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Barry Zingman 1 , Jamal Suleiman 2 , Edwin DeJesus 3 , Jihad Slim 4 , Carmen Mak 5 , Michael McCarthy 5 , Natalie Case 5

Vicriviroc, a Next Generation CCR5 Antagonist, Exhibits Potent, Sustained Suppression of Viral Replication in Treatment-Experienced Adults: VICTOR-E1 48-week Results.

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Barry Zingman 1 , Jamal Suleiman 2 , Edwin DeJesus 3 , Jihad Slim 4 , Carmen Mak 5 , Michael McCarthy 5 , Natalie Case 5

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  1. Vicriviroc, a Next Generation CCR5 Antagonist, Exhibits Potent, Sustained Suppression of Viral Replication in Treatment-Experienced Adults: VICTOR-E1 48-week Results Barry Zingman1, Jamal Suleiman2, Edwin DeJesus3, Jihad Slim4, Carmen Mak5, Michael McCarthy5, Natalie Case5, and Lisa Dunkle5 Montefiore Medical Center, Bronx, NY, US1, Brazilmed Assistencia Medica e Pesquisa, Sao Paolo, Brazil2, Orlando Immunology Center, Orlando, FL, US3, St. Michael`s Medical Center- Infectious Diseases, Newark, NJ, US4, and Schering-Plough Research Institute, Kenilworth, NJ, US5 15th Conference on Retroviruses and Opportunistic Infections Boston, MA, USA, February 3-6, 2008, 39LB

  2. Oral CCR5 receptor antagonist Plasma concentrations increased markedly by CYP3A4 inhibitors1 Plasma half-life >24 hours Once-daily dosing2 No food effect3 Potent and durable antiretroviral activity in CCR5-tropic ART-experienced subjects4 Vicriviroc O N F N F O N F N N • Sansone A, et al. CROI 2006 [abstr. 582]. • Seiberling M, et al. IWCPHT 2005 [poster 6.4]. • Sansone A, et al. ICAAC 2005 [abstr. A-1200]. • Gulick R, et al. JID 2007;196:304-12.

  3. VICTOR E-1 Phase 2 Study Design Planned interim 24 week analysis *Optimized background therapy; >3 drugs, including a PI with >100 mg RTV. • Key Eligibility Criteria • R5 tropic virus; HBV/HCV co-infection allowed • Triple-class experienced: >1 RTI and >1 PI resistance mutation required • HIV-RNA >1000 copies/mL • Stable ARV >6 weeks prior to screening • Acceptable laboratory parameters • Primary Efficacy Endpoint • Mean change in log10 HIV RNA at Wk 48 • Secondary Efficacy Endpoints • % subjects <50 copies/mL • % subjects <400 copies/mL

  4. Demographics and Baseline Characteristics * Defined as fully sensitive treatment in OBT by Monogram PhenoSense

  5. Patient Disposition Through Week 48

  6. Primary Study Endpoint Overall Population Subjects Baseline HIV-1 RNA >100,000 copies/mL VCV 30 mg VCV 20 mg Placebo Placebo VCV 20 mg VCV 30 mg + OBT + OBT + OBT + OBT + OBT + OBT n = 39 n = 40 n = 35 n = 10 n = 12 n = 12 0 0 -0.2 - 0.2 -0.4 - 0.4 -0.6 - 0.6 -0.8 - 0.8 -0.79 Mean Change in HIV-1 RNA from baseline (log 10 copies/ml) Mean Change in HIV-1 RNA from baseline (log 10 copies/ml) -1 - 1 -1.2 - 1.2 -1.14 - 1.4 -1.4 -1.47 - 1.6 -1.6 Difference: -.33 - 1.8 -1.8 -1.75 -1.75 -1.77 Difference: -.61 Difference: -.98 P=0.0026* Difference: -.98 P=0.0017* - 2 -2 Mean Change in HIV-1 RNA from Baseline at Week 48All ITT Subjects *Comparing VCV to Control based on ANOVA Missing values of change from baseline imputed by the average of immediately preceeding and following non-missing values; in other cases, missing values imputed by zero.

  7. % Subjects with HIV-1 RNA <400 Copies/mL at Week 48 By No. Active Drugs in OBT* Overall ≥3 2 1 0 100% 85% 90% 83% 83% p=0.0004 30 mg 80% 71% 69% 67% 70% 60% 57% 60% VCV 30 mg + OBT % of Subjects 46% 50% 45% VCV 20 mg + OBT 40% 33% Placebo + OBT 26% 30% 25% 18% 20% 10% 0% 0% 7 8 7 N = 26 24 9 7 6 6 6 13 11 16 13 11 * OSS: Defined as fully sensitive treatment in OBT by Monogram PhenoSense. Partially sensitive patients were designated as resistant

  8. % Subjects with HIV-1 RNA <400 Copies/mL at Week 48 By No. Active Drugs in OBT* Overall ≥3 2 1 0 100% 90% 83% p=0.0002 30 mg 80% 77% 71% 67% 70% 62% 60% 56% 53% VCV 30 mg + OBT % of Subjects 50% VCV 20 mg + OBT 38% 40% Placebo + OBT 29% 30% 27% 18% 20% 14% 12% 10% 0% 0% 0% 7 8 7 N = 26 24 9 7 6 6 6 13 11 16 13 11 * OSS: Defined as fully sensitive treatment in OBT by Monogram PhenoSense. Partially sensitive patients were designated as resistant

  9. Mean Change in CD4 Count from Baseline at Week 48 p = 0.04 (95% CI: +3.6, +135) Difference: +69 150 p = 0.26 (95% CI: -28.1, +103) Difference: +37 134 102 100 Mean Change in CD4 Count from Baseline at Week 48 65 50 0 VCV 30 mg + OBT N = 39 VCV 20 mg + OBT N = 39 Placebo + OBT N = 35

  10. Adverse Event Rate by Time on Study *Rate>10/100 person-years.

  11. Grade 3/4 Liver Enzyme Elevations All treated subjects. *DAIDS Criteria

  12. Occurrence by time 30 mg 10/12 (83%) < 8 weeks 20 mg 4/8 (50%) < 8 weeks PBO 3/5 (60%) < 8 weeks Detection of DM/X4 Variants 45 40 35 30 25 20 15 10 5 0 30 mg 20 mg PBO Total Subjects Number with DM/X4 # D/Ced with >400 copies/mL

  13. Cmin Threshold: Correlation with Virologic Efficacy Relationship between Vicriviroc Cmin and HIV RNA Virologic Suppression Cmin vs. Treatment Groups 500 70% Median 60% 400 50% 300 40% Cmin 30% 202 200 141 20% 100 10% 0 0% < 100 > 100 Placebo n = 35 20 mg N = 40 30 mg N = 39 Cmin (ng/mL) Treatment Groups HIV RNA<50 HIV RNA <400

  14. VICTOR E-1 Conclusions • Vicriviroc + OBT was significantly superior to OBT alone in this ART-experienced population • added benefit was achieved regardless of number of active drugs in OBT • trends to superiority of 30 mg dose were observed in subjects with >100,000 copies/mL HIV-1 RNA and ≤1 active drug in OBT • greater efficacy was associated with Cmin >100 ng/mL • Detection of DM/X4 virus occurred early in treatment in a small number of subjects and was not necessarily associated with discontinuation • No clinically relevant safety differences observed between vicriviroc and placebo • Vicriviroc, a potent CCR5 antagonist, has strong potential as a new treatment option for HIV-infected subjects • Vicriviroc 30 mg QD was selected for ongoing phase 3 clinical trials in ART-experienced subjects

  15. Acknowledgements Jose Luiz de Andrade Neto, MD Jonathan Angel, MD Cynthia Brinson, MD Clovis Arns da Cunha, MD Margareth da Eira, MD Edwin DeJesus, MD Ellen de Mendivelson, MD Ricardo Sobhie Diaz, MD Joseph Gathe, MD Beatriz Grinsztejn, MD David Henry, MD Christian Hoffman, MD Shubha Kerkar, MD Maria Patelli Juliana Souza Lima, MD Max Igor Banks Ferreira Lopes, MD Jose Valdez Ramalho Madruga, MD Javier O. Morales-Ramirez, MD Eduardo Martins Netto, PhD Rebeca Northland, MD All of the PLWHA participating in the trial Investigators and the study site staff Milos Opravil, MD Michael Para, MD Maria Patelli Juliani Souza Lima, MD Rogerio De Jesus Pedro, MD Jennifer A. Pitt, MPH Carlos Rodriguez, MD Peter Ruane, MD Gladys E. Sepulveda-Arzola, MD Jihad Slim, MD Louis Sloan, MD Fiona Smaill, MD Jamal Muhamad Abdul Hamid Suleiman, MD Otto Sussman, MD Melanie Thompson, MD Angela Tobon, MD William Towner, MD Thanes Vanig, MD Sharon Walmsley, MD Barry Zingman, MD

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