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Huyen Cao9, Marshall Fordyce9

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1 Huyen Cao9, Marshall Fordyce9
Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Combined Safety Results of Studies GS-US and GS-US Paul Sax1, Michael Saag2, Michael Yin3, Frank Post4, Shinichi Oka5, Ellen Koenig6, Benoit Trottier7, Jaime Andrade-Villanueva8, Huyen Cao9, Marshall Fordyce9 1Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 2University of Alabama Birmingham, Birmingham, AL; 3College of Physicians and Surgeons, Columbia University, New York, NY; 4King’s College, London, UK; 5National Center for Global Health and Medicine, Tokyo, Japan; 6Dominican Institute for Virologic Studies, Santo Domingo, Dominican Republic; 7Clinique Medicale L’Actuale in Montreal, Montreal, Canada; 8Unidad de VIH del Hospital Civil de Guadalajara, Guadalajara, Mexico; 9Gilead 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

3 Tenofovir Alafenamide (TAF, GS-7340) Novel Prodrug of Tenofovir
Lymphoid Cell Plasma TFV-MP TFV-DP Gut TFV TAF TDF X Tenofovir (TFV) Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) Gilead Sciences, Inc. - Confidential

4 Background Although potent and generally well tolerated, tenofovir disoproxil fumarate (TDF) may cause clinically significant renal and bone toxicity1-3 Relative to TDF 300 mg, TAF 25 mg has 90% lower circulating plasma TFV, while maintaining high antiviral activity4 In a phase II comparative study, TAF associated with reduced renal and bone effects5 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 Jul 17;24(11): ; 2. Morlat PLoS One. 2013;8:e66223; 3. Mccomsey J Infect Dis. 2011;203: ; 4. Ruane P, et al. JAIDS 2013; 63:449-54; 5. Sax PE.. et al. JAIDS 2014;67:52-58

5 Study Design: Studies 104 and 111
Primary Endpoint 48 144 96 Week n=866 E/C/F/TAF QD Tx-Naïve Adults HIV-1 RNA ≥1000 c/mL eGFR ≥50 mL/min 1:1 E/C/F/TDF QD (Stribild, STB) 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 5

6 Baseline Characteristics Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF n=866 E/C/F/TDF n=867 Median age, year 33 35 Sex, % Male 85 Female 15 Race/ethnicity, % Black or African descent 26 25 Hispanic/Latino ethnicity 19 Median HIV-1 RNA, log10 c/mL 4.58 % with HIV-1 RNA >100,000 c/mL 23 Median CD4 count, cells/μL 404 406 % with CD4 count ≤200 13 14 Median estimated GFR*, mL/min 117 114 Dipstick proteinuria (any grade), % 10 *Cockcroft-Gault.

7 Mean TFV Concentration, ng/mL (SD)
Plasma TFV and Intracellular TFV-DP Levels Studies 104 and 111: Week 48 Combined Analysis Plasma TFV Intracellular TFV-DP 20 Geometric mean (95% CI) E/C/F/TDF (n=29) E/C/F/TAF (n=36) 15 4.1 X Mean TFV Concentration, ng/mL (SD) TFV Exposure (μM*h) 10 5 X E/C/F/TDF (n=14) E/C/F/TAF (n=21) Time (h) Steady State TFV PK E/C/F/TDF n=29 E/C/F/TAF n=36 % Reduction Mean AUCtau, ng*h/mL (%CV) 3,410 (25) 297(20) 91

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

9 Renal Adverse Events and Tubulopathy Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF n=866 E/C/F/TDF n=867 Events Renal adverse events leading to discontinuation 4 (0.5)* Tubulopathy/Fanconi syndrome Laboratory Abnormalities Subclinical tubulopathy† 1 (0.1) Serum creatinine (≥0.4 mg/dL increase) Hypophosphatemia (≥1 grade decrease) 3 (0.3) 4 (0.5) Normoglycemic glycosuria (≥1 grade increase urine glucose; serum glucose ≤100 mg/dL) 2 (0.2) Proteinuria (≥2 grade increase) *Renal failure (2), decreased GFR (1), nephropathy (1). †Confirmed abnormality in any 2 categories at 2 consecutive post-baseline visits.

10 Urine [protein]:Creatinine Ratio Retinol Binding Protein
Changes in Quantitative Proteinuria at Week 48 Studies 104 and 111: Week 48 Combined Analysis Urine [protein]:Creatinine Ratio Protein (UPCR) Albumin (UACR) Retinol Binding Protein Beta2- microglobulin 76 133 168 E/C/F/TAF E/C/F/TDF Median % Change from Baseline (Q1, Q3) p <0.001 for all 57 Baseline 44 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g

11 Changes in Spine and Hip BMD Through Week 48 Studies 104 and 111: Week 48 Combined Analysis
‒0.66 ‒1.30 Mean (SD) % Change from Baseline ‒2.86 ‒2.95 24 48 Week 24 48 Week E/C/F/TAF, n 845 E/C/F/TDF, n 850 797 816 784 773 836 848 789 815 780 767

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

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

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

15 Additional Data Study primary results presented Feb 25th (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 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

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.


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