Module 2.5 Clinical Overview

1 CONFIDENTIALM odule Clinical Overview1 Module OverviewCopyright 2012 ViiV Healthcare and the GlaxoSmithKline group of companies. All rights reserved. Unauthorizedcopying or use of this information is Clinical Overview2 TABLE OF PRODUCT DEVELOPMENT Therapies and its Unmet Clinical Indication and Development with Good Clinical Practice (GCP)..132. Overview OF Overview OF , Distribution, Metabolism and Elimination of and in Healthy Subjects and Target Patient of Dolutegravir PK in Special with Hepatitis B or of Dolutegravir on thePharmacokinetics of Other of Other Agents on the Pharmacokinetics of Dolutegravir and Dose of DTG on Cardiac of DTG on Renal Pharmacodynamic Relationships and Definition of No Effect Boundaries.

2 Relationship for Combination Relationship for Safety ..30 CONFIDENTIALM odule Clinical of No Effect Boundaries of Alteration in DTG Pharmacology Overview OF of Patient Populations in Pivotal and Supportive Efficacy for Dose Selection in Clinical ve/ART-Experienced (INI-Na ve) (INI-Resistant) Trial Methodology and Design (Pivotal Efficacy Study Designs).. in INI-Na ve in INI-Resistant Endpoints and Statistical Considerations of Efficacy and Secondary Efficacy Results in all of Key Demographic Subpopulations in ING113086, ING114467, and and Baseline Efficacy of Primary Efficacy Results in (INI-Na ve) and Baseline Efficacy of Principal Efficacy Results in Emergent Resistance in INI-Na ve (INI-Resistant)

3 And Baseline Efficacy Emergent Resistance in INI-resistant of Primary Efficacy Results in Antiviral Activity of DTG by Baseline Resistance in INI-resistant Subjects in Overview OF Cut-off Data Relevant to Human in the Clinical Development in Clinical Pharmacology Reported Clinical Serious Adverse Events Leading to Laboratory Evaluations and Vital Adverse Adverse in Pediatrics - ING112578 (P1093).. in Phase II and III Population for Phase II and III Adverse Reported Adverse ve Adult (INI-Na ve) Adult (INI-Resistant) Adult and Adverse Drug PK/PD Safety Adverse ve Adult (INI-Na ve) Adult (INI-Resistant) Adult Events Leading to ve Adult (INI-Na ve) Adult (INI-Resistant) Adult of Special and (GI) Reconstitution Inflammatory Syndrome (IRIS).

4 Laboratory in Special Groups and Effects, Abuse Potential, BENEFITS AND RISKS of Dolutegravir in the Treatment of HIV-1 Clinical of Dolutegravir in the Treatment of HIV-1 Dosing Table 1 Explanation for Empty Submission Clinical Overview6 ABBREVIATIONS3 TClamivudineABCabacavirAEAdverse eventAIDSA cquired immunodeficiency syndromeALTA lanine aminotransferaseAPIA ctive pharmaceutical ingredientsATVatazanavirASTA spartate aminotransferaseARTA ntiretroviral therapyAUCArea under the curveAUC(0-t)Area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentrationAUC(0- )Area under the concentration-time curve over the dosing intervalAUC(0- )Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite timeAUC(0-24)Area under the concentration-time curve from time zero (pre-dose)

5 To 24 hours post dose or over 24 hoursBIDT wice dailyC24 Concentration at 24 hours post doseCL/FApparent clearance following oral dosingCmaxMaximum observed concentrationCMCC hemistry, manufacturing and controlsC0 Pre-dose concentrationC0_avgAverage of concentrations at time 0C Concentration at the end of the dosing periodc/mLcopies per milliliterCavgAverage of concentrationsCDCC enters for Disease Control and PreventionCSFC erebrospinal fluidCIConfidence IntervalCOBI cobicistatCPSRC linical Pharmacology Study ReportCrCLCreatinine clearanceCSRC linical Study ReportCYPC ytochrome P450CV%Coefficient of varianceCVbBetween-subject variability (or coefficient of variation)DNAD eoxyribonucleic acidDRVdarunavirDTGdolutegravir, S/GSK1349572 EFVefavirenzEMAE uropean Medicines AgencyEmaxMaximum effectERPFE ffective renal plasma flowETRetravirineCONFIDENTIALM odule Clinical Overview7 EVGelvitegravirFCFold changeFDA(US)

6 Food and Drug AdministrationFDCF ixed dose combinationFPVfosamprenavirFTCemtricitab ineGCPGood Clinical PracticeGFRG lomerular filtration rateGIGastrointestinalGSKG laxoSmithKlineHBVH epatitis B VirusHCVH epatitis C VirusHIVH uman Immunodeficiency VirusHIV-1 Human Immunodeficiency Virus Type 1 HIV-2 Human Immunodeficiency Virus Type 2IC50 Half-maximal inhibitory concentrationICHI nternational Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human UseINIntegraseINDI nvestigational New DrugINII ntegrase inhibitorITT-EIntent-to-Treat ExposedLOCFDBLast observation carried forward (discontinuation equals Baseline)LPVlopinavirMAAM arketing Authorization ApplicationmgMilligrammITT-EModified Intent-to-Treat Exposedmm3 Cubic millimeterMSDFM issing.

7 Switch or Discontinuation = FailureNDANew Drug ApplicationNDSNew Drug SubmissionngNanogramNRTIN ucleoside reverse transcriptase inhibitorNNRTINon-nucleoside reverse transcriptase inhibitorOBRO ptimized background regimenOCT2 Organic cation transporter 2 OMPO meprazoleOSSO verall susceptibility scorePAHPara-aminohippuratePBMCP eripheral blood mononuclear cellPDVFP rotocol defined virologic failurePIProtease inhibitorPKPharmacokineticPDPharmacodyna micPPPer-protocol PSSP henotypic susceptibility scoreCONFIDENTIALM odule Clinical Overview8 PGxPharmacogeneticsRALraltegravirRIFR ifampinRNAR ibonucleic acidRTVritonavirt1/2 Terminal phase half-lifeTLOVRTime to Loss of Virologic ResponseTDFtenofovir disoproxil fumarateTPVtipranavirUGTU ridine diphosphate glucuronyltransferaseUNAIDSJ oint United Nations Programme on HIV/AIDSUSU nited StatesVd/FApparent volume of distributionVLViral loadVz/FApparent volume of distribution after extravascular ( , oral) administration at terminal phaseTrademark InformationTrademarks of ViiV HealthcareTrademarks not owned by ViiV HealthcareEPZICOMA triplaKIVEXAI sentressStribildTruvadaCONFIDENTIALM odule Clinical DEVELOPMENT InfectionAn estimated million adults and children worldwide, were living with Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) in 2011 [UNAIDS, 2012a].

8 In 2011, the global adult (15 to 49 years) HIV prevalence rate was [UNAIDS, 2012b]. During that year, millionpeople were newly infected with HIV, and there were milliondeaths due to HIV/AIDS. Of newly infected people, an estimated million were women and girls, and 330,000were children. As well, younger than 15 years were living with HIV in 2011 [UNAIDS, 2012a]. In 2009, an estimated 370,000 children contracted HIV during the perinatal and breastfeeding period. Overall, the epidemic appears to have stabilized in most regions, although prevalence continues to increase in Eastern Europe and Central Asia and in other parts of Asia due to a high rate of new HIV infections [UNAIDS, 2010].

9 In 2011, Sub-Saharan Africa remained the most heavily affected region, accounting for 68% ( million) of all new HIV infections among adults and children [UNAIDS, 2012b]. Therapies and its Unmet ClinicalNeedCombination antiviral therapy with HIV type-1 (HIV-1) protease and reverse transcriptase inhibitors has significantly reduced AIDS-related morbidity and mortality. However, emerging multi-class drug-resistant HIV strains and long-term toxicities warrant development of new classes of antiretroviral therapies. Integrase inhibitors (INIs) are a newer class of antiretroviral drugs designed to block the action of the integrase (IN) viral enzyme, which catalyzes two key steps in the HIV life cycle and is responsible for insertion of the viral genome into the deoxyribonucleic acid (DNA) of the host cell.

10 Since genome integration is a vital step in retroviral replication, it is an attractive target for HIV (DTG, GSK1349572) is an INI owned by ViiV Healthcare, which is working with GlaxoSmithKline (GSK) to develop the (RAL), the first marketed INI, and elvitegravir (EVG), which recently gained United States (US) Food and Drug Administration (FDA) approval (in August 2012in a combination product), have demonstrated good antiviral activity in Clinical trials, confirming the INI class as a new option for constructing effective HIV-1 treatment regimens. In the STARTMRK study, RAL demonstrated excellent antiviral activity as first-line treatment and was shown to be non-inferior to an efavirenz (EFV)-containing standard of care regimen [Lennox, 2010].