Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


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

2 FármacoCompañíaFamilia Nº abstract LEDFG/P75PfizerINI98 QuadGileadINI 101, 627 DolutegravirViiVINI102LB GS-7340GileadITIAN103 CenicrivirocTobira CCR5 CCR5600 Nitazoxanida U. Milan ?583

3 FármacoCompañíaFamilia Nº abstract LEDFG/P75PfizerINI98 QuadGileadINI 101, 627 DolutegravirViiVINI102LB GS-7340GileadITIAN103 CenicrivirocTobira CCR5 CCR5600 Nitazoxanida U. Milan ?583

4 The Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (“Quad”) Compared to Efavirenz/Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects: Primary Results of Study GS-US Paul Sax 1, Edwin DeJesus 2, Anthony Mills 3, Andrew Zolopa 4, Calvin Cohen 5, David Wohl 6, Joel Gallant 7, Hui C Liu 8, Kirsten White 8, Erin Quirk 8, and Brian Kearney 8 1 Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US; 2 Orlando Immunology Center, Orlando, FL, US; 3 Anthony Mills MD, Inc., Los Angeles, US; 4 Stanford University, Palo Alto, CA, US; 5 Community Research Initiative of New England, Boston, MA, US; 6 University of North Carolina, Chapel Hill, NC, US; 7 Johns Hopkins School of Medicine, Baltimore, MD, US; 8 Gilead Sciences, Foster City, CA, US 19 th Conference on Retroviruses and Opportunistic Infections March 7, 2012 Paper #: 101

5 Background A single-tablet regimen of efavirenz, emtricitabine and tenofovir DF (EFV/FTC/TDF) is a preferred initial HIV-1 regimen 1-3 The efficacy and safety of coformulated EVG/COBI/FTC/TDF (“Quad”) was comparable to EFV/FTC/TDF in a Phase 2 study 4 –elvitegravir (EVG): potent once-daily HIV integrase inhibitor (150 mg) –cobicistat (COBI): pharmacoenhancer lacking HIV activity (150 mg) –emtricitabine (FTC)/tenofovir DF (TDF): approved, preferred first line NRTI combination (200 mg/300 mg) Thompson et al, JAMA, 2010;304(3): EACS Guidelines for the Clinical Management and Treatment of HIV Infected Adults in Europe. Version October Cohen C, et al, AIDS 2011;25 (6):F7-12

6 Study Design: Treatment- naive (N = 700 planned) Quad QD EFV/FTC/TDF QHS Placebo EFV/FTC/TDF QHS Quad Placebo QD Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/mL) n=350 Primary Endpoint: Proportion with HIV-1 RNA < 50 copies/mL at Week 48 –FDA snapshot analysis, 12% noninferiority margin –HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5 Week 48 Week 192 Conducted in parallel with Study comparing Quad to FTC/TDF + ATV/r (DeJesus et al, Poster #627)

7 Baseline Characteristics Study Characteristic Quad (n=348) EFV/FTC/TDF (n=352) Age (years), Mean38 Male (%)88%90% Non-white (%) Black or African descent (%) 39% 31% 36% 26% Asymptomatic HIV Infection (%)83%84% HBV – HCV seropositive (%)1% - 5%3% - 4% HIV-1 RNA (log 10 copies/mL), Median >100,000 (%)34%33% CD4 count (cells/mm 3 ), Mean (%) ≤200 cells/mm 3 12%14% 200 to ≤35032%27% 351 to ≤50032%39% >50023%20%

8 Subject Disposition Through Week 48 Study % Discontinued (N=37) Screened (N=917) Randomized and Treated EFV/FTC/TDF (N=352) Randomized and Treated Quad (N=348) 13% Discontinued (N=46) 89% Continued (N=311) 87% Continued (N=306) Adverse event 12 Death 1 Pregnancy 1 Lack of efficacy 5 Investigator’s discretion 1 Withdrew consent 3 Lost to follow-up 10 Subject non-compliance 3 Protocol violation 1 Adverse event 18 Death 1 Lack of efficacy 4 Withdrew consent 5 Lost to follow-up 12 Subject non-compliance 6

9 Primary Endpoint: HIV-1 RNA < 50 copies/mL Study Quad was non-inferior to EFV/FTC/TDF at Week 48 95% CI for Difference 12% Favors EFV/FTC/TDF 3.6 Favors Quad 0 -12%

10 Percent Difference in Response by Subgroups Study Overall Age (years) <40 ≥40 Sex Male Female Race White Non-white Baseline HIV-1 RNA Level ≤100,000 c/mm 3 >100,000 c/mm 3 Baseline CD4 Count ≤350 (cells/µL) >350 (cells/µL) Study Drug Adherence (%) <95 ≥95 Differences in Percentages (95% CI) Favors Quad Favors EFV/FTC/TDF FDA Snapshot Week 48, HIV-1 RNA <50 copies/mL

11 Efficacy in Baseline HIV-RNA and CD4 Subgroups Study Virologic Success (<50 c/mL)

12 Mean Change from Baseline in CD4 Count Study P =.009 Change from Baseline in CD4 (cells/mm 3 ) BL Week Quad (n=): EFV/FTC/TDF (n=): a Anova P value. EFV/FTC/TDF, 206 Quad, 239

13 Integrase & NNRTI Resistance Through Week 48 Study Quad (n=348) EFV/FTC/TDF (n=352) Subjects Analyzed for Resistance*, n (%)14 (4)17 (5) Subjects with Resistance to ARV Regimen, n (%)8 (2) Any Primary Integrase-R, n7 E92Q7 T66I1 Q148R1 N155H1 Any Primary NNRTI-R n 8 K103N7 V108I2 Y188Y/F/H/L1 G190A1 Any Primary NRTI-R, n82 M184V/I82 K65R32 *Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and 1 log 10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit.

14 Quad (n=348) EFV/FTC/TDF (n=352) Treatment Emergent Adverse Events in ≥ 10% of subjects (%) Diarrhea23%19% Nausea *21%14% Abnormal Dreams ^ 15%27% Upper Respiratory Infection14%11% Headache14%9% Fatigue12%13% Insomnia *9%14% Depression9%11% Dizziness ^ 7%24% Rash # 6%12% Adverse Events Leading to Study Drug Discontinuation in > 1 subject (n) Depression13 Abnormal Dreams02 Blood Creatinine Increased20 Fatigue11 Paranoia11 Rash02 Renal Failure20 Common Adverse Events and Discontinuations due to Adverse Event Study * p < 0.05 ^ p < # p=0.009

15 Grade 3 and 4 Laboratory Abnormalities Study Grade 3-4 Labs * Quad (n = 348) EFV/FTC/TDF (n = 352) Creatine Kinase5%11% AST2%3% ALT1%3% GGT2%5% Neutrophils2%3% Amylase2% Hematuria2%1% *>5 subjects in any treatment group

16 Median Change from Baseline in Serum Creatinine Median change at Week 48: 0.14 mg/dL vs mg/dL (Quad vs. EFV/FTC/TDF group, p<0.001) Quad (n=): EFV/FTC/TDF (n=): \\\\\\\\\\ BL Change from BL in Serum Creatinine (mg/dL) (IQR) Week

17 Change From BL at Week 48 (mg/dL ) Total CholesterolLDLHDLTriglycerides Median Change from Baseline in Fasting Lipids through Week 48 Study P <0.001P =0.001 P =0.44

18 Conclusions Study High and comparable efficacy in Quad and EFV/FTC/TDF –Non-inferior virologic suppression rates across protocol-specified subgroups, including HIV-1 RNA >100,000 copies/mL at baseline Quad was well tolerated –Similar low-rates of treatment discontinuation –Fewer reports of abnormal dreams, insomnia, dizziness, and rash –Higher rate of Grade 1 (not Grade 2 or higher) nausea –Median 0.14 mg/dL increase in serum creatinine, with 5/348 (1.4%) discontinuing due to renal events –Smaller increases in total cholesterol and LDL

19 Summary Consistent results between studies and (DeJesus, et al, Poster #627) –Virologic success with Quad (90%) was noninferior to ATV/r+FTC/TDF (87%) per FDA snapshot analysis (95% CI for difference -1.9% to 7.8%) –Quad was well tolerated compared to ATV/r+FTC/TDF Smaller increases in triglycerides 0.3% of subjects in both arms discontinued due to renal events Full results of studies and submitted for peer-reviewed publication Health authority filings submitted in Europe, Australia, Canada, Switzerland, and the U.S. (FDA decision expected by August 27, 2012)

20 20 Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF “ Quad ” Compared to Ritonavir-boosted Atazanavir plus Emtricitabine/Tenofovir DF in Treatment Na ï ve HIV-1 Infected Subjects E DeJesus 1, JK Rockstroh 2, K Henry 3, J-M Molina 4, J Gathe 5, S Ramanathan 6, X Wei 6, J Szwarcberg 6, M Rhee 6, A Cheng 6 1 Orlando Immunology Center, Orlando, FL, US; 2 Department of Medicine I, University of Bonn, Bonn, Germany; 3 Hennepin County Medical Center, Minneapolis, MN, US; 4 Saint Louis Hospital, Paris, France; 5 Therapeutic Concepts P.A., Houston, TX, US; 6 Gilead Sciences, Foster City, CA, US 19 th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012 Seattle, WA Poster #: 627

21 21 Background Elvitegravir (EVG)/ cobicistat (COBI)/emtricitabine (FTC)/tenofovir DF (TDF) has been coformulated as the first integrase inhibitor- containing single-tablet regimen “Quad” –EVG is a potent once-daily HIV integrase inhibitor (150 mg) –COBI is a pharmacoenhancer lacking anti-HIV activity (150 mg) –FTC/TDF is a preferred first line NRTI combination (200 mg/300 mg) 1-3 Recommended initial HIV regimen 1-3 –Efavirenz (EFV)/FTC/TDF –Atazanavir/ritonavir (ATV/r) + FTC/TDF –Darunavir/ritonavir (DRV/r) + FTC/TDF –Raltegravir (RAL) + FTC/TDF 1 2 Thompson et al, JAMA, 2010;304(3): EACS Guidelines for the Clinical Management and Treatment of HIV Infected Adults in Europe. Version October 2011 DeJesus E, et al., CROI 2012; Seattle. Poster 627.

22 22 Randomized, double-blind, double-dummy, active- controlled, non-inferiority study Eligibility criteria –Treatment naïve –Genotypic sensitivity to ATV, FTC, and TDF –HIV-1 RNA > 5,000 c/mL –eGFR ≥ 70 mL/min (Cockcroft-Gault equation) Primary endpoint –HIV-1 RNA < 50 c/mL at Week 48 (Amplicor HIV-1 Monitor Test, version 1.5) –FDA snapshot algorithm –Prespecified primary analysis of non-inferiority margin 12% Exploratory analysis of PK/PD relationship Study Design DeJesus E, et al., CROI 2012; Seattle. Poster 627.

23 23 Study Design Treatment naive (N = 700 planned) Quad QD ATV/r+FTC/TDF Placebo QD ATV/r + FTC/TDF QD Quad Placebo QD International Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/mL) (n=350) Primary Endpoint: Proportion with HIV-1 RNA < 50 c/mL at Week 48 –FDA snapshot analysis, 12% non-inferiority margin –HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5 Week 48 Week 192 Conducted in parallel with Study comparing Quad to EFV/FTC/TDF DeJesus E, et al., CROI 2012; Seattle. Poster 627.

24 24 Baseline Characteristics Characteristic Quad (n=353) ATV/r + FTC/TDF (n=355) Age (years), Mean3839 Male92%89% Non-White Black or African Descent 29% 20% 22% 13% Asymptomatic HIV Infection81%83% HBV – HCV Seropositive1% – 5%2% – 3% HIV-1 RNA (log 10 c/mL), Median HIV-1 RNA > 100,000 c/mL43%40% CD4 count (cells/mm 3 ), Mean < 20015%11% 201 to ≤ 35035% 351 to ≤ 50035%34% > 50016%20% DeJesus E, et al., CROI 2012; Seattle. Poster 627.

25 25 Subject Disposition Through Week % Discontinued (N = 33) Adverse event13 Pregnancy1 Lack of efficacy4 Investigator’s discretion 1 Withdrew consent 1 Lost to follow-up7 Subject non- compliance 5 Protocol violation 1 Screened (N = 1017) QUAD Randomized and Treated (N = 353) ATV/r + FTC/TDF Randomized and Treated (N = 355) 91% Continuing (N = 320) 11% Discontinued (N = 40) Adverse event18 Lack of efficacy1 Investigator Discretion 3 Withdrew consent6 Lost to follow-up7 Subject non- compliance 5 89% Continuing (N = 315) DeJesus E, et al., CROI 2012; Seattle. Poster 627.

26 26 Primary Endpoint: HIV-1 RNA < 50 c/mL QUAD was non-inferior to ATV/r + FTC/TDF at Week 48 95% CI for Difference 12% Favors ATV/r + FTC/TDF 3.0 Favors Quad 0 -12% DeJesus E, et al., CROI 2012; Seattle. Poster 627.

27 OVERALL AGE <40 years ≥40 years SEX Male Female RACE White Non-white BASELINE CD4 COUNT ≤350 cells/mm 3 >350 cells/mm 3 BASELINE HIV-1 RNA LEVEL ≤100,000 c/mL >100,000 c/mL STUDY DRUG ADHERENCE <95% ≥95% Favors QUAD Favors ATV/r + FTC/TDF Differences in Percentages (95% CI) Virologic Success 1 by Subgroups FDA snapshot at Week 48 DeJesus E, et al., CROI 2012; Seattle. Poster 627.

28 28 HIV-1 RNA < 50 c/mL through Week 48 (M=F) Subjects with HIV-1 RNA <50 c/mL (%) BL Week QUAD (n=): ATV/r (n=): Diff: 3.5% (95% CI: -1.0 to 8.0) Quad: 92% ATV/r + FTC/TDF: 88% DeJesus E, et al., CROI 2012; Seattle. Poster 627.

29 29 Efficacy in Baseline HIV-1 RNA and CD4 Subgroups Virologic Success (%) DeJesus E, et al., CROI 2012; Seattle. Poster 627.

30 30 Efficacy by Baseline Demographics Virologic Success (%) Age (years)RaceSex DeJesus E, et al., CROI 2012; Seattle. Poster 627.

31 31 Mean Change from Baseline in CD4 Cells (cells/mm 3 ) Mean Change from Baseline in CD4 (cells/mm 3 ) BL Week QUAD (n=): ATV/r (n=): (P=0.61) Quad, 207 ATV/r+FTC/TDF, 211 DeJesus E, et al., CROI 2012; Seattle. Poster 627.

32 32 Integrase, PI, NRTI Resistance Through Week Quad (n=353) ATV/r + FTC/TDF (n=355) Subjects Analyzed for Resistance a, n (%)12 (3)8 (2) Subjects with Resistance to ARV Regimen, n (%)5 (1)0 Any Primary Integrase-R, n4- E92Q1- T66I1- Q148R2- N155H2- Any Primary PI-R, n-0 Any Primary NRTI-R, n40 M184V/I4 K65R1 a. Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and 1 log 10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit. DeJesus E, et al., CROI 2012; Seattle. Poster 627.

33 33 Virologic Success by EVG Exposure – Quad PK/PD Analysis Set, n=192 DeJesus E, et al., CROI 2012; Seattle. Poster 627.

34 34 Summary of Adverse Events (AE) Quad (n=353) ATV/r + FTC/TDF (n=355) Grade 3 or 4 AE13%14% Drug-related AE45%57% SAE7%9% Drug-related SAE1% AE leading to DC of study drug4%5% Death, (n)01% (3) a a Causes of death included septic shock, Pneumocystis jiroveci pneumonia, and cardiopulmonary arrest after overdose of recreational drugs. DeJesus E, et al., CROI 2012; Seattle. Poster 627.

35 35 Common Adverse Events Adverse Event a Quad (n=353) ATV/r + FTC/TDF (n=355) Diarrhea22%27% Nausea20%19% Upper respiratory infection15%16% Headache15%12% Fatigue14%13% Ocular icterus1%14% a > 10% in either treatment group DeJesus E, et al., CROI 2012; Seattle. Poster 627.

36 36 Common Adverse Events Leading to DC Adverse Event a,b Quad (n=353) ATV/r + FTC/TDF (n=355) Overall4%5% Diarrhea1%<1% Pyrexia1%0% Nausea<1%1% Vomiting<1%1% Fatigue<1%1% Ocular Icterus0%1% Jaundice0%1% Dizziness0%1% Drug Eruption0%1% DeJesus E, et al., CROI 2012; Seattle. Poster 627. a At least 2 subjects in either treatment group b One subject from each treatment group discontinued due to renal adverse event; one subject in Quad group due to blood creatinine increased, one subject in ATV/r+FTC/TDF group due to nephropathy toxic.

37 37 Grade 3 and 4 Laboratory Abnormalities Grade 3 or 4 Labs a Quad (n=353) ATV/r + FTC/TDF (n=355) Creatine Kinase6%7% Hematuria4%2% AST2%3% Amylase2%3% ALT2% Hyperbilirubinemia1%58% a At least 2% in either treatment group DeJesus E, et al., CROI 2012; Seattle. Poster 627.

38 38 Change from Baseline in Serum Creatinine Median change W48: 0.12 mg/dL vs mg/dL (Quad vs. ATV/r + FTC/TDF group, p<0.001) BL Change from Baseline in Serum Creatinine (mg/dL) Week QUAD (n=): ATV/r +FTC/TDF (n=): DeJesus E, et al., CROI 2012; Seattle. Poster 627.

39 39 Change from Baseline in Fasting Lipids at Week P =.006 Median Change From BL at Week 48 (mg/dL) DeJesus E, et al., CROI 2012; Seattle. Poster 627.

40 40 Bone Mineral Density at Week Quad (n=353) ATV/r + FTC/TDF (n=355) P value Fracture events, (n)1% (3)2% (6)0.51 Median BMD change from BL, % SpineHip Median BMD change from BL, % Week -2.87% -3.59% P= % -3.46% P= BL2448 QUAD (n=54) ATV/r + FTC/TDF (n=66) BL2448 QUAD (n=54) ATV/r + FTC/TDF (n=66) DEXA Analysis Set, n=120 DeJesus E, et al., CROI 2012; Seattle. Poster 627.

41 41 Conclusions High and comparable efficacy in Quad and ATV/r + FTC/TDF –Robust, durable, and consistent efficacy on all endpoints –High virologic suppression rates in all subgroups, including those with baseline HIV-1 RNA > 100,000 c/mL Quad was well-tolerated –Similar low rates of treatment discontinuation –Smaller increases in triglyceride in Quad –Discontinuations due to renal adverse events were 0.3% in ATV/r + FTC/TDF and 0.3% in Quad DeJesus E, et al., CROI 2012; Seattle. Poster 627.

42 42 Summary Study comparing Quad to EFV/FTC/TDF, an oral presentation on Wednesday, March 7 th 10:45AM (Sax P et al. Paper #101) Full results of studies and submitted for peer-reviewed publication Health authority filings submitted in Europe, Australia, Canada, Switzerland, and the U.S. (FDA decision expected by August 27, 2012) DeJesus E, et al., CROI 2012; Seattle. Poster 627.

43 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington Shionogi-ViiV Healthcare LLC Hans-Juergen Stellbrink, 1 Jacques Reynes, 2 Adriano Lazzarin, 3 Eugene Voronin, 4 Federico Pulido, 5 Franco Felizarta, 6 Steve Almond, 7 Marty St. Clair, 8 Nancy Flack, 8 and Sherene Min, 8 on behalf of the extended SPRING-1 Team 1 ICH Study Center, Hamburg, Germany; 2 Hopital Gui de Chauliac, Montpellier, France; 3 Fondazione Centro San Raffaele del Monte Tabor, Milano, Italy; 4 Hospital of Infectious Diseases, St. Petersburg, Russia; 5 Hospital 12 Octubre, Madrid, Spain; 6 Office of Franco Felizarta, Bakersfield, CA; 7,8 GlaxoSmithKline, 7 Mississauga, Canada, 8 Research Triangle Park, NC, USA Dolutegravir (DTG; S/GSK ) in Combination Therapy Exhibits Rapid and Sustained Antiviral Response in Antiretroviral-Naïve Adults: 96-Week Results from SPRING-1 (ING112276)

44 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington Dolutegravir Attributes ●Once daily, unboosted 1 ●Low PK variability and predictable exposure- response relationship 2 ●Low potential for drug interactions 2 ●Distinct in vitro resistance profile including higher barrier to resistance 3 ●Highly potent antiviral activity in monotherapy 1 –At 50mg DTG, 90% were <400 c/mL and 70% <50 c/mL after 10d of monotherapy 1.Min, S. et al. AIDS. 2011; 25:1737– Min, S. et al. AAC. 2010; 54: 254– Kobayashi, M et al. AAC. 2011; 55(2): Antiviral Activity in Phase IIa Study 1

45 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington ●Phase IIb dose-ranging, partially blinded, N~200 ART-naïve patients ●All arms include 2 NRTI backbone given once daily ●Primary endpoint: % <50 c/mL at 16 weeks (TLOVR), for Ph3 dose selection ●Planned analysis: % <50 c/mL at 96 weeks (TLOVR) ING Study Design HIV-1 RNA >1000 c/mL CD4 ≥200 cells/mm 3 1:1:1:1 Randomization HIV-1 RNA >1000 c/mL CD4 ≥200 cells/mm 3 1:1:1:1 Randomization EFV 600 mg DTG 50 mg DTG 25 mg DTG 10 mg Stratified by HIV RNA >100,000 or ≤100,000 c/mL Epzicom/Kivexa or Truvada Week 96 DTG 50 mg Selected Dose DTG 50 mg Selected Dose

46 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington DTG 10 mg (N=53) DTG 25 mg (N=51) DTG 50 mg (N=51) EFV 600 mg (N=50) Total (N=205) Age, median (range), years32 (21-61)38 (20-64)37 (22-55)40 (20-79)37 (20-79) Male gender42 (79%)46 (90%)45 (88%)44 (88%)177 (86%) Race African American/African heritage7 (13%)6 (12%)8 (16%)4 (8%)25 (12%) White41 (77%)42 (82%)38 (75%)43 (86%)164 (80%) Other5 (10%)3 (6%)5 (10%)4 (8%)17 (8%) Baseline HIV-1 RNA Mean (log 10 c/mL) >100,000 c/mL11 (21%)10 (20%)12 (24%)11 (22%)44 (21%) Baseline CD4+ (cells/mm 3 ) Mean <30030 (57%)20 (39%)24 (47%)24 (48%)98 (48%) Investigator-selected NRTIs TDF/FTC36 (68%)34 (67%) 34 (68%)138 (67%) ABC/3TC17 (32%)17 (33%) 16 (32%)67 (33%) Baseline Characteristics

47 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington Dolutegravir Dose Selection DTG demonstrated low PK variability. DTG trough levels on 50mg remain19-fold above antiviral target, PA-IC90. A priori, maximum tolerated dose to be selected for use in phase III trials based on data from 16 and 24 weeks May simplify dosing in the presence of modest drug interactions Comparable virologic responses, safety and tolerability were seen across all three DTG doses at 16 and 24 weeks of therapy

48 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington Dolutegravir: Rapid and Durable Antiviral Activity Week 96 Efficacy Analysis (<50 c/mL) 95% confidence intervals are derived using the normal approximation. 88% 78% 79% 72% Percent Subjects with HIV-1 RNA <50 c/mL (TLOVR) Week 1. van Lunzen, Lancet ID, 2012;12: 111–18.

49 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington Primary Outcomes: <50 c/mL (TLOVR) at Week 96 Outcome DTG 10 mg (N=53) DTG 25 mg (N=51) DTG 50 mg (N=51) EFV 600 mg (N=50) Responder42 (79%)40 (78%)45 (88%)36 (72%) Virologic nonresponders Rebound by TLOVR7 (13%)4 (8%) 2 (4%) * 4 (8%) Re-suppressed by Week Other nonresponders Adverse event01 (2%) 5 (10%) Protocol deviation1 (2%)2 (4%)1 (2%)0 Subject reached protocol-defined stopping criteria0001 (2%) Lost to follow-up/decision by subject2 (4%)3 (6%)2 (4%) Death 1 (2%)**000 Not discontinued but no data at Week 96 and beyond01 (2%)02 (4%) * Includes one subject discontinued from study drug due to Burkitt’s lymphoma prior to retest **By motor vehicle accident

50 19 th Conference on Retroviruses and Opportunistic Infections March 2012 Seattle, Washington Protocol Defined Virologic Failure ●PDVF = confirmed HIV-1 RNA >400 c/mL OR < 1.0 log 10 c/mL decrease by Week 4 ●Amongst DTG-treated subjects (N=155), no integrase mutations were detected through Week 96 ●No subjects in 50 mg arm had confirmed VL ≥400 c/mL through Wk 96 * Non-adherence in DTG 10mg (n=1) and DTG 25mg subjects by report/pill count at time of PDVF **<1.0 log 10 decrease by Wk 4 Outcome DTG 10mg (N=53) DTG 25mg (N=51) DTG 50mg (N=51) EFV 600mg (N=50) Protocol-defined Virologic Failure2 *1 *01 ** Genotype/phenotype Determinable2001 INI Mutations Present0000 NNRTI Mutations Present0000 NRTI Mutations PresentM184V (1)000

51 19 th Conference on Retroviruses and Opportunistic Infections March 2012 Seattle, Washington Median (95% CI) Change from Baseline CD4+ Cell Count (cells/mm 3 ) Week 24 p=0.008; Week 48 p=0.076; Week 96 p=0.155 Wilcoxon two-sample test, EFV vs. DTG total Change from Baseline CD4+ Cell Count (cells/mm 3 )

52 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington DTG 10 mg (N=53) DTG 25 mg (N=51) DTG 50 mg (N=51) DTG Subtotal (N=155) EFV 600 mg (N=50) Number of Subjects with any Grade 2-4 Drug-Related Event 4 (8%)5 (10%)8 (16%)17 (11%)12 (24%) Gastrointestinal1 (2%)2 (4%)1 (2%)4 (3%)2 (4%) Psychiatric disorders00003 (6%) Metabolic disorders03 (6%)1 (2%)4 (3%)0 Skin disorders00003 (6%) Infections2 (4%)002 (1%)0 General disorders1 (2%) 3 (2%)1 (2%) Laboratory Abnormalities01 (2%) 2 (1%)1 (2%) Nervous system disorders001 (2%)1 (<1%)1 (2%) Serious Adverse Events (all)5 (9%)5 (10%)7 (14%)17 (11%)7 (14%) AEs Leading to WD/IP Discontinuation1 (2%) 2 (4%)4 (3%)5 (10%) ●Fewer AEs leading to withdrawal on DTG vs EFV –DTG (4/155, 3%): dyspepsia, Burkitt’s lymphoma, death due to motor vehicle accident, lipoatrophy –EFV (5/50, 10%): abnormal dreams, suicide attempt, drug intolerance, drug hypersensitivity, insomnia AEs (by System Organ Class) Reported in >1 Subject on Investigational Product

53 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington ●Clinically significant liver chemistry abnormalities were rare –1 Gr3 ALT (DTG 25 mg, Acute HCV infection), 1 Gr4 ALT (EFV, Acute HCV infection) ●No subject with elevated bilirubin had corresponding ALT elevation Laboratory Results: ALT and Bilirubin Maximum Treatment Emergent Toxicity DTG 10mg (N=53) DTG 25mg (N=51) DTG 50mg (N=51) DTG Subtotal (N=155) EFV 600mg (N=50) Alanine Amino Transferase (ALT) Grade 21 (2%)3 (6%)1 (2%)5 (3%)6 (12%) Grade 301 (2%)01 (<1%)0 Grade (2%) Total Bilirubin Grade 201 (2%) 2 (1%)0 Grade Grade

54 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington Laboratory Results: Creatinine & Urine Protein ●Small changes in mean serum creatinine (0.1 – 0.15 mg/dL) observed –Observed with both NRTI backbones, did not progress over time –No effect of DTG on GFR (as measured by iohexol clearance) 1 ●At Week 96, no evidence for higher urine protein in DTG arms. 1 Koteff J, et al. 51 st ICAAC; September 17-20, 2011: Chicago, Illinois. Abstract A Armn (Wk 96) Mean Urine Alb/Cr ratio (mg/mmol Cr) at Wk96 (SD) Min/Max DTG 10mg (1.699)0.2 / 9.4 DTG 25mg (0.95)0.3 / 5.2 DTG 50mg (1.113)0.3 / 6.2 EFV 600mg (2.908)0.2 / 16.3 In vitro and clinical data are consistent with non-significant inhibition of the renal transporter (OCT2) responsible for tubular secretion of creatinine.

55 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington ●DTG administered once daily with two NRTIs was associated with good treatment response at all doses –Proportion with HIV RNA <50 c/mL for selected 50mg dose (88%) compares favorably with EFV (72%) through 96 weeks –No INI mutations detected through 96 weeks, consistent with high barrier to resistance demonstrated in vitro ●Fewer subjects treated with DTG discontinued therapy due to adverse events when compared to EFV ●Data through 96 weeks continue to support 50mg once daily for INI-naïve subjects, and provide evidence for durable efficacy and tolerability for DTG in combination therapy Conclusions

56 19th Conference on Retroviruses and Opportunistic Infections March 5-8, 2012, Seattle, Washington We thank everyone who has contributed to the success of this study, including: All of our study participants and their families The SPRING-1 Clinical Investigators and their staff: France: J Reynes, L Cotte, F Raffi, C Katlama, P Yeni, J-M Molina Germany: J van Lunzen, H-J Stellbrink, M Stoll, T Lutz Italy: G Carosi, F Maggiolo, G Rizzardini, A Lazzarin Russia: O Tsybakova, E Voronin, A Rakhmanova Spain: F Pulido, J Arribas, S Moreno-Guillen, J Gatell, B Clotet United States: E DeJesus, F Felizarta, T Hawkins, J Lalezari, L McCurdy, G Richmond, S Schneider, L Sloan, J Torres, B Young, T Vanig, M Mustafa, A LaMarca And the extended ViiV Healthcare-Shionogi-GlaxoSmithKline SPRING-1 study team Acknowledgments

57 GS mg and 40 mg Demonstrate Greater Antiviral Activity Compared with TDF 300 mg in a 10-Day Monotherapy Study of HIV-1 Infected Patients PJ Ruane 1, E DeJesus 2, D Berger 3, M Markowitz 4, UF Bredeek 5, C Callebaut 6, L Zhong 6, S Ramanathan 6, MS Rhee 6, K Yale 6 1 Peter J Ruane MD Inc., Los Angeles, CA; 2 Orlando Immunology Center, Orlando, FL; 3 Northstar Healthcare, Chicago, IL; 4 Aaron Diamond AIDS Research Center, New York, NY; 5 Metropolis Medical, San Francisco, CA; 6 Gilead Sciences, Foster City, CA 19 th Conference on Retroviruses and Opportunistic Infections March 7, 2012 Paper #: 103

58 58 Compound EC 50 HIV-1 [  M] MT-2sPBMCsMacrophages Tenofovir TDF GS Tenofovir TDF GS-7340 Lee et al. Antimicrob Agents Chemother GS-7340: Novel Prodrug of Tenofovir (TFV) Greater in vitro Potency

59 59 GS-7340 TFV GS-7340 TDF TFV-DP BloodLymphocytesGut Lumen TDF (Viread ® ) GS-7340 TFV TDF TFV TFV-DPTFV GS-7340: Novel Prodrug of Tenofovir (TFV) Designed to Deliver TFV to Cells

60 60 Randomized, double-blind, active controlled study –HIV-1 infected, treatment naïve subjects –HIV-1 RNA ≥ 15,000 c/mL –GS mg, GS mg, TDF 300 mg –Once-daily monotherapy for 14 days GS-7340 (50 mg or 150 mg) led to significantly greater decreases in HIV-1 RNA, compared with TDF 300 mg 50 mg of GS-7340 had 88% lower plasma TFV exposures, and 4-fold higher intracellular TFV-DP concentrations, compared with TDF 300 mg Markowitz M et al. CROI 2011; Paper#152LB. First Proof-of-Concept Study (GS-US )

61 61 Study Design (GS-US ) Primary objective –To evaluate the antiviral activity of 3 different doses of GS-7340 Primary endpoint –Time-weighted average change in HIV-1 RNA (DAVG11) Randomized, partially-blinded, placebo and active controlled 10-day monotherapy study Treatment naïve adults HIV-1 RNA ≥ 2,000 c/mL CD4 ≥ 200 cells/mm ³ (N = 38) TDF 300 mg QD GS mg QD GS mg QD GS mg QD GS-7340 Placebo QD

62 62 All subjects (n=38) Age (mean)38 Sex (males)97% Race White53% African American37% Others11% Median HIV-1 RNA (log 10 c/mL)4.6 Median CD4 cell count (cells/mm 3 )444 Baseline Characteristics

63 63 Treatment GroupN Median DAVG 11 [log 10 c/mL] P value vs. TDF 300 mg Placebo TDF 300 mg GS mg GS mg GS mg Primary Efficacy Endpoint

64 64 Viral Dynamics

65 65 Treatment Group Median ΔVL Day 11 [log 10 c/mL] P value vs. TDF 300 mg Median first phase decay slope P value vs. TDF 300 mg Placebo TDF 300 mg GS mg GS mg GS mg Viral Dynamics Summary

66 66 GS-7340: Lower Plasma TFV

67 67 TDFGS X ~1X ~7X >20X 300 mg 40 mg25 mg8 mg Intracellular TFV-DP (µM*h) GS-7340: Higher Intracellular (PBMC) TFV-DP

68 68 No study drug discontinuations No drug-related serious adverse events No clinically significant laboratory abnormalities Most adverse events were mild to moderate No mutations associated with TDF resistance Safety and Viral Resistance

69 69 GS mg, compared to TDF (Viread ® ) 300 mg, achieves –Greater antiviral activity in 10-day monotherapy –Higher intracellular TFV-DP by ~7-fold –Lower circulating plasma TFV by ~90% At 1/10 th the mass of TDF 300 mg, GS-7340 offers the possibility to formulate new single-tablet regimens (STRs) Conclusion

70 70 GS-7340 Phase 2 Program Two Novel STRs in Treatment Naïve Patients QUAD Placebo GS-7340 QUAD GS-7340 QUAD Placebo QUAD DRV + COBI + FTC/TDF Placebo DRV/COBI/FTC/GS-7340 DRV/COBI/FTC/GS-7340 Placebo DRV + COBI + FTC/TDF Currently Enrolling Screening to be started soon


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

Similar presentations


Ads by Google