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Background

Activity of Next Generation Integrase Inhibitor (INI) S/GSK1349572 in Subjects with HIV Exhibiting Raltegravir Resistance: Initial Results of VIKING Study (ING112961).

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Background

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  1. Activity of Next Generation Integrase Inhibitor (INI) S/GSK1349572 in Subjects with HIV Exhibiting Raltegravir Resistance: Initial Results of VIKING Study (ING112961) J. Eron 1, J. Durant2, I. Poizot-Martin3, J Reynes4, V Soriano5, P Kumar6, G Richmond7, D Vittecoq8, T Fujiwara9, M Ait-Khaled10, S Min11, D Thomas11, R Cuffe10, J Yeo10 1Center for AIDS Research Clinical Core, UNC School of Medicine, NC; 2Hôpital l'Archet, Nice; 3Hôpital Sainte Marguerite, Marseille; 4Hôpital Guide Chauliac, Montpellier; 5Hospital Carlos III, Madrid; 6Georgetown Univ, Washington; 7Fort Lauderdale; 8Hôpital Paul Brousse, Villejuif; 9Shionogi & Co., Ltd., Osaka, Japan; 10GlaxoSmithKline, London; 11GlaxoSmithKline, Research Triangle Park, NC

  2. Background • Virologic failure occurred in 23% of treatment experienced subjects receiving raltegravir (RAL) in BENCHMRK-1 and 2 • 70% harbored virus with RAL-resistance signature mutations • 3 RAL-resistance pathways – Y143, Q148 and N155 • Additional substitutions increase resistance and/or fitness • In vitro susceptibility to S/GSK1349572, suggested two RAL-resistant viral populations: • Variable increase in fold-change (FC) to S/GSK1349572 (Q148 plus secondary mutations) • No or minimal increase in FC to S/GSK1349572 (N155 pathway, Y143 pathway, Q148 single mutants) • The clinical evaluation of S/GSK1349572 in subjects with RAL-resistant virus is warranted

  3. VIKING Study Design Cohort I • Current or historic RAL-failures with evidence of RAL-resistance • At least 3 ART-class resistant (includes INI) • All subjects receiveS/GSK1349572 50mg QD Q148H/K/R + one or more secondaryresistance mutations* N~ 15 Allocated to one of two groups based on genotype at screen to ensure broad sensitivity range Functional Monotherapy Phase Replace RAL with S/GSK1349572 or add, if RAL already stopped Continuation Phase S/GSK1349572 + OBR All other mutations (including codon148 single mutation)** N~ 15 Day 1 Day 11 Week 24 *Q148H/K/R plus changes in L74 and/or E138 and/or G140 **N155H and Y143H pathways or Q148H/K/R single mutants

  4. VIKING Objectives and End-points • Primary Objective • To assess the short-term antiviral activity of S/GSK1349572 + failing background regimen • Primary End-point • Proportion of subjects with Day 11 plasma HIV-1 RNA <400c/mL or at least 0.7 log10 c/mL below their Baseline value • Secondary End-points • Includes measures of safety, antiviral response, INI-resistance emergence and pharmacokinetic parameters at Day 11 and over time

  5. Baseline Characteristics

  6. Baseline (Day 1) Viral IN Mutation Pathways and Phenotypic Susceptibility to S/GSK1349572 Fold Change, median (range): RAL 161 (0.6 - >166) S/GSK1349572 1.5 (0.6 - 35) • More advanced Q148 pathway genotypes exhibit higher fold change to S/GSK1349572 20 Mixtures: n=1 Q148H + G140S / Y143H n=1 Q148H+ E138A+G140S / Y143H Others: n=1 E92Q (screen: E92Q, N155H) n=1 none (screen: G140G/S, Q148H/Q) 10 6 Baseline 572 Fold Change 4 2 1 0.6 Q148+2 n=3 Q148+1n=4 Mixture n=2 N155n=4 Y143 n=12 Other IN mutations n=2 Baseline Mutation Pathway

  7. Plasma HIV-RNA Response at DAY 11 by Viral IN Baseline Genotypic Profile * Halted enrollment early in this group due to less robust virologic response

  8. Q148 + 2 Q148 + 1 Mixture Y143 N155 Other Virologic Response at DAY 11: Correlation with Baseline Fold Change (FC) in Susceptibility to S/GSK1349572 • Strong correlation between baseline FC and Day 11 response (r=0.79, p value <0.001) -0.5 -1.0 Day 11 VL Change From Baseline (log 10 c/mL) -1.5 -2.0 Mixtures: N=1 Q148H + G140S / Y143H N=1 Q148H+ E138A+G140S / Y143H Others: N=1 E92Q (screen: E92Q, N155H) N=1 none (screen: G140G/S, Q148H/Q) -2.5 0.5 1.0 2.0 5.0 10.0 20.0 Day 1 S/GSK1349572 Fold Change

  9. HIV IN Genotypic and Phenotypic Changes at Day 11 • 18* paired viral isolates (Day 1 & Day 11) were evaluated • No signature RAL mutations emerged on therapy • 17 paired isolates: susceptibility change was <2 fold • 1 paired isolate: susceptibility change was ~6-fold • Detailed resistance data presented by Clotet B et al. TUPE0130 IAC 2010 *Viral load too low to analyze genotype and phenotype in remaining isolates at Day 11

  10. Adverse Events • Most common clinical AEs (>1 subject): Diarrhea & insomnia (3/27 subjects, 11%) • Grade 3/4 clinical AEs: 3 (11%) subjects • Grade 3: syncope & vertigo (n=1), hypercholesterolaemia (n=1) • Grade 4: neurosyphilis (n=1) • Drug related AEs: 4 (15%) subjects • Grade 1: diarrhoea & nausea (n=1), anaemia (n=1) • Grade 2: fatigue & insomnia (n=1), diarrhoea (n=1) • Grade 3 laboratory toxicities: 6 (22%) subjects • 1 amylase increase • 1 total cholesterol increase • 2 lipase increase • 2 phosphorus decrease • No Grade 4 laboratory toxicities • Serious Adverse Events: 2 (7%) subjects, neither considered related to S/GSK1349572 • 1 neurosyphilis ~ Wk 1 • 1 brain mass ~ Wk 6

  11. VIKING Study Conclusions • Baseline isolates exhibited high FC in susceptibility to RAL (median 161) with substantially lower FC in susceptibility to S/GSK1349572 (median 1.5). • A broad spectrum of susceptibility to S/GSK1349572 ranging from 0.6 to 35 was observed • 21/27 (78%) subjects achieved the primary end-point (<400c/mL or a ≥0.7log10c/mL decline in plasma HIV-1 RNA) at Day 11 • 18/18 subjects with isolates exhibiting the N155H, Y143H pathways achieved the primary end-point • A strong correlation was observed between change from baseline in plasma HIV-1 RNA and baseline fold change in susceptibility to S/GSK1349572 • S/GSK1349572 was generally well tolerated in this advanced HIV-1 infected population

  12. Acknowledgments • All SUBJECTS who participated in VIKING in the screening or treatment phases • VIKING Investigators: • France: Jacques Reynes, Isabelle Poizot-Martin, Jacques Durant, Philippe Morlat, Daniel Vittecoq, Christine Katlama, Jean-Michel Livrozet • Italy: Adriano Lazzarin • Spain: Bonaventura Clotet, Vincente Soriano • USA: Edwin DeJesus, Joseph J. Eron Jr., Trevor Hawkins, Princy Kumar, Jacob P Lalezari, Anthony LaMarca, Gary J Richmond, Louis A Sloan, Benjamin Young • Contributors from GSK, SHIONOGI and ViiV HC

  13. Backups 13

  14. S/GSK1349572 Day 10 PK Parameters Geometric Mean (95% Confidence Interval) GSK1349572 PK observed in VIKING is consistent with accumulated PK data in humans.

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