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47th ICAAC Chicago, USA, September 17–20, 2007

47th ICAAC Chicago, USA, September 17–20, 2007. Efficacy and Safety of Maraviroc in Antiretroviral-Experienced Patients Infected With CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1.

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47th ICAAC Chicago, USA, September 17–20, 2007

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  1. 47th ICAAC Chicago, USA, September 17–20, 2007 Efficacy and Safety of Maraviroc in Antiretroviral-Experienced Patients Infected With CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1 J Lalezari1, J Goodrich2 , E DeJesus3, R Gulick4, H Lampiris5, M Saag6, N Bellos7, J Nadler8, P Tebas9, B Trottier10, M Wohlfeiler11, C Ridgeway12, M McHale12, E van der Ryst12, H Mayer2, on behalf of the MOTIVATE 1 Study Team 1Quest Clinical Research, UCSF, San Francisco, CA, USA 2Pfizer Global Research and Development, New London, CT, USA 3Orlando Immunology Center, Orlando, FL, USA 4Weill Medical College of Cornell University, New York, NY, USA 5San Francisco Veterans Affairs Medical Center, UCSF, San Francisco, CA, US 6University of Alabama at Birmingham, Birmingham, AL, USA 7Southwest Infectious Disease Associates, Dallas, TX, USA 8University of South Florida, Tampa, FL, USA 9University of Pennsylvania, Philadelphia, PA, USA 10Clinique Medicale L'Actuel, Montreal, QC, CANADA 11Wohlfeiler, Piperato & Associates, North Miami Beach, FL, USA 12Pfizer Global Research and Development, Sandwich, UK

  2. Background • MOTIVATE 1 is one of two randomized, double-blind, placebo-controlled, Phase 3 studies investigating the safety and efficacy of the CCR5 antagonist maraviroc, in treatment-experienced patients with R5 HIV-1 • In a planned interim analysis at 24 weeks1, maraviroc (QD and BID) + OBT vs OBT alone demonstrated • significantly greater virologic suppression rates • significantly greater increases in CD4+ count • no clinically relevant differences in safety profile • The MOTIVATE 1 primary efficacy endpoint is the change from baseline in HIV-1 RNA at 48 weeks 1. Lalezari J et al. 14th CROI 2007; Presentation 104bLB

  3. MOTIVATE 1 Trial Design Randomization 1:2:2 N=601 OBT* + placebo OBT* + maraviroc (150 mg† QD) OBT* + maraviroc (150 mg† BID) Screening(6 weeks) 0 24w 48w • Patient eligibility criteria: • R5HIV-1 infection • HIV-1RNA ≥5,000 copies/mL • Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks • Resistance to and/or ≥ 6 months’ experience with ≥ one ARVfrom three classes (≥ two for PIs) • Patients stratified by: • Enfuvirtide use in OBT • HIV-1RNA < and ≥100,000 copies/mL at screening * OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV) † Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC

  4. Demographics and Baseline Characteristics Includes all patients who received at least one dose of study medication (full analysis set) § Two patients (1 MVC QD, 1 OBT alone) were assigned to the wrong treatment group due to a transcription error* Calculated for each patient as the mean of up to three pre-dose assessments (screening, randomization, and baseline)† According to overall susceptibility score MOTIVATE 1-Week 48

  5. OBT alone (N=118) MVC QD + OBT (N=232) MVC BID + OBT (N=235) Mean Change from Baseline in HIV-1 RNA Includes all patients who received at least one dose of study medication Study week 24 48 Mean change in HIV-1 RNA from baseline (log10 copies/mL) Difference: -0.85* (97.5% CI: -1.22, -0.49) Difference: -0.79* (97.5% CI: -1.14, -0.44) Difference: -1.02* (97.5% CI: -1.39, -0.66) Difference: -0.92* (97.5% CI: -1.28, -0.57) HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks*Treatment difference vs OBT alone MOTIVATE 1-Week 48

  6. MVC BID + OBT (N=235) MVC QD + OBT (N=232) OBT alone (N=118) 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Percentage of Patients with Undetectable HIV-1 RNA Includes all patients who received at least one dose of study medication Number of patients remaining on study treatment at Week 48: OBT alone, 27 (30%); MVC QD + OBT, 109 (60%); MVC BID + OBT, 127 (66%) <400 copies/mL <50 copies/mL 60.4%* 57.5%* 48.5%* 46.8%* Patients(%) 54.7%* 50.9%* 42.2%# 41.8%* 31.4% 24.6% 22.0% 16.1% 0 4 8 12 16 20 24 28 32 36 40 44 48 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (weeks) Time (weeks) HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks*P<0.0001 vs OBT alone#P<0.0006 vs OBT alone MOTIVATE 1-Week 48

  7. OBT alone (N=116) MVC QD + OBT (N=227) MVC BID + OBT (N=233) Mean Change from Baseline in CD4+ Count Includes all patients who received at least one dose of study medication Difference: +69 *(95% CI: +44, +93) Difference: +59 *(95% CI: +35, +83) Difference: +59 *(95% CI: +34, +84) Difference: +55 *(95% CI: +30, +79) Mean change from baselinein CD4+ count (cells/mm3) 24 48 Study week Last observation carried forward* P<0.0001 vs OBT alone MOTIVATE 1-Week 48

  8. OBT alone MVC QD + OBT MVC BID + OBT Percentage of Patients With HIV-1 RNA <50 copies/mL at Week 48 According to Screening HIV-1 RNA* Includes all patients who received at least one dose of study medication and had a post-baseline observation <100,000 copies/mL ≥100,000 copies/mL Total population Patients (%) N = 70 135 139 46 93 95 116 228 234 Last observation carried forward* Protocol-defined randomization stratum MOTIVATE 1-Week 48

  9. OBT alone Maraviroc QD + OBT Maraviroc BID + OBT 59 59 91 91 108 108 30 30 75 75 72 72 ENF first use ENF first use ENF experienced/resistance ENF experienced/resistance MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use <400 copies/mL <50 copies/mL Patients (%) N= MOTIVATE 1 & 2-Week 48 Last observation carried forward

  10. Safety Analyses Unadjusted for Duration of Exposure Includes all patients who received at least one dose of study medication AEs = adverse events; SAEs = serious adverse events*Includes deaths reported up to 28 days after stopping study drugNo deaths were related to study drug according to the investigator MOTIVATE 1-Week 48

  11. Incidence of Adverse Events Occurring in ≥10% of Patients in Any Group, Unadjusted for Exposure Includes all patients who received at least one dose of study medication Total exposure in patient-years: OBT alone 64, MVC QD + OBT 168, MVC BID + OBT 169 OBT alone (N=118) MVC QD + OBT (N=232) MVC BID + OBT (N=235) Patients (%) RTI = respiratory tract infection; ISR = injection site reaction MOTIVATE 1-Week 48

  12. Number of Category C Events Includes all patients who received at least one dose of study medication *Includes T-cell and diffuse large B-cell lymphomas MOTIVATE 1-Week 48

  13. Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline * Total patients evaluated for each laboratory parameter†Upper limit of normal MOTIVATE 1-Week 48

  14. MOTIVATE 1 and 2: Change in CD4+ Cell Count from Baseline by Tropism Result at Time of Failure * Includes patients with non-reportable/non-phenotypable tropism result at baseline and patients with non-reportable/non-phenotypable/missing tropism result at time of failure MOTIVATE 1 & 2-Week 48

  15. MOTIVATE 1: Summary of 48-Week Primary Analysis • Maraviroc (BID or QD) + OBT provided significantly greater virologic suppression rates and increases in CD4+ count compared to OBT alone at 48 weeks in this treatment-experienced population • No new or unique safety findings emerged • Adverse events, serious adverse events, and lab abnormalities (including grade 3/4 transaminase elevations) occurred with similar frequency between treatment groups • Category C (AIDS-defining events) were balanced across treatment groups • These results demonstrate that treatment with maraviroc + OBT provides sustained antiretroviral efficacy and tolerability in treatment-experienced patients

  16. Acknowledgments • Investigators and study site staff • Patients who participated in the study • Colleagues from Monogram Biosciences: J Whitcomb, E Coakley, C Petropoulos • R Harrigan, BC Centre for Excellence in HIV • Colleagues from Quintiles • Colleagues from Pfizer: S Felstead, A Bullivant, I Oborska, K George, M Westby, K Turner, D Lindell, D Paige, S Nuttall, J Merson, L Kapili, M Dunne

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