AREVIR 11.04.2008 CCR5 Antagonists Antagonists CCR5 In Clinical - PowerPoint PPT Presentation

AREVIR 11.04.2008 CCR5 Antagonists Antagonists CCR5 In Clinical Clinical Practice Practice In Dr. Bjö örn Jensen rn Jensen Dr. Bj Klinik fü ür r Gastroenterologie Gastroenterologie, , Hepatologie Hepatologie und und Infektiologie Infektiologie Klinik f Universitä ätsklinikum D tsklinikum Dü üsseldorf sseldorf Universit

Chemokine Receptor Tropism Study/Source Population N R5, % D/M, % X4, % ACTG 5211 [1] Experienced 391 49 47 4 SCOPE [2] Experienced 186 60 39.5 0.5 MOTIVATE 1 & 2 [3] Experienced 2560 56 41 3 TORO [4] Experienced 627 50 48 2 HOMER cohort [5] Naive 979 82 18 < 1 Chelsea & Naive 402 81 19 < 1 Westminster cohort [6] Demarest [7] Naive 299 88 12 0 Pfizer 1026 [3] Naive 1428 85 15 < 1 1. Wilkin T, et al. CROI 2006. Abstract 655. 2. Hunt, et al. J Infect Dis. 2006;194:926-930. 3. Coakley E, et al. Second Viral Entry Wkshp. Abstract 8. 4. Melby T, et al. EI 2005. 5. Brumme ZL, et al. J Infect Dis. 2005;192:466-474. 6. Moyle GJ, et al. J Infect Dis. 2005;191:866-872. 7. Demarest J, et al. ICAAC 2004. Abstract H-1136.

Association Between Tropism and baseline CD4+ Cell Count Cross-sectional Canadian study of 979 patients beginning triple therapy BL CD4+ R5 virus, % D/M or X4 virus, % cell count, cells/mm 3 > 500 93 7 350-499 91 9 200-349 91 9 100-199 72 28 50-99 74 26 25-49 69 31 < 25 46 54 Brumme ZL, et al. J Infect Dis. 2005;192:466-474.

Consequences for the clinician � Demand for a tropism test which should be readily available and should produce reliable results as soon as possible in almost all patients � Problems: � patients with low viremia (esp. phenotypic tests) � time lag between sampling and receiving the result/starting therapy � minorities (clinical relevance?) � Non-B-Subtypes?

MERIT Study: Trial Design Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)* Randomization 1:1 Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)* Screening 0 96 wk 48 wk (6 weeks) First Primary patient visit analysis Nov 2004 Patient eligibility criteria: • ≥ 16 years of age • HIV-1 RNA ≥ 2,000 copies/mL • Treatment naive • No evidence of resistance to EFV, ZDV, or 3TC • R5 HIV-1 infection Patients stratified by: • HIV-1 RNA < and ≥ 100,000 copies/mL at screening • Geographic location: Northern Hemisphere and Southern Hemisphere *Patients experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative NRTI Saag M, et al. IAS 2007. Abstract WESS104.

Percentage of Patients with Undetectable HIV-1 RNA at Week 48 (Primary Endpoint) <400 copies/mL <50 copies/mL 100 –3.0* (–9.5 † ) –4.2* (–10.9 † ) 90 EFV + CBV 80 73.1 70.6 69.3 MVC + CBV 70 65.3 Patients (%) 60 50 40 30 20 10 0 N= 360 361 360 361 Includes all patients who received at least one dose of study medication, ITT *Difference (adjusted for randomization strata) † Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10% Saag M, et al. IAS 2007. Abstract WESS104.

MERIT: Maraviroc vs Efavirenz in Treatment-Naive Pts � MVC failed to meet primary endpoint of noninferiority in HIV-1 RNA <50 copies/mL at Week 48 (lower 97.5% CI: -10.9%) � MVC noninferior in HIV-1 RNA < 400 copies/mL � MVC associated with higher CD4+ cell count increases � Superior safety profile for MVC vs EFV

MERIT Substudy: Viral Suppression at Week 48 by Baseline Tropism Change in detected HIV-1 tropism � from R5 at screening to D/M at BL and potentially adherence may Patients With VL < 50 c/mL at Week 48 (%) 100 explain some treatment failures on EFV 90 MVC MVC 80 � 3.5% of patients experienced 69.3 69.3 68.0 70 65.3 change in detected tropism 60 between screening and BL 54.6 50 � 50.0% of patients with R5 virus 40 at BL and without confirmed X4 30 at failure had plasma MVC concentrations below limit of 20 7.1 detection 10 n = 361 360 339 331 11 14 Tropism changes more common in 0 � Overall Tropism at Tropism at patients with lower mean CD4+ cell Baseline Baseline count at screening as well as with (R5) (D/M) clade B or other/undetermined HIV-1 subtype vs clade C Heera J, et al. CROI 2008. Abstract 40LB.

VICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced Patients with R5-Virus Screening* Week 48 (Weeks 4-6) VCV 20 mg once daily + NRTI-, NNRTI-, OBR including RTV-boosted PI PI-experienced HIV-infected adults with ≥ 1 RT mutation, ≥ 1 primary PI mutation, VCV 30 mg once daily + CCR5 tropism, HIV-1 RNA OBR including RTV-boosted PI > 1000 copies/mL, and on stable antiretroviral therapy (N = 116) Placebo + OBR including RTV-boosted PI *Confirmation of tropism required before randomization. Zingman B, et al. CROI 2008. Abstract 39LB.

VICTOR-E1: Virological Efficacy at Week 48 VCV 30 mg VCV 20 mg Placebo 100 n = 39 n = 40 n = 35 0 90 Mean Change in HIV-1 RNA from BL -0.2 80 Patients With HIV-RNA-1 -0.4 < 50 copies/mL (%) 70 (log 10 copies/mL) -0.6 56 60 53 -0.8 50 -0.79 -1.0 40 -1.2 30 -1.4 20 14 -1.6 10 -1.8 -1.75 -1.77 0 Difference: Difference: -2.0 -0.98 -0.96 VCV 30 mg VCV 20 mg Placebo n = 26 n = 24 n = 9 P = .0017 P = .0028 � No clinically significant differences in adverse events between VCV arms and placebo Zingman B, et al. CROI 2008. Abstract 39LB.

MOTIVATE: Maraviroc in Treatment-Experienced Patients with R5 Virus � Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies � Primary endpoint: mean change in HIV-1 RNA at Week 24 2:2:1 randomization; Planned interim analysis stratified by ENF use Week 24 Week 48 and VL < or ≥ 100,000 c/mL Maraviroc 150 mg or 300 mg twice daily + OBR* (n = 426) Triple-class–resistant or triple-class– experienced patients with R5 virus and HIV-1 RNA ≥ 5000 copies/mL Maraviroc 150 mg or 300 mg once daily + OBR* (n = 414) ( MOTIVATE 1 : N = 601; Canada, US) ( MOTIVATE 2 : N = 475; Europe, Placebo + OBR Australia, US) (n = 209) *Patients receiving PI (except TPV) or delavirdine received 150 mg; all others received 300 mg. Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.

MOTIVATE 1 and 2: Combined Virologic and Immunologic Efficacy � MVC + OBR associated with significantly greater viral suppression than placebo + OBR in treatment-experienced patients Patient Outcome at Week 48 Placebo + MVC QD + MVC BID + OBR OBR OBR (n = 209) (n = 414) (n = 426) Median HIV-1 RNA change from -1.84 † -0.78 -1.68* BL, log 10 copies/mL* Mean CD4+ cell count change 61 116 124 from baseline, cells/mm 3 *Difference vs placebo: -0.89 (95% CI: -1.17 to -0.62). † Difference vs placebo: -1.05 (95% CI: -1.33 to -0.78). Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48 100 90 Placebo + OBR (n = 209) Patients with VL < 50 c/mL (%) MVC QD + OBR (n = 414) 80 MVC BID + OBR (n = 426) 70 60 50 45.5%* 43.2%* 40 30 20 16.7% 10 * P < .0001 vs placebo 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (Weeks) Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48 100 <100.000 copies/mL >100.000 copies/mL 90 Patients <50 c/mL (%) 80 70 59 58 60 50 35 40 32 26 30 20 10 10 0 Placebo MVC QD + OBR MVC BID + OBR Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1 and 2: HIV-1 RNA < 50 c/mL at Wk 24 by Active Drugs in OBR Combined Analysis: MOTIVATE 1 and 2 100 90 Placebo + OBR MVC QD + OBR MVC BID + OBR 80 70 61 Patients (%) 58 55 60 53 52 50 43 43 40 29 30 19 18 20 9 10 3 0 n = 51 56 44 130 134 59 64 132 121 35 88 104 Number of Active Drugs in OBR 0 1 2 ≥ 3 Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.

Immunological Efficacy of CCR5-Coreceptor- Antagonists � Meta-analysis of 37 arms from 16 clinical trials in treatment- experienced patients (9 arms from 4 trials used CCR5 inhibitors): CCR5 inhibitor-use associated with greater increase in CD4+ cell count after controlling for baseline viral load and virologic response (+32 cells/mm 3 ; 95% CI: 19-54) � Redistribution of CD4 cells to the periphery by blocking CCR5 receptors which serve as a homing receptor to lymphatic tissues ? Wilkin T, et al. CROI 2008. Abstract 800.

CCR5 Antagonists: Safety issues � Development of Aplaviroc discontinued due to severe liver toxicity � ACTG 5211 (Phase-II Vicriviroc) with a higher incidence of cancer in patients treated with the active drug, though relationship with drug doubtful 1 � Postural hypotension was the dose-limiting AE for Maraviroc in Phase I-Study – only seen at rates higher than placebo for doses of ≥ 600 mg 2 1. Gulick R, et al. IAS 2007. Abstract TUAB102. 2. McHale M, et al. IAS 2005. Oral TuOa0204.

MOTIVATE 1 and 2: Side effects Hardy D, et al. CROI 2008. Poster 792.

MOTIVATE 1 and 2: Maraviroc Safe and Well Tolerated at Week 48 � Similar frequency of serious all-grade AEs, toxicity-driven discontinuations, laboratory abnormalities, AIDS-defining infections, and AIDS- or non-AIDS–defining malignancies among MVC vs placebo arms at Week 48 � Most common AEs across study arms: diarrhea, nausea, fatigue, headache � No deaths reported during the study or up to 28 days of stopping study drug were considered to be related to study medication. Hardy D, et al. CROI 2008. Poster 792.