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Nuevos fármacos

Nuevos fármacos. Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau Barcelona pdomingo@santpau.cat. Análogos de nucleósidos. Elvucitabina. A Phase II, randomized, double-blind trial at 16 sites in the United States and 3 sites in India.

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Nuevos fármacos

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  1. Nuevos fármacos Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau Barcelona pdomingo@santpau.cat

  2. Análogos de nucleósidos

  3. Elvucitabina A Phase II, randomized, double-blind trial at 16 sites in the United States and 3 sites in India. Primary endpoint: proportion of subjects with HIV-1 RNA levels < 50 copies/mL at Week 12. Secondary endpoints at Weeks 12, 24, 48 and 96 included: • Change in HIV-1 RNA level from Baseline • Proportion of subjects with HIV-1 RNA levels < 400 copies/mL • Proportion of subjects with HIV-1 RNA levels < 50 copies/mL (Weeks 24, 48, 96) • Time to occurrence of less than 400 copies/mL and less than 50 copies/mL • Change in CD4 count from Baseline DeJesus E, et al. CROI. 2010. # 511

  4. Diseño DeJesus E, et al. CROI. 2010. # 511

  5. Situación de los pacientes DeJesus E, et al. CROI. 2010. # 511

  6. Eficacia (< 50 copias/ml) DeJesus E, et al. CROI. 2010. # 511

  7. Eficacia (< 400 copias/ml) DeJesus E, et al. CROI. 2010. # 511

  8. Eficacia: disminución de carga viral DeJesus E, et al. CROI. 2010. # 511

  9. Eficacia: en tratamiento DeJesus E, et al. CROI. 2010. # 511

  10. Eficacia: incremento de CD4 DeJesus E, et al. CROI. 2010. # 511

  11. Efectos adversos DeJesus E, et al. CROI. 2010. # 511

  12. Fracasos virológicos DeJesus E, et al. CROI. 2010. # 511

  13. Conclusiones DeJesus E, et al. CROI. 2010. # 511

  14. Antagonistas de CCR5

  15. Oral CCR5 receptor antagonist In vitro protein-adjusted EC50 = 0,29 nM (clinical isolates) Plasma t ½ = 35-40 hours Once-daily dosing Metabolized by CYP and non-CYP pathways Neither CYP inducer nor inhibitor Additive or synergistic activity with other ART classes in vitro Oral bioavailability of current formulation enhanced by food TBR-652 Palleja S, et al. CROI. 2010. Abstract 51

  16. CCR2 activity: IC50 = 5.9 nM CCR2 is a chemokine receptor found on the cell surface of monocytes, dendritic celles (immature) and memory T cells Monocyte chemoatractant protein 1 (MCP-1) is the primary ligand for CCR2 CCR2 has been associated with and studied in a variety of inflammation-associated diseases: Atherosclerosis Metabolic syndrome/insulin resistance To date no significant safety signals have been identified with CCR2 antagonists TBR-652: CCR2 characteristics Palleja S, et al. CROI. 2010. Abstract 51

  17. Evaluate antiviral potency, safety, tolerability, PK, and CCR2 activity Randomized, double-blind, placebo-controlled dose-escalating study in HIV-infected subjects with: CD4 ≥ 250 cells/mm3 HIV-1 RNA > 5000 copies/ml CCR5-tropic virus Treatment experienced, no HIV treatment for ≥ 6 weeks 5 dose cohorts TBR-652 (≥ 8): 25, 50, 75, and 150 mg (F1 formulation) TBR-652 (n = 10): 100 mg (F2 formulation) PBO (n = 2) 10-day monotherapy MCP-1 measured on day 1 and 10 Protocol designTBR-652-201 Thompson M, et al. CROI. 2009. Abstract 571a

  18. Phase 3 Trials of Vicriviroc in Treatment-Experienced Subjects Demonstrate Safety but Not Significantly Superior Efficacy over Potent Background Regimens J. Gathe,1 R. Diaz,2 G. Fätkenheuer,3J. Zeinecker,4 C. Mak,5 R.A. Vilchez,5 W. Greaves,5S. Kumar,5 C. Onyebuchi,5 L.M. Dunkle5 1Therapeutic Concepts PA, Houston, Texas; 2Federal University of São Paulo, São Paulo, Brazil; 3University of Cologne, Koln, Germany; 4Institute of Infectious Diseases and Molecular Medicine, Cape Town, South Africa; 5Merck, Kenilworth, New Jersey

  19. VICTOR-E3 & 4: Phase 3 Trial Design • VICTOR-E3 and 4 were identically designed, randomized, double-blind, placebo-controlled, 48-week multicenter Phase 3 studies • Subjects were ART-experienced with: • Documented resistance to ≥2 then available drug classes (NRTI, NNRTI, or PI) orART experience of at least 6 months • MITT population = 721 of 857 enrolled subjects • R5 subjects enrolled based on Trofile • Confirmed by Trofile ES at study conclusion (blinded) Treatment-experienced R5-HIV onlyTotal N =721 VCV 30 mg + OBT 2:1 Placebo + OBT • Primary endpoint: % HIV RNA <50 copies/mL at 48 weeks Week 24 Interim analysis Week 48 Final analysis

  20. Baseline Characteristics (MITT)

  21. Disposition at 48 WeeksPooled VICTOR-E3 & 4 (MITT)

  22. Pooled Efficacy (VICTOR-E3 & 4) MITT Population

  23. Virologic Response by OSS VCV 100% Control 80% 70% 65% 61% 60% 55% % HIV RNA <50 c/mL 40% 20% n=176 n=85 n=293 n=145 0% ≥3 ≤2* Overall Sensitivity Score (No. of Active Drugs in Background) *Pre-specified subset; not adjusted for multiple analyses; Odds Ratio 1.9, P = 0.02.

  24. Phenotypic Sensitivity Scores in Recent HIV Trials PSS = total number of phenotypically active drugs in background regimen Most vicriviroc trial participants had fully active background regimens In the MITT population, 461 (64%) of patients had ≥3 active drugs in OBT 70 60 50 40 30 20 10 0 PSS =0 PSS =1 PSS =2 PSS ≥3 67% 37% 31% 30% 29% 26% 25% 19% 16% 12% 4% <1% Vicriviroc Phase 3 Maraviroc Phase 3 Raltegravir Phase 3 Schering-Plough Corp. Data on file; Fätkenheuer G, et al. NEJM 2008; Steigbigel RT, et al. NEJM 2008.

  25. Protocol-Defined Virologic Failures *Resistance = relative MPI <94%.

  26. Resistance in Virologic Failures Frequency of OBT resistance similar in VCV and Control arms (~20%) Affected one or several drugs in OBT NRTI resistance was most commonly observed PI/r next most frequent Raltegravir resistance infrequent (~3%)

  27. Common Adverse EventsAll Treated Subjects Adverse events in ≥5% of VCV-treated patients adjusted for total exposure Adverse events in ≥5% of VCV-treated patients adjusted for total exposure LPV/r *Per 100 patient years, all treated subjects.

  28. Events of InterestAll Treated Subjects *Per 100 patient years, normalized by exposure; all treated subjects.

  29. Summary and Conclusions • VCV was well tolerated in both phase 3 studies • VCV did not meet the primary efficacy endpoint in these trials • OBT in these trials included more potent antiretroviral drugs than in the VCV Phase 2 trial or Phase 3 trials of recently approved HIV drugs • 64% of subjects had ≥3 fully active drugs in their OBT • Resistance to VCV was observed very infrequently

  30. Implications • For subjects with 2 or fewer available active drugs, VCV provided additional opportunity to achieve full viral suppression (<50 copies/mL) • With the success of recently available therapies for treatment-experienced subjects, new agents will require novel study designs to demonstrate efficacy

  31. Inhibidores de la Integrasa

  32. What Attributes Make a Next Generation HIV Integrase Inhibitor? Differentiation in four key areas was viewed necessary: Dose: Unboosted, low mg doses desirable to facilitate FDC regimens. Less drug advantageous for patients (e.g., toxicity, exposure, variability) Dosing interval: Q24hr dosing considered a must, patient convenience critical for compliance, long term durability. Potential for forgiveness is also an important consideration. Resistance profile: Superior resistance profile against INI mutants Barrier to resistance: Should show higher potential barrier to resistance (time and nature of selected mutants) S/GSK1349572 engineered to deliver these attributes

  33. Most raltegravir- and elvitegravir-resistant mutantsare susceptible to S/GSK1349572 Seki T, et al. CROI 2010, Friday poster abstract J-122.

  34. S/GSK1349572:Attributes of a Next Generation INI Only once daily, unboosted INI in clinical development1 Low PK variability and predictable exposure-response relationship with a low mg dose2,3 Unprecedented antiviral activity in a ph2a study1 Superior in vitro resistance profile with potential for higher genetic barrier to resistance4,5,6 Dosing period Follow-up period 0.5 0.0 -0.5 -1.0 Mean Change from Baseline in HIV-1 RNA (log10 copies/mL) -1.5 -2.0 2 mg 10 mg -2.5 50 mg PBO 1(BL) 2 3 4 7 8 9 10 11 14 21(FU) Day • Lalezari J. et al. IAS 2009, Cape Town, abstract TUAB105. • Min S, et al. IAS 2009, Cape Town, abstract WEPEA099. • Song I, et al. IAS 2009, Cape Town, abstract WEPEB250. • Sato A, et al. IAS 2009, Cape Town, abstract WEPEA097. • Underwood M, et al. IAS 2009, Cape Town, abstract WEPEA098. • Seki T, et al. CROI 2010, Poster abstract J-122.

  35. The Single-Tablet, Fixed-Dose Regimen of Elvitegravir/GS-9350/Emtricitabine/Tenofovir DF (Quad) Achieves a High Rate of Virologic Suppression and GS-9350 is an Effective Booster Calvin Cohen1, David Shamblaw2, Peter Ruane3, Richard Elion4, Edwin DeJesus5, Hui C. Liu6, Lijie Zhong6, David Warren6, Brian P. Kearney6, and Steven L. Chuck6 1Community Research Initiative of New England, Boston, MA; 2San Diego, CA; 3Los Angeles, CA; 4Whitman Walker Clinic, Washington, D.C.; 5Orlando Immunology Center, Orlando, FL; and 6Gilead Sciences, Foster City, CA CROI 2010

  36. Boosted elvitegravir 150 mg is a potent, once-daily HIV integrase inhibitor GS-9350 is a CYP3A inhibitor that lacks anti-HIV activity GS-9350 150 mg boosts EVG or atazanavir (ATV) equivalently to ritonavir 100 mg Elvitegravir (EVG)/GS-9350/Emtricitabine (FTC)/Tenofovir Disoproxil Fumarate (TDF) has been co-formulated in one tablet (“Quad”) Background

  37. GS-9350 + RTV placebo ATV + FTC/TDF n = 50 GS-9350 2:1 vs. RTV + GS-9350 placebo ATV + FTC/TDF n = 29 RTV Design of the Two Phase 2 Studies Comparison Quad + EFV/FTC/TDF placebo n = 48 EVG/GS-9350 Eligible Subjects Treatment-naïve HIV RNA ≥5,000 copies/mL CD4 cells >50 cells/mm3 No Resistance to NRTIs NNRTIs PIs HBV- and HCV-negative 2:1 vs. EFV/FTC/TDF + Quad placebo n = 23 Efavirenz • Randomization was stratified by HIV RNA (≤ or > 100,000 copies/mL) • Primary Endpoint: Proportions with HIV RNA < 50 copies/mL at Week 24 • 48-week trials

  38. Baseline Characteristics

  39. Quad vs. EFV/FTC/TDF Primary Endpoint: Percentage with HIV RNA < 50 copies/mL (ITT M=F) 100 90% Quad 83% EFV/FTC/TDF 80 60 Percentage with HIV RNA <50 copies/mL Week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%) 40 20 0 0 4 8 12 16 20 24 Week

  40. GS-9350 vs. RTV with ATV + FTC/TDF Primary Endpoint: Percentage with HIV RNA < 50 copies/mL (ITT M=F) 100 86% RTV 84% GS-9350 80 60 HIV RNA < 50 copies/mL Percentage with Week 24 stratum-weighted difference -1.9% (95% CI: -18.4% to 14.7%) 40 20 0 0 4 8 12 16 20 24 Week

  41. Disposition of Subjects aProtocol violation (n=4); withdrew consent (n=2); these 6 subjects are excluded from all ITT analyses

  42. Quad vs. EFV/FTC/TDF Percentage with HIV RNA < 50 copies/mL (ITT M=E) 100 96% Quad 95% EFV/FTC/TDF 80 60 HIV RNA <50 copies/mL Percentage with 40 20 0 0 4 8 12 16 20 24 Week At Week 24: 3 subjects had HIV RNA > 50 copies/mL but < 400 copies/mL At Week 32: 3 of the 3 subjects had HIV RNA <50 copies/mL

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