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Nuevos fármacos Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau

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Presentation on theme: "Nuevos fármacos Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau"— Presentation transcript:

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

2 FármacoCompañíaFamilia Nº abstract RS-788 RFS Pharma ITIAN489 Elvucitabina Achillion Ph ITIAN511 Boehringer I. Inh cápside 50 QNL111 BioAlliance Ph Integrasa492 S/GSK1349572GSKIntegrasa55 Vicriviroc Merck Res Labs CCR554LB QuadGileadVarios58LB TBR 652 Tobira Ther CCR553 Lectina banana U. Michigan Microbicida Microbicida487

3 FármacoCompañíaFamilia Nº abstract RS-788 RFS Pharma ITIAN489 Elvucitabina Achillion Ph ITIAN511 Boehringer I. Inh cápside 50 QNL111 BioAlliance Ph Integrasa492 S/GSK1349572GSKIntegrasa55 Vicriviroc Merck Res Labs CCR554LB TBR 652 Tobira Ther CCR553 QuadGileadVarios58LB Lectina banana U. Michigan Microbicida Microbicida487

4 Análogos de nucleósidos

5 RS-788: características A 5’-monophosphate prodrug of β-D-3’-azido- 2,6-diamino-2’,3’-dideoxypurine (AZD) The prodrug is metabolized 73:1 to both AZD-TP ( an “A” analog) and AZG-TP ( a “G” analog) Herman BD, et al. CROI. 2010. # ****.

6 RS-788: actividad frente a cepas resistentes Herman BD, et al. CROI. 2010. # ****.

7 Conclusiones

8 Elvucitabina DeJesus E, et al. CROI. 2010. # 511 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 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 < 400 copies/mL Proportion of subjects with HIV-1 RNA levels < 50 copies/mL (Weeks 24, 48, 96) 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 Time to occurrence of less than 400 copies/mL and less than 50 copies/mL Change in CD4 count from Baseline Change in CD4 count from Baseline

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

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

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

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

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

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

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

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

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

18 Conclusiones

19 Antagonistas de CCR5

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

21 TBR-652: CCR2 characteristics CCR2 activity: IC50 = 5.9 nMCCR2 activity: IC50 = 5.9 nM CCR2 is a chemokine receptor found on the cell surface of monocytes, dendritic celles (immature) and memory T cellsCCR2 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 CCR2Monocyte 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: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 antagonistsTo date no significant safety signals have been identified with CCR2 antagonists Palleja S, et al. CROI. 2010. Abstract 51

22 Protocol designTBR-652-201 Thompson M, et al. CROI. 2009. Abstract 571a Evaluate antiviral potency, safety, tolerability, PK, and CCR2 activityEvaluate antiviral potency, safety, tolerability, PK, and CCR2 activity –Randomized, double-blind, placebo-controlled dose- escalating study in HIV-infected subjects with: CD4 ≥ 250 cells/mm 3CD4 ≥ 250 cells/mm 3 HIV-1 RNA > 5000 copies/mlHIV-1 RNA > 5000 copies/ml CCR5-tropic virusCCR5-tropic virus Treatment experienced, no HIV treatment for ≥ 6 weeksTreatment experienced, no HIV treatment for ≥ 6 weeks –5 dose cohorts TBR-652 (≥ 8): 25, 50, 75, and 150 mg (F1 formulation)TBR-652 (≥ 8): 25, 50, 75, and 150 mg (F1 formulation) TBR-652 (n = 10): 100 mg (F2 formulation)TBR-652 (n = 10): 100 mg (F2 formulation) PBO (n = 2)PBO (n = 2) –10-day monotherapy –MCP-1 measured on day 1 and 10

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30 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, 3 J. Zeinecker, 4 C. Mak, 5 R.A. Vilchez, 5 W. Greaves, 5 S. Kumar, 5 C. Onyebuchi, 5 L.M. Dunkle 5 1 Therapeutic Concepts PA, Houston, Texas; 2 Federal University of São Paulo, São Paulo, Brazil; 3 University of Cologne, Koln, Germany; 4 Institute of Infectious Diseases and Molecular Medicine, Cape Town, South Africa; 5 Merck, Kenilworth, New Jersey

31 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) or ART 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 only Total N =721 Treatment- experienced R5-HIV only Total N =721 VCV 30 mg + OBT Placebo + OBT Week 24 Interim analysis Week 48 Final analysis Primary endpoint: % HIV RNA <50 copies/mL at 48 weeks 2:1

32 Baseline Characteristics (MITT) VICTOR-E3VICTOR-E4 VCVControlVCVControl N 252 252 123 123 234 234 112 112 Age, years (SE) Age, years (SE) 43 (0.6) 43 (0.6) 44 (0.9) 44 (0.9) 43 (0.6) 43 (0.6) 44 (0.8) 44 (0.8) White, n (%) White, n (%) 163 (65%) 163 (65%) 85 (69%) 85 (69%) 121 (52%) 121 (52%) 67 (60%) 67 (60%) Female, n (%) Female, n (%) 85 (34%) 85 (34%) 37 (30%) 37 (30%) 66 (28%) 66 (28%) 22 (20%) 22 (20%) Mean baseline HIV RNA, log 10 (SE) 4.5 (0.1) 4.5 (0.1) 4.8 (0.1) 4.8 (0.1) 4.5 (0.1) 4.5 (0.1) Mean CD4 count, cells/mm 3 (SE) 246 (11.9) 246 (11.9) 221 (17.1) 221 (17.1) 273 (11.3) 273 (11.3) 287 (18.0) 287 (18.0) OSS ≤2, n (%) 106 (42%) 106 (42%) 54 (44%) 54 (44%) 70 (30%) 70 (30%) 31 (28%) 31 (28%) OSS ≥3, n (%) 141 (56%) 141 (56%) 67 (54%) 67 (54%) 152 (65%) 152 (65%) 78 (70%) 78 (70%) Raltegravir in OBT regimen, n (%) 95 (38%) 95 (38%) 47 (38%) 47 (38%) 59 (25%) 59 (25%) 31 (28%) 31 (28%) Darunavir in OBT regimen, n (%) 94 (37%) 94 (37%) 51 (41%) 51 (41%) 90 (38%) 90 (38%) 46 (41%) 46 (41%)

33 Disposition at 48 Weeks Pooled VICTOR-E3 & 4 (MITT) VCV (N=486) Control (N=235) Completed 48 weeks, n (%)368 (75)183 (78) Total discontinuations, n (%)118 (24)52 (22) Investigator-defined treatment failure 54 (46)31 (60) Adverse Event17 (14)4 (8) Lost-to-follow-up17 (14)7 (13) Administrative30 (25)10 (19)

34 Pooled Efficacy (VICTOR-E3 & 4) MITT Population VCVControl Overall N = 721 486235 HIV RNA <50 at week 48, n (%) 313 (64%) 145 (62%) HIV RNA <400 at week 48, n (%) 352 (72%) 166 (71%) Mean change in CD4, cells/mm 3 (SE) +138 (7.3) +129 (9.4)

35 70% n=176 55% n=85 ≤2* 61% n=293 65% n=145 ≥3 % HIV RNA <50 c/mL Overall Sensitivity Score (No. of Active Drugs in Background) 80% 60% 40% 20% 0% 100% VCV Control Virologic Response by OSS *Pre-specified subset; not adjusted for multiple analyses; Odds Ratio 1.9, P = 0.02.

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

37 Protocol-Defined Virologic Failures *Resistance = relative MPI <94%. VCVN=486Control N= 235 Total N= 721 Protocol-defined virologic failures (PDVF) 71 (15%) 38 (16%) 109 (15%) PDVFs with DM/X4 virus 9/71 (13%) 1/38 (3%) 10/109 (9%) PDVFs with VCV resistance* (R5 virus only) 3/71 (4%) 0/38 3/109 (3%) PDVFs with OBT resistance 14/71 (20%) 8/38 (21%) 22/109 (20%)

38 Resistance in Virologic Failures Frequency of OBT resistance similar in VCV and Control arms (~20%)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%)

39 Common Adverse Events All Treated Subjects Adverse events in ≥5% of VCV-treated patients adjusted for total exposure *Per 100 patient years, all treated subjects. VCV (n = 568) Years of exposure = 455 Control (n = 285) Years of exposure = 227 Number (%) Rate* Rate* Any SAE 55 (10) 55 (10)12 26 (9) 11 Any TEAE 477 (84) 105 247 (87) 109 Diarrhea Diarrhea 133 (23) 29 61 (21) 27 Nausea Nausea 88 (15) 19 19 (7) 8 Headache Headache 69 (12) 15 42 (15) 19 Nasopharyngitis Nasopharyngitis 48 (8) 11 21 (7) 9 Influenza Influenza 40 (7) 9 20 (7) 9 URTI URTI 37 (7) 8 20 (7) 9 Vomiting Vomiting 34 (6) 7 12 (4) 5 Insomnia Insomnia 30 (5) 7 15 (5) 7 Back pain Back pain 27 (5) 6 17 (6) 8 Rash Rash 27 (5) 6 12 (4) 5 Cough Cough 26 (5) 6 18 (6) 8 Adverse events in ≥5% of VCV-treated patients adjusted for total exposure LPV/r

40 Events of Interest All Treated Subjects *Per 100 patient years, normalized by exposure; all treated subjects. VCV n=568 Yrs of Exposure = 455 Control n=285 Yrs of Exposure = 227 Population Number (%) Rate* Rate* Any adverse event 218 (38) 218 (38)48 118 (41) 52 Seizure00 1 (  1) <1 Malignancy 7 (1) 2 4 (1) 2 Hepatocellular injury 57 (10) 13 25 (9) 11 Dyslipidemia 33 (6) 7 21 (7) 9 URI 131 (23) 29 69 (24) 30 HSV infection 37 (7) 8 23 (8) 10 Ischemic cardiovascular event 2 (  1) 2 (  1)<1 3 (1) 1

41 Summary and Conclusions VCV was well tolerated in both phase 3 studiesVCV was well tolerated in both phase 3 studies VCV did not meet the primary efficacy endpoint in these trialsVCV 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 infrequentlyResistance to VCV was observed very infrequently

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

43 Inhibidores de la Integrasa

44 What Attributes Make a Next Generation HIV Integrase Inhibitor? Differentiation in four key areas was viewed necessary: 1.Dose: Unboosted, low mg doses desirable to facilitate FDC regimens. Less drug advantageous for patients (e.g., toxicity, exposure, variability) 2.Dosing interval: Q24hr dosing considered a must, patient convenience critical for compliance, long term durability. Potential for forgiveness is also an important consideration. 3.Resistance profile: Superior resistance profile against INI mutants 4.Barrier to resistance: Should show higher potential barrier to resistance (time and nature of selected mutants) S/GSK1349572 engineered to deliver these attributes

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

46 S/GSK1349572: Attributes of a Next Generation INI Only once daily, unboosted INI in clinical development 1 Low PK variability and predictable exposure-response relationship with a low mg dose 2,3 Unprecedented antiviral activity in a ph2a study 1 Superior in vitro resistance profile with potential for higher genetic barrier to resistance 4,5,6 Dosing periodFollow-up period -2.5 -2.0 -1.5 -0.5 0.0 0.5 1 (BL) 23478910111421 (FU) Day Mean Change from Baseline in HIV-1 RNA (log 10 copies/mL) 2 mg 10 mg 50 mg PBO 1.Lalezari J. et al. IAS 2009, Cape Town, abstract TUAB105. 2.Min S, et al. IAS 2009, Cape Town, abstract WEPEA099. 3.Song I, et al. IAS 2009, Cape Town, abstract WEPEB250. 4.Sato A, et al. IAS 2009, Cape Town, abstract WEPEA097. 5.Underwood M, et al. IAS 2009, Cape Town, abstract WEPEA098. 6.Seki T, et al. CROI 2010, Poster abstract J-122.

47 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 Cohen 1, David Shamblaw 2, Peter Ruane 3, Richard Elion 4, Edwin DeJesus 5, Hui C. Liu 6, Lijie Zhong 6, David Warren 6, Brian P. Kearney 6, and Steven L. Chuck 6 1 Community Research Initiative of New England, Boston, MA; 2 San Diego, CA; 3 Los Angeles, CA; 4 Whitman Walker Clinic, Washington, D.C.; 5 Orlando Immunology Center, Orlando, FL; and 6 Gilead Sciences, Foster City, CA CROI 2010

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

49 Design of the Two Phase 2 Studies Eligible Subjects Treatment-naïve HIV RNA ≥5,000 copies/mL CD4 cells >50 cells/mm 3 No Resistance to NRTIs NNRTIs PIs HBV- and HCV-negative 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 Comparison Quad + EFV/FTC/TDF placebo n = 48 EFV/FTC/TDF + Quad placebo n = 23 2:1 Efavirenz EVG/GS-9350 GS-9350 + RTV placebo ATV + FTC/TDF n = 50 RTV + GS-9350 placebo ATV + FTC/TDF n = 29 2:1 GS-9350 RTV vs.

50 Baseline Characteristics Quadn=48EFV/FTC/TDFn=23GS-9350n=50RTVn=29 Age, mean years 36353734 Male92%91%94%86% Race White White Black Black69%25%78%22%62%36%55%28% HIV RNA Mean, log 10 copies/mL Mean, log 10 copies/mL >100,000 copies/mL >100,000 copies/mL4.5923%4.5822%4.5624%4.6938% CD4 cells/mm 3, median 354436341367 AIDS6%4%16%10%

51 Week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%) Primary Endpoint: Percentage with HIV RNA < 50 copies/mL (ITT M=F) Quad vs. EFV/FTC/TDF 04812162024 0 20 40 60 80 100 Quad EFV/FTC/TDF 83% 90% Week Percentage with HIV RNA <50 copies/mL

52 Primary Endpoint: Percentage with HIV RNA < 50 copies/mL (ITT M=F) Week 24 stratum-weighted difference -1.9% (95% CI: -18.4% to 14.7%) GS-9350 vs. RTV with ATV + FTC/TDF 04812162024 0 20 40 60 80 100 GS-9350 RTV 84% 86% Week Percentage with HIV RNA < 50 copies/mL

53 Disposition of Subjects QuadEFV/FTC/TDFGS-9350RTV Randomized Never dosed Never dosed482356 6 a 29 Discontinued Study Drugs before Week 24 Adverse Event Adverse Event Lost to Follow up Lost to Follow up Investigator’s Discretion Investigator’s Discretion Withdrew Consent Withdrew Consent 3 (6%) 0210 3 (13%) 1101 4 (8%) 2110 3 (10%) 1101 Subjects on Study Drugs through Week 24 through Week 24 45 (94%) 20 (87%) 46 (92%) 26 (90%) a Protocol violation (n=4); withdrew consent (n=2); these 6 subjects are excluded from all ITT analyses

54 Percentage with HIV RNA < 50 copies/mL (ITT M=E) Quad vs. EFV/FTC/TDF Week 24 Median ∆ CD4 cells Quad+123 EFV/FTC/TDF+124 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 04812162024 0 20 40 60 80 100 Quad EFV/FTC/TDF 95% 96% Week Percentage with HIV RNA <50 copies/mL

55 Percentage with HIV RNA < 50 copies/mL (ITT M=E) Week 24 Median ∆ CD4 cells GS-9350+206 RTV+190 At Week 24: 5 subjects had HIV RNA > 50 copies/mL At Week 32: 3 of the 5 had HIV RNA < 50 and 1 had 59 copies/mL; 1 virologic failure GS-9350 vs. RTV with ATV + FTC/TDF 048121620 24 0 20 40 60 80 100 GS-9350 RTV 96% 91% Week Percentage with HIV RNA <50 copies/mL

56 Summary of Treatment- Emergent Adverse Events Quadn=48EFV/FTC/TDFn=23GS-9350n=50RTVn=29 Adverse Events related to Randomized Drug, Grades 1-4 17 (35%) 13 (57%) 10 (20%) 7 (24%) Grade 3/4 Adverse Events 0 2 (9%) 2 (4%) 0 Adverse Events leading to discontinuation of study drug 0 1 (4%) 2 (4%) 1 (3%) Serious Adverse Events (none related to study drugs) 1 (2%) 1 (4%) 0 1 (3%)

57 Adverse Events >5% Related to Randomized Drug in Any Treatment Group Quadn=48EFV/FTC/TDFn=23GS-9350n=50RTVn=29 Abnormal Dreams, Nightmares 5 (10%) 8 (35%) 00 Dizziness0 3 (13%) 00 Fatigue 4 (8%) 3 (13%) 1 (2%) 2 (7%) Somnolence 2 (4%) 2 (9%) 00 Headache 2 (4%) 2 (9%) 1 (2%) 0 Diarrhea 4 (8%) 1 (4%) 3 (6%) 3 (10%) Nausea 2 (4%) 1 (4%) 5 (10%) 1 (3%)

58 Treatment-Emergent Laboratory Abnormalities Grades 2-4 Occurring in >5% of Any Treatment Arm Quadn=48EFV/FTC/TDFn=23GS-9350n=50RTVn=29 Bilirubin, total 00 40/49 (82%) 25 (86%) Amylase 2 (4%) 2 (10%) 6 (12%) 2 (7%) Neutrophils, decreased 3 (7%) 2 (10%) 1 (2%) 1 (3%) Cholesterol*, total 4 (9%) 2 (10%) 3 (6%) 0 Proteinuria 1 (2%) 2 (10%) 2 (4%) 0 *Similar small median increases in cholesterol, LDL, HDL, triglycerides between arms in each study

59 Other Treatment-Emergent Laboratory Abnormalities Quadn=48EFV/FTC/TDFn=23GS-9350n=50RTVn=29 ALT Grades 2-4 00 1 (2%) 1 (3%) AST Grades 2-4 000 1 (3%) Hypophosphatemia (All were Grade 1) 00 1 (2%) 1 (3%) Creatinine (All were Grade 1) 1 (2%) 0 6 (12%) 0

60 Small Increases in Serum Creatinine Affected Estimated GFR (Cockcroft-Gault) Quadn=48EFV/FTC/TDFn=23GS-9350n=50RTVn=29 ∆ Mean Serum Creatinine Baseline to Week 24 +0.14 mg/dL +0.04 mg/dL +0.18 mg/dL +0.14 mg/dL ∆ Mean eGFR* Baseline to Week 24 -18 mL/min -7 mL/min -15 mL/min -14 mL/min Mean eGFR* At Week 24 111 mL/min 126 mL/min 102 mL/min 111 mL/min *Estimated GFR by Cockcroft-Gault

61 Renal Study of GS-9350 Without ARVs in Healthy Volunteers Study of GS-9350 (no ARVs) in healthy volunteers Study of GS-9350 (no ARVs) in healthy volunteers – Administered GS-9350 or placebo for 7 days – Measured serum creatinine and iohexol clearance concurrently GS-9350 is associated with lower estimated GFR GS-9350 is associated with lower estimated GFR – Onset in days, reversible in days GS-9350 has no effect on actual GFR GS-9350 has no effect on actual GFR GS-9350 Alters Estimated GFR—Not Actual GFR 0714 -30 -20 -10 0 10 20 30 Dosing GS-9350 150 mg Placebo Day Mean Change Estimated GFR (mL/min; Cockcroft-Gault)

62 Creatinine is excreted primarily by glomerular filtration but ~10-15% by active tubular secretion Creatinine is excreted primarily by glomerular filtration but ~10-15% by active tubular secretion GS-9350 may inhibit tubular secretion of creatinine GS-9350 may inhibit tubular secretion of creatinine – Similar to the over-the-counter medicine, Cimetidine GS-9350 Does Not Affect Actual GFR But Can Increase Serum Creatinine

63 Conclusions from Phase 2 Studies Quad (vs. EFV/FTC/TDF) Quad (vs. EFV/FTC/TDF) – Efficacy met criteria for non-inferiority (90% vs. 83%) – Fewer study drug-related adverse events (particularly CNS) GS-9350-boosted ATV (vs. RTV-boosted ATV) + FTC/TDF GS-9350-boosted ATV (vs. RTV-boosted ATV) + FTC/TDF – Similar efficacy – Similar safety and tolerability Results support proceeding toPhase 3 studies Results support proceeding to Phase 3 studies The generic name of GS-9350 is cobicistat

64 Funny how the new things are the old things Rudyard Kipling (1865-1936)


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