48 p=0.076 Wilcoxon two-sample test, EFV vs. DTG total

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy AEs (by System Organ Class) Reported in >1 Subject on Investigational Product ●No SAEs judged related to DTG ●One SAE judged related to EFV (suicide attempt) ●No clear dose-response relationship in DTG AEs ●Events leading to withdrawal: –DTG (n=2): dyspepsia and Burkitt’s lymphoma –EFV (n=4): abnormal dreams, suicide attempt, drug intolerance, drug hypersensitivity DTG 10mg (N=53) DTG 25mg (N=51) DTG 50mg (N=51) DTG Subtotal (N=155) EFV 600mg (N=50) Grade 2-4 Drug Related (all)5 (9%)4 (8%) 13 (8%)10 (20%) Gastrointestinal1 (2%) 3 (2%)2 (4%) Psychiatric disorders00003 (6%) Metabolic disorders03 (6%)1 (2%)4 (3%)0 Skin disorders00002 (4%) Infections2 (4%)002 (1%)0 General disorders1 (2%)0 2 (1%)1 (2%) Serious Adverse Events (all)3 (6%)1 (2%)4 (8%)8 (5%)4 (8%) AEs Leading to WD/IP Discontinuation01 (2%) 2(1%)4 (8%)

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Laboratory Findings ●> Grade 3 lab abnormalities were rare (DTG 12% vs. EFV 14%) ●No Grade 3 or 4 ALT elevations in any subject ●Small changes in serum creatinine (0.1 – 0.15 mg/dL) were observed 1 –Observed with both NRTI backbones, did not progress over time –No effect of DTG on GFR (as measured by iohexol clearance) –In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine  DTG inhibits the organic anion transporter OCT2 (with IC 50 of 1.9 µM), like trimethoprim or cimetidine 1. Min S et al. Safety Profile of Dolutegravir (DTG, S/GSK ), a Next Generation Integrase Inhibitor (INI) in Combination Therapy in Antiretroviral (ART)-naïve and ART-experienced Adults from Phase 2b Studies. IAS. July 17-20, Rome. Abstract TUPE238.

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy DTG: Lower Impact on Plasma Lipids than EFV DTG TotalEFV 600 mg Lipid Parameter Week 48 Change from Baseline (95% CI) Chol HDL Chol/HDL LDL Trig Note: Individual lipids are expressed in mg/dL; Chol/HDL is a unitless ratio.

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy DTG Week 2 Pharmacokinetic Data DTG demonstrated low pharmacokinetic variability and drug exposure increased with dose. IQ values ranged 5-19 fold PA-IC ug/mL Post-dose Time (hour) Mean DTG concentration (ug/mL) DTG 10mg once daily DTG 25mg once daily DTG 50mg once daily

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Conclusions ●DTG administered once-daily without a PK booster showed a rapid and sustained response at all doses explored through Week 48 –No IN resistance mutations detected through 48 weeks ●DTG was well tolerated with fewer discontinuations than EFV and less impact on lipid parameters –Grade 3/4 lab abnormalities were uncommon –Small increases in creatinine noted early without progression or safety- related withdrawals 1  likely due to non-pathologic inhibition of creatinine secretion ●These data provide longer term efficacy and safety data for DTG in combination therapy –Subjects continue on their randomized regimen until Week Min S et al. Safety Profile of Dolutegravir (DTG, S/GSK ), a Next Generation Integrase Inhibitor (INI) in Combination Therapy in Antiretroviral (ART)-naïve and ART-experienced Adults from Phase 2b Studies. IAS. July 17-20, Rome. Abstract TUPE238.

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Acknowledgments We thank everyone who has contributed to the success of this study, including: All of our study participants and their families The SPRING-1 Clinical Investigators and their staff: France: J Reynes, L Cotte, F Raffi, C Katlama, P Yeni, J-M Molina Germany: J van Lunzen, H-J Stellbrink, M Stoll, T Lutz Italy: G Carosi, F Maggiolo, G Rizzardini, A Lazzarin Russia: O Tsybakova, E Voronin, A Rakhmanova Spain: F Pulido, J Arribas, S Moreno-Guillen, J Gatell, B Clotet United States: E DeJesus, F Felizarta, T Hawkins, J Lalezari, L McCurdy, G Richmond, S Schneider, L Sloan, J Torres, B Young, T Vanig, M Mustafa, A LaMarca And the extended ViiV Healthcare-Shionogi-GlaxoSmithKline SPRING-1 study team

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Back-ups

6 th IAS Conference on HIV Pathogenesis, Treatment and Prevention July 2011 Rome, Italy Laboratory Findings ●> Grade 3 lab abnormalities were rare (DTG 12% vs. EFV 14%) ●No Grade 3 or 4 ALT elevations in any subject ●Changes (+/- SD) in serum creatinine over time Note: no clinically relevant events nor discontinuations related to creatinine See also abstract TUPE238 (Min et. al.)