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Next Generation HIV Integrase Inhibitors

S/GSK1265744: A Next Generation Integrase Inhibitor (INI) with Activity Against Raltegravir-Resistant Clinical Isolates. 1 Mark R Underwood, 1 Marty St Clair, 1 Brian A Johns, 2 Akihiko Sato, 2 Tamio Fujiwara, 1 William Spreen

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Next Generation HIV Integrase Inhibitors

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  1. S/GSK1265744: A Next Generation Integrase Inhibitor (INI) with Activity Against Raltegravir-Resistant Clinical Isolates 1Mark R Underwood, 1Marty St Clair, 1Brian A Johns, 2Akihiko Sato, 2Tamio Fujiwara, 1William Spreen 1GlaxoSmithKline Inc., RTP, NC, United States; 2Shionogi & CO., LTD., Osaka, Japan

  2. Next Generation HIV Integrase Inhibitors • Develop multiple compounds with1: • Low mg and once daily dosing without PK booster • Good potency against clinically important INI mutants • Potential for higher barrier to resistance • S/GSK1349572: Lead INI in Phase2b Development • Activity against RAL-resistant isolates in vitro2 and in vivo3,4 • Antiviral activity in treatment naïves5 • S/GSK1265744: Backup to S/GSK1349572 • Present study: evaluate activity against clinically important site directed INI mutants and INI resistant clinical isolates 1 Johns B. et al. 7th Conference on Retroviruses and Opportunistic Infections. Oral Paper 55. 2010. 2 Underwood. et al. International AIDS Poster WEPEA098. 2009. 3 Eron J. et al. International AIDS Conference. Oral MOAB0105. 2010. 4 Clotet B. et al. International AIDS Conference. Poster TUPE130. 2010. 5 Nichols G et al. International AIDS Conference. Oral THLBB205 2010.

  3. Study Methods and Samples • Assay via Monogram Biosciences Integrase PhenoSense1 • Thirty-nine clinical isolate samples • Nine isolates (e.g. pre-RAL therapy) had wildtype IN sequence • Thirty had IN resistance mutations including Y143, N155, and Q148 • Twenty two longitudinal isolate samples from nine patients2 (SCOPE) • Eight isolate samples from Monogram library • Eleven RAL resistant SDMs included for breadth and as controls • Fold change (FC) as proportional change in IC50 vs. wild type virus 1 Fransen S, et al. 2008. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy 2 Hatano H, et al. 2010. J Acquir Immune Defic Syndr.

  4. Activity Against Viral Isolates Evolving During RAL + OBR Therapy - I RAL Therapy * >81 * * Subject 9 RAL G140S/Q, Q148H E138E/A, G140G/S, Q148Q/H E138E/K, G140G/S, Q148Q/H N155N/H G140G/S, Q148Q/H E138E/M, G140G/S, Q148Q/H S/GSK1265744 WT S/GSK1265744 FC IC50 range − 0.89 (WT) to 7.83

  5. Activity Against Viral Isolates Evolving DuringRAL + OBR Therapy - II Subject 1 Subject 4 40.00 100.0 * RAL >87 stopped * * Max FC IC50 = 12.6 (Month 7.8) MAX FC IC50 = 1.92 (Month 7.5) 90.0 35.00 80.0 30.00 N155H G140S, Q148H 70.0 25.00 60.0 FC IC50 FC IC50 20.00 50.0 RAL RAL 40.0 15.00 30.0 10.00 20.0 S/GSK1265744 WT 5.00 10.0 S/GSK1265744 WT WT 0.00 0.0 0 2 4 6 8 10 - 2 0 2 4 6 8 10 Months following RAL initiation Months following RAL initiation Subject 6 Subject 10 90.00 * >81 90.00 * MAX FC IC50 = 5.94 (Month 2.8) Max FC IC50 = 1.23 (Month 5.6) * > 81 * E92Q, 80.00 80.00 N155N/H, T97T/A, 70.00 G140G/S, 70.00 Y143Y/C Q148Q/R T97A, 60.00 60.00 Y143Y /C E92E/Q, 50.00 50.00 T97T/A, FC IC50 FC IC50 Y143R RAL 40.00 40.00 30.00 30.00 RAL 20.00 20.00 10.00 S/GSK1265744 10.00 WT S/GSK1265744 0.00 0.00 - 2 0 2 4 6 8 0 5 10 15 20 Months following RAL initiation Months following RAL initiation

  6. Activity Against Single IN Resistance Mutations S/GSK1265744 RAL 100.00 10.00 Log FC 1.00 0. 1 0 E92Q Genotype Q148R N155H N155H N155H Q148H Q148K S153Y N155H N155H N155H Sample¥ SD SD SD SD SD SD L L 4 4 7 ¥ SD: site direct mutant, L: Monogram library isolate, Single digit :SCOPE isolate

  7. S/GSK1265744 RAL Activity Against Y143 or N155 + ≥1 IN Mutation * * * * * 100.00 10.00 Log FC 1.00 0. 1 0 E92Q, N155H T97A, E138E/K, Y143R T97A, Y143Y/C T97A, Y143R T97A, Y143C Genotype E92Q, N155H E92E/Q, T97T/A, Y143R T97T/A, N155N/H T97T/A, Y143Y/C T97T/A, Y143Y/C Sample¥ SD 5 5 L 6 6 6 8 10 L ¥ SD: site direct mutant, L: Monogram library isolate, Single digit :SCOPE isolate * >81 - >87 FC

  8. Activity Against 148H or 148R + 140S Genotypes S/GSK1265744 RAL * * * * * * * * * * 100.00 10.00 Log FC 1.00 G140S, Q148R G140S, Q148H G140S, Q148H G140S, Q148H G140S, Q148H G140S, Q148H G140S, Q148H G140S, Q148R G140S, Q148H G140S, Q148R G140S, Q148H Genotype G140G/S, Q148Q/H Sample¥ 9 SD L L 1 1 2 3 9 SD L L ¥ SD: site direct mutant, L: Monogram library isolate, Single digit :SCOPE isolate * >87 FC

  9. Activity Against 148H/K/R + 138A/K Genotypes S/GSK1265744 RAL * 100.00 * * * 10.00 Log FC 1.00 E92Q, N155N/H, G140G/S, Q148Q/R E138E/K, G140G/S, Q148Q/H, N155N/D E138E/A, G140G/S, Q1481/H E138E/A, G140G/S, Q1481/H E138E/A, G140G/S, Q1481/H E138E/A, G140G/S, Q1481/H E138K, Q148K E138K, Q148R Genotype Sample¥ SD SD 9 9 9 9 10 9 ¥ SD: site direct mutant, L: Monogram library isolate, Single digit :SCOPE isolate * >81 - >87 FC

  10. Summary of Activity Across All Isolates • 83% (25/30) were > 5-fold more susceptible to S/GSK1265744 than RAL • 19/22 longitudinal isolates (SCOPE) • 6/8 Monogram library isolates • 60% (18/30) isolates had RAL FC > 50 • 30/30 isolates had S/GSK1265744 FC ≤ 40 and 67% (20/30) had FC < 5

  11. S/GSK1265744 had greatest activity against virus with Y143 and N155H genotypes and had broadest range of activity and highest FC IC50 against Q148 genotypes Summary of Activity for Isolates Relative to RAL Signature Resistance Mutations

  12. S/GSK1265744 had significant activity against a broad panel of viruses with RAL resistant genotypes Viruses with Y143 and N155H genotypes or Q148 alone had greatest susceptibility to S/GSK1265744 S/GSK1265744 activity against viruses with Q148 mutations plusadditional mutations was variable Sources of variability may include presence of mixtures or additional as yet unidentified secondary mutations S/GSK1265744 has a virologic resistance profile distinct from RAL, and consistent with the potential to treat patients with RAL resistance Conclusions

  13. Acknowledgements The authors gratefully acknowledge the patients in the UCSF SCOPE Cohort, SG Deeks, UCSF, and many others at Shionogi, GSK, and ViiV. S/GSK1265744 is owned by Shionogi-ViiV Healthcare LLC.

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