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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
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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
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MOTIVATE 1 Trial Design OBT* + placebo OBT* + maraviroc (150 mg† QD)
Randomization 1:2:2 N=601 OBT* + placebo OBT* + maraviroc (150 mg† QD) OBT* + maraviroc (150 mg† BID) Screening (6 weeks) 24w 48w Patient eligibility criteria: R5 HIV-1 infection HIV-1 RNA ≥5,000 copies/mL Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks Resistance to and/or ≥ 6 months’ experience with ≥ one ARV from three classes (≥ two for PIs) Patients stratified by: Enfuvirtide use in OBT HIV-1 RNA < 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
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Demographics and Baseline Characteristics
Includes all patients who received at least one dose of study medication (full analysis set) Treated N=585 § OBT alone N=118 MVC QD + OBT N=232 MVC BID + OBT N=235 Mean age, yrs (range) 46 (31–71) 46 (19–75) 46 (25–69) Male, n (%) 106 (90) 210 (91) 212 (90) White, n (%) 99 (84) 187 (81) 197 (84) Median CD4+ count*, cells/mm3 (range) 160 (1675) 168 (1812) 150 (2678) Mean HIV-1 RNA*, log10 copies/mL (range) (3.466.02) (3.206.75) (3.266.88) Enfuvirtide in OBT, % 42 44 46 ≤2 active drugs in OBT†, % 65 69 75 Tipranavir use in OBT, % 11 10 Darunavir use in OBT Not Permitted § 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
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Mean Change from Baseline in HIV-1 RNA
Includes all patients who received at least one dose of study medication MVC QD + OBT (N=232) MVC BID + OBT (N=235) OBT alone (N=118) Study week 24 48 from baseline (log10 copies/mL) Mean change in HIV-1 RNA 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
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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%) OBT alone (N=118) MVC QD + OBT (N=232) MVC BID + OBT (N=235) <400 copies/mL <50 copies/mL 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 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% 4 8 12 16 20 24 28 32 36 40 44 48 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< vs OBT alone #P< vs OBT alone MOTIVATE 1-Week 48
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Mean Change from Baseline in CD4+ Count
Includes all patients who received at least one dose of study medication MVC QD + OBT (N=227) MVC BID + OBT (N=233) OBT alone (N=116) 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 baseline in CD4+ count (cells/mm3) 24 48 Study week Last observation carried forward * P< vs OBT alone MOTIVATE 1-Week 48
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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 MVC QD + OBT MVC BID + OBT OBT alone <100,000 copies/mL ≥100,000 copies/mL Total population Patients (%) N = Last observation carried forward * Protocol-defined randomization stratum MOTIVATE 1-Week 48
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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 OBT alone Maraviroc QD + OBT Maraviroc BID + OBT <400 copies/mL <50 copies/mL Patients (%) N= ENF first use ENF experienced/ resistance 91 108 59 30 75 72 ENF first use ENF experienced/ resistance 91 108 59 30 75 72 MOTIVATE 1 & 2-Week 48 Last observation carried forward
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Safety Analyses Unadjusted for Duration of Exposure
Includes all patients who received at least one dose of study medication All causalities and severities OBT alone N=118 MVC QD + OBT N=232 MVC BID + OBT N=235 Total exposure, patient-years 64 168 169 Patients with AEs 86% 90% 92% Patients discontinuing due to AEs 6% 5% Patients with grade 3 AEs 25% 17% 23% Patients with grade 4 AEs 7% 9% 10% Patients with SAEs 16% 14% Patients with Category C events Deaths* 1% 2% AEs = adverse events; SAEs = serious adverse events *Includes deaths reported up to 28 days after stopping study drug No deaths were related to study drug according to the investigator MOTIVATE 1-Week 48
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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 (%) MOTIVATE 1-Week 48 RTI = respiratory tract infection; ISR = injection site reaction
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Number of Category C Events
Includes all patients who received at least one dose of study medication Event, n OBT alone N=118 MVC QD + OBT N=232 MVC BID + OBT N=235 Total exposure, patient-years 64 168 169 Cryptosporidial gastroenteritis 1 Cytomegalovirus infection* Herpes simplex 2 5 Mycobacterium avium Esophageal candidiasis 6 Pneumocystis jiroveci pneumonia Pneumonia Progressive multifocal leukoencephalopathy Kaposi’s sarcoma Lymphoma* Total number of events Total number of patients, n (% ) 6 6 patients (5.1%) patients (4.7%) patients (5.1%) * Includes T-cell and diffuse large B-cell lymphomas MOTIVATE 1-Week 48
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Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline
All causalities, n (%) Unadjusted for duration of exposure OBT alone N=116* MVC QD + OBT N=228* MVC BID + OBT N=234* AST: Grade 3 (5–10 x ULN†) Grade 4 (>10 x ULN†) 4 (3.4) 0 7 (3.1) 3 (1.3) 7 (3.0) 4 (1.7) ALT: Grade 3 (5–10 x ULN†) Grade 4 (>10 x ULN†) 2 (1.7) 0 11 (4.8) 1 (0.4) 5 (2.1) 3 (1.3) Total bilirubin: Grade 3 (2.5–5 x ULN†) Grade 4 (>5 x ULN†) 4 (3.4) 2 (1.7) 17 (7.4) 2 (0.9) 10 (4.3) 2 (0.9) * Total patients evaluated for each laboratory parameter † Upper limit of normal MOTIVATE 1-Week 48
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MOTIVATE 1 and 2: Change in CD4+ Cell Count from Baseline by Tropism Result at Time of Failure
Tropism result, Baseline → Treatment Failure Mean change from baseline in CD4+ count in patients with treatment failure (cells/mm3 ) OBT alone N=271 MVC QD + OBT N=477 MVC BID + OBT N=487 All treatment failures* +24 (n=111) +64 (n=92) +74 (n=96) R5 → R5 +25 (n=89) +77 (n=33) +133 (n=24) R5 → D/M or X4 +61 (n=6) +47 (n=35) +57 (n=41) * 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
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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
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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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