Perspectivas del Maraviroc en el Tratamiento del VIH

1. Perspectivas del Maraviroc en el Tratamiento del VIH Hernán Valdez, MD Director Médico Global, Virología Pfizer, Inc.

2. Tópicos Tropismo Efectos extra-antivirales de Maraviroc, alguna evidencia? Se puede usar el Maraviroc una vez al dia?

3. Tropismo

4. Trofile Patient Population Virologic benefit with MVC R5 MOTIVATE 1 and 2 N = 1049 Screening Population 1434 R5 patients (56%) and 1126 DM or X4 patients (44%) 1216 Randomized Patients (47%) Nonet virologic benefit with MVC NON-R5 A4001029 n = 167 Harrigan, IAS 2009

5. Genotype Patient Population R5 MOTIVATE 1 and 2 N = 999 96% of clinical validation set 1216 Randomized Patients NON-R5 A4001029 n = 165 Harrigan, IAS 2009

6. Methods Triplicate PCR with fully automated sequence analysis Tropism prediction using “Geno2pheno” algorithm (g2P - 5% FPR) without knowledge of clinical outcome Initial endpoint of 8 week change in viral load; 24 weeks endpoint also analyzed Harrigan, IAS 2009

7. Median Viral Load Reduction in the MVC BID Arm is Predicted by Trofile 0.0 P < 0.001 -0.5 -1.0 Log10 Change in Viral Load(copies/mL) -1.5 X X X X -2.0 -2.5 -3.0 0 4 8 12 Weeks From Start of Treatment Trofile R5 (n = 406) Harrigan, IAS 2009 X Trofile X4 (n = 57)

8. Median Viral Load Reduction in the MVC BID Arm is Predicted by Trofile and Genotype 0.0 P < 0.001 P = 0.002 -0.5 -1.0 Log10 Change in Viral Load(copies/mL) X -1.5 X X X X X -2.0 X -2.5 -3.0 0 4 8 12 Weeks From Start of Treatment g2p R5 (n = 394) Trofile R5 (n = 406) Harrigan, IAS 2009 X Trofile X4 (n = 57) g2p X4 (n = 69) X

9. Trofile and Genotype Have Similar Sensitivity and Specificity to Predict Antiviral Activity to MVC at Week 8:MVC BID * A response at week 8 was defined as a viral load < 50 or a viral load reduction of  2 log. Harrigan, IAS 2009

10. Concordant and Discordant Results in Combined MVC Arms: Similar Virologic Responses Regardless of the Direction of Discordance Concordant R5 n = 735 Concordant X4 n = 80 Concordant Results Discordant Results Weeks From Start of Treatment 0 4 8 12 0 4 8 12 0.0 0.0 -0.5 -0.5 -1.0 -1.0 Log10 Change in Viral Load (copies/mL) -1.5 -1.5 -2.0 -2.0 -2.5 -2.5 -3.0 -3.0 Trofile X4/g2p R5 n = 31 Trofile R5/g2p X4 n = 60 Harrigan, IAS 2009

11. Genotype is Comparable to Trofile in Predicting the Percent of R5 Patients Viral Load <50 copies (Week 24; MVC BID) 100 80 46.4% 95%CI 41.6- 51.3 46.1% 95%CI 41.2, 51.0 60 Patients Achieving HIV RNA< 50 c/mL (%) 40 20 0 Trofile g2P n = 188/405 181/393 MOTIVATE+1029 studies enrolled triple class experienced and/or resistant patients. The use of raltegravir, darunavir, or etravirine was not allowed Harrigan, IAS 2009

12. Conclusiones El genotipo es un método viable para identificar pacientes con experiencia previa que responderán al Maraviroc Las características del genotipo son muy similares a las de la prueba de Trofile original La genotipificación ofrece un método más viable para identificar a candidatos para el maraviroc

13. Efectos extra-antivirales del Maraviroc, hay alguna evidencia?

14. Greater CD4 Cell Increases on MVC in Non-responders (> 50 c/mL) at Week 48 Were Related to a Lower Incidence of Category C Events Maraviroc Efavirenz Patients (%) Median CD4+ change from baseline to week 48 131 77 N= 256 285 104 75 MaravirocN=96 EfavirenzN=63 < 50 copies/mL > 50 copies m/L Non-responders (> 50 c/mL) at Week 48 Viral Load at Week 48 Lazzarin, ICAAC 2008

15. Background and Objectives • Untreated HIV-infection is associated with chronic immune activation (IA) and evidence of inflammation • Decreases in immune activation and inflammation during HAART have been associated with decreased expression of adhesion molecules and a redistribution of CD4+ cells from lymphoid tissues to blood1 • This redistribution may account for the rise in peripheral blood CD4+ cells that occurs early after HAART initiation • MVC treatment has been associated with larger increases in CD4+ cell counts than is attributable to its antiviral activity2-5 • Differences in CD4+ rises between MVC and control occur early in therapy2,4 • It is unknown whether these CD4+ cell rises are related to MVC’s potential effect on markers of immune activation or inflammation • We analyzed a subset of patients from the MERIT study to explore whether MVC for HIV‑infected treatment-naive patients has different effects than EFV on clinically relevant markers of immune activation and inflammation • Secondary objectives included: • Explaining differences in clinical or laboratory outcomes in the MERIT study • Exploring whether MVC has early immunologic effects beyond those expected after antiviral activity • Identifying potential clinical markersto be studied prospectively

16. Change in plasma HIV-1 RNA levels: ACTG 315 • After treatment with HAART there is a 99.9% decrease in HIV-RNA in the first 3 months • Most of that decrease (99%) occurs in the first 4 weeks Lederman, JID 1998

17. ACTG 315: Effects of HAART on co-expression of activation antigens - CD38, HLA-DR • Whereas decrease in activation occurs more slowly • Less than half of the decrease in activated CD8 occurs in the first month of HAART • Similar kinetics are observed in decreases in TNF-alpha 59 CD8+ 25 29 CD4+ 13 Lederman, JID 1998

18. MERIT Study: Phase 3 Trial Design Randomization 1:1 Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)* Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)* Screening(6 weeks) 0 96 wk 48 wk First patient visit Nov 2004 Primary analysis • Patient eligibility criteria: • ≥ 16 years of age • Treatment naive • R5HIV-1 infection • HIV-1RNA ≥ 2,000 copies/mL • No evidence of resistance to EFV, ZDV, or 3TC • Patients stratified by: • HIV-1RNA < and ≥100,000 copies/mL at screening • Geographic location: Northern Hemisphere and Southern Hemisphere MVC QD arm discontinued at end of Phase 2b (Week 16) for failure to meet protocol-defined criteria to continue (205 patients completed 16 weeks) * Patients experiencing toxicity to zidovudine (ZDV) or lamivudine (3TC) were permitted to substitute an alternative NRTI

19. Markers of Activation and Inflammation Funderburg, ICAAC 2009

20. Earlier Decreases in CD38 Expression on CD4+ T cells on MVC 20 EFV MVC 10 + 0.29 0 -10 –23.3 Median percent change in CD38 antibodies/CD4+ cell -20 –20.1 -30 –26.8 -40 -50 -60 0 24 48 Weeks Vertical lines represent interquartile ranges (IQR; 25th–75th percentile) Funderburg, ICAAC 2009

21. Earlier Decrease in D-Dimer Concentration on MVC 30 EFV MVC 10 -10 Median percent change in D-dimer concentration -30 -50 -70 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Vertical lines represent interquartile ranges (IQR; 25th–75th percentile) Funderburg, ICAAC 2009

22. Although a Smaller Percentage of Patients had HsCRP > 2 on MVC at Baseline, by Week 48 Twice as many EFV Patients had hsCRP > 2 100 MVC + CBV EFV + CBV 90 80 66 70 60 Patients with hsCRP > 2 (%) 45 50 36 36 40 30 20 10 0 Baseline Week 48 Funderburg, ICAAC 2009

23. 23 MVC-Treated Patients Showed Significantly Greater Increases in Mean CD4+ Cell Count with the Difference Accentuated in those with a Higher Screening Viral Load4,5 EFV + CBV Screening HIV-1 RNA MVC + CBV 35 cells/mm3 (95% CI 13, 58) ≥ 105 copies/mL < 105 copies/mL 227 250 250 207* 190 178 200 200 167 171* 150 150 Mean CD4+ Cell Changes From Baseline (per mm3) Mean CD4+ Cell Changes From Baseline (per mm3) 100 100 50 50 0 0 Week 96 (all patients) N= 205 199 143 153 Week 96 Funderburg, ICAAC 2009 * Mean value adjusted for randomization strata Last observation carried forward; blinded therapy values only. Includes all patients who received at least one dose of study medication

24. Larger Increases in CD4+ cells are Associated with Larger Decreases in Cell-associated Immune Activation Markers Funderburg, ICAAC 2009

25. Immune activation and HIV Replication Treated HIV HAART HIV replication Decrease in immune activation Viral load decrease Untreated HIV HIV replication + + Immune activation Direct drug effect: rapid Indirect drug effect: Slow and variable Other factors: CMV, HBV, HCV, microbial translocation Early changes on activation markers would suggest direct drug effect

26. 26 Conclusiones • En comparación con EFV, los pacientes que reciben MVC tienen una reducción modesta y más temprana en ciertos marcadores de activación inmunológica e inflamación • Este efecto parece ser independiente y aditivo al efecto que resulta de la actividad antiviral del MVC • La disminución de la activación en células CD4 y CD8 está asociada a un aumento mayor en las células CD4

27. ¿Se puede usar el Maraviroc una vez al día en pacientes con experiencia previa?

28. ¿Maraviroc una vez al día en pacientes experimentados? • Razones para escoger la dosis de dos veces al día • Dosis respuesta del Maraviroc y farmacología del Maraviroc con IP potenciados • Experiencia clínica de Maraviroc una vez al día

29. 0 1 2 ≥ 3 MOTIVATE 1 and 2: Percentage of Patients with HIV-1 RNA < 50 copies/mL by Number of Active Drugs in OBT* Includes all patients who received at least one dose of study medication Placebo + OBT MVC QD + OBT 100 MVC BID + OBT 90 80 70 61 58 60 55 53 52 Patients (%) 50 43 43 40 29 30 19 18 20 9 10 3 0 N= 51 56 44 130 134 59 64 132 121 35 104 88 Number of active drugs in OBT* * Based on overall susceptibility score LOCF MOTIVATE 1 & 2-Week 24 CROI 2007

30. Correlation of Phase 2a Monotherapy and Phase 2b/3 Clinical Data • Phase 2a Monotherapy Dose/exposure response studies (A4001007 and 1015) • Unboosted MVC 300 mg BID achieved a reproductive ratio <1 in all subjects • Based on exposure-response analysis from MOTIVATE, Cave required for therapeutic effect of MVC is 100 ng/mL • Pop PK analyses in MOTIVATE: • Median Cave of MVC when dosed 150 mg QD concomitantly with • ATV/r: 109 ng/mL • LPV/r: 149 ng/mL • This is consistent with achieving a Cave in the region of 100 ng/mL that correlates with near maximal virologic efficacy Data on File

31. A4001052 - Effect of Darunavir/r on the Pharmacokinetics of Maraviroc in Healthy Subjects Mean Maraviroc Plasma Concentration vs Time MVC AUC increased 405% in the presence of DRV/r 600/100 mg BID Abel S, et al. 8th Int Wkshp Clin Pharm HIV Ther 2007. Abstract 55

32. Simulated Patient with mean BL VL of 4.6 log10 c/mL with Different DRV-containing Regimens Data on File

33. Patients with HIV-1 RNA < 50 Copies/mL by Screening Viral Loads and Baseline CD4+ Cell Count (Week 48) Includes all patients who received at least one dose of study medication * Patients were stratified at time of randomization by screening HIV-1 RNA (< or ≥100,000 copies/mL) † Baseline CD4+ cell count calculated as the average of all pre-dose measurements Includes all treated patients with valid baseline and on-treatment measurements; Missing values imputed using last observation carried forward MOTIVATE 1 & 2 – Week 48, HARDY CROI 2008

34. 100 All Subjects Placebo + OBT 90 MVC QD + OBT 72 70 80 MVC BID + OBT 70 56 51 51 60 <50 copies/mL at wk 48 (%) 50 33 33 40 30 17 20 0 10 0 N= 76 81 41 87 113 35 41 78 77 <1 1–<2 ≥2 100 Subjects ≥50 CD4+ cells/mm3 at baseline 81 90 78 80 66 70 59 53 60 <50 copies/mL at wk 48 (%) 43 50 37 40 20 30 20 0 10 0 N= 60 61 35 67 94 32 31 64 63 <1 1–<2 ≥2 Week 48 Virologic Responses by wOBTSS Valdez ICAAC 2008

35. En Resumen • La determinación de tropismo por genotipo es tan buena como el Trofile original en predecir respuestas clínicas al Maraviroc • Maraviroc parece tener efectos anti-inflamatorios y anti-activación independientes de su actividad antiviral • Numerosos estudios están investigando la relevancia clínica de estos hallazgos • En pacientes con terapia antiviral previa que reciben algunos IP potenciados (atazanavir, lopinavir, saquinavir, darunavir), Maraviroc a una dosis de 150 mg una vez al día parece ser adecuado • Tres estudios clínicos están analizando la actividad antiviral de estas combinaciones con Maraviroc una vez al día