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CROI 2015, Seattle Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Combined Safety Results of Studies GS-US-292-0104 and.

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Presentation on theme: "CROI 2015, Seattle Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Combined Safety Results of Studies GS-US-292-0104 and."— Presentation transcript:

1 CROI 2015, Seattle Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Combined Safety Results of Studies GS-US-292-0104 and GS-US-292-0111 Paul Sax 1, Michael Saag 2, Michael Yin 3, Frank Post 4, Shinichi Oka 5, Ellen Koenig 6, Benoit Trottier 7, Jaime Andrade-Villanueva 8, Huyen Cao 9, Marshall Fordyce 9 1 Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 2 University of Alabama Birmingham, Birmingham, AL; 3 College of Physicians and Surgeons, Columbia University, New York, NY; 4 King’s College, London, UK; 5 National Center for Global Health and Medicine, Tokyo, Japan; 6 Dominican Institute for Virologic Studies, Santo Domingo, Dominican Republic; 7 Clinique Medicale L’Actuale in Montreal, Montreal, Canada; 8 Unidad de VIH del Hospital Civil de Guadalajara, Guadalajara, Mexico; 9 Gilead Sciences, Foster City, CA Abstract 143LB

2 Author Disclosures  Dr. Sax has served as a consultant or Scientific Advisory Board member for Gilead Sciences, AbbVie, BMS, GSK/ViiV, Merck, and Janssen, and his institution, Harvard Medical School/Brigham and Women’s Hospital, has received support from Gilead Sciences, BMS, GSK/ViiV, and Merck 2

3 Tenofovir Alafenamide (TAF, GS-7340) Novel Prodrug of Tenofovir 3 Tenofovir alafenamide (TAF) Tenofovir disoproxil fumarate (TDF) Tenofovir (TFV) L YMPHOID C ELL P LASMA TFV-MP TFV-DP G UT TFV TAF TDF TFV X

4 Background  Although potent and generally well tolerated, tenofovir disoproxil fumarate (TDF) may cause clinically significant renal and bone toxicity 1-3  Relative to TDF 300 mg, TAF 25 mg has 90% lower circulating plasma TFV, while maintaining high antiviral activity 4  In a phase II comparative study, TAF associated with reduced renal and bone effects 5  We sought to confirm these findings in fully powered clinical trials using extensive protocol-specified renal and bone endpoints – Virologic efficacy of E/C/F/TAF non-inferior to E/C/F/TDF (Wohl # 113-LB) E/C/F, elvitegravir, cobicistat, emtricitabine. 1. Mocroft AIDS. 2010 Jul 17;24(11):1667-78; 2. Morlat PLoS One. 2013;8:e66223; 3. Mccomsey J Infect Dis. 2011;203:1791-1801; 4. Ruane P, et al. JAIDS 2013; 63:449-54; 5. Sax PE.. et al. JAIDS 2014;67:52-58 4

5 E/C/F/TAF QD Study Design: Studies 104 and 111 5 Tx-Naïve Adults HIV-1 RNA ≥1000 c/mL eGFR ≥50 mL/min 1:1 E/C/F/TDF QD (Stribild, STB) n=866 n=867  Two Phase 3 randomized, double-blind, double-dummy, active-controlled studies – Study 104 (North America, EU, Asia), Study 111 (North America, EU, Latin America) – Stratified by HIV-1 RNA, CD4 cell count, geographic region  Primary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL (Taqman 2.0) – Non-inferiority (12% margin) based on Week 48 FDA snapshot analysis – Combined efficacy analysis pre-specified – Pre-specified Week 48 safety endpoints: serum creatinine, proteinuria, hip BMD, spine BMD Primary Endpoint 48144960Week

6 Baseline Characteristics Studies 104 and 111: Week 48 Combined Analysis *Cockcroft-Gault. 6

7 Plasma TFV and Intracellular TFV-DP Levels Studies 104 and 111: Week 48 Combined Analysis 7 E/C/F/TDF (n=14) E/C/F/TAF (n=21) 0 5 10 15 20 Geometric mean (95% CI) 4.1 X X Intracellular TFV-DP Plasma TFV E/C/F/TDF (n=29) E/C/F/TAF (n=36) Mean TFV Concentration, ng/mL (SD) Time (h)

8 Change in eGFR (Cockcroft-Gault) Studies 104 and 111: Week 48 Combined Analysis 8 *Cockroft-Gault (mL/min). -6.6 -11.2 p <0.001 Time (Weeks) Mean (SD) Change from Baseline eGFR*

9 Renal Adverse Events and Tubulopathy Studies 104 and 111: Week 48 Combined Analysis *Renal failure (2), decreased GFR (1), nephropathy (1). † Confirmed abnormality in any 2 categories at 2 consecutive post-baseline visits. 9

10 Changes in Quantitative Proteinuria at Week 48 Studies 104 and 111: Week 48 Combined Analysis 10 Median % Change from Baseline (Q1, Q3) Protein (UPCR) Albumin (UACR) Retinol Binding Protein Beta2- microglobulin E/C/F/TAF E/C/F/TDF p <0.001 for all Urine [protein]:Creatinine Ratio Baseline 44 mg/g 44 mg/g 5 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g 76133168 57

11 Changes in Spine and Hip BMD Through Week 48 Studies 104 and 111: Week 48 Combined Analysis 11 E/C/F/TAF, n 845 E/C/F/TDF, n 850 797 816 784 773 836 848 789 815 780 767 ‒ 0.66 p <0.001 ‒ 2.95 ‒ 1.30 p <0.001 ‒ 2.86 HipSpine Mean (SD) % Change from Baseline 2448 Week 02448 Week 0

12 12 E/C/F/TDF (N=850) E/C/F/TAF (N=845) BMD Categorical Changes at Week 48 Studies 104 and 111: Week 48 Combined Analysis ≥3% gain BMD Change Hip Spine Gain or loss <3% ≥3% loss

13 Fasting Lipids at Week 48 Studies 104 and 111: Week 48 Combined Analysis 13 Total CholesterolLDLHDLTriglyceridesTC:HDL Ratio Median Values (mg/dL) Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42). p <0.001 p <0.001 p <0.001 p=0.027 p=0.84 189 177 115 109 51 48 108 3.7 114 3.7 E/C/F/TAF Baseline Week 48 E/C/F/TDF Baseline Week 48

14 Conclusions Studies 104 and 111: Week 48 Combined Analysis  In these two large randomized clinical trials, detailed protocol-specified renal and bone endpoints confirmed the favorable safety and tolerability profile of TAF  Compared with TDF, TAF demonstrated: – No discontinuations due to renal AEs – Significantly smaller decreases in eGFR – Significantly less proteinuria, albuminuria, and tubular proteinuria – Significantly less impact on spine and hip BMD – Greater increases in fasting lipids, TC:HDL same  The most likely explanation for these findings is the 90% lower tenofovir plasma exposure with TAF vs TDF 14

15 Additional Data  Study 104+111 primary results presented Feb 25 th (Wohl, 113LB) – E/C/F/TAF non-inferior to E/C/F/TDF at Week 48 (92.4% vs 90.4%) – Treatment-emergent resistance <1% in both arms – Both drugs well tolerated through 48 weeks  Patients with mild to moderate renal impairment (eGFR 30-69 mL/min) who switch to E/C/F/TAF improve BMD and markers of kidney function through 48 weeks (Pozniak, Poster #795)  Complete results of Studies 104 and 111 submitted for peer-reviewed publication  Health authority filings submitted and under review in multiple countries 15

16 Acknowledgments We extend our thanks to the patients, their partners and families, and all participating Study 104 & 111 investigators C Achenbach, F Ajana, B Akil, H Albrecht, J Andrade Villanueva, J Angel, A Antela Lopez, J Arribas Lopez, A Avihingsanon, D Baker, J-G Baril, D Bell, N Bellos, P Benson, J Berenguer, I Bica, A Blaxhult, M Bloch, P Brachman, I Brar, K Brinkman, C Brinson, B Brown, J Brunetta, J Burack, T Campbell, M Cavassini, A Cheret, P Chetchotisakd, A Clarke, B Clotet, N Clumeck, C Cohen, P Cook, L Cotte, D Coulston, M Crespo, C Creticos, G Crofoot, F Cruickshank, J Cunha, E Daar, E DeJesus, J De Wet, M Doroana, R Dretler, M Dube, J Durant, H Edelstein, R Elion, J Fehr, R Finlayson, D Fish, J Flamm, S Follansbee, H Furrer, F Garcia, J Gatell Artigas, J Gathe, S Gilroy, P-M Girard, J-C Goffard, E Gordon, P Grant, R Grossberg, C Hare, T Hawkins, R Hengel, K Henry, A Hite, G Huhn, M Johnson, M Johnson, K Kasper, C Katlama, S Kiertiburanakul, JM Kilby, C Kinder, D Klein, H Knobel, E Koenig, M Kozal, R Landovitz, J Larioza, A Lazzarin, R LeBlanc, B LeBouche, S Lewis, S Little, C Lucasti, C Martorell, C Mayer, C McDonald, J McGowan, M McKellar, G McLeod, A Mills, J-M Molina, G Moyle, M Mullen, C Mussini, R Nahass, C Newman, S Oka, H Olivet, C Orkin, P Ortolani, O Osiyemi, F Palella, P Palmieri, D Parks, A Petroll, G Pialoux, G Pierone, D Podzamczer Palter, C Polk, R Pollard, F Post, A Pozniak, D Prelutsky, A Rachlis, M Ramgopal, B Rashbaum, W Ratanasuwan, R Redfield, G Reyes Teran, J Reynes, G Richmond, A Rieger, B Rijnders, W Robbins, A Roberts, J Ross, P Ruane, R Rubio Garcia, M Saag, J Santana- Bagur, L Santiago, R Sarmento e Castro, P Sax, B Schmied, T Schmidt, S Schrader, A Scribner, S Segal- Maurer, B Sha, P Shalit, D Shamblaw, C Shikuma, K Siripassorn, J Slim, L Sloan, D Smith, K Squires, D Stein, J Stephens, K Supparatpinyo, K Tashima, S Taylor, P Tebas, E Teofilo, A Thalme, M Thompson, W Towner, T Treadwell, B Trottier, T Vanig, N Vetter, P Viale, G Voskuhl, B Wade, S Walmsley, D Ward, L Waters, D Wheeler, A Wilkin, T Wilkin, E Wilkins, T Wills, D Wohl, M Wohlfeiler, K Workowski, B Yangco, Y Yazdanpanah, G-P Yeni, M Yin, B Young, A Zolopa, C Zurawski This study was funded by Gilead Sciences, Inc. 16


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