Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Combined Safety Results of Studies GSUS2920104 and GSUS2920111 Paul Sax 1 Michael Saag 2 Michael Yin 3 Frank Post ID: 921100
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Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil FumarateCombined 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
Slide2Author DisclosuresDr. 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
Slide3Tenofovir Alafenamide (TAF, GS-7340)Novel Prodrug of Tenofovir3Tenofovir alafenamide (TAF)Tenofovir disoproxil fumarate (TDF)
Tenofovir
(TFV)
Lymphoid Cell
Plasma
TFV-MP
TFV-DP
Gut
TFV
TFV
TAF
TDF
TFV
X
TFV
Slide4BackgroundAlthough potent and generally well tolerated, tenofovir disoproxil fumarate (TDF) may cause clinically significant renal and bone toxicity1-3Relative 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 endpointsVirologic 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
Slide5E/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
=866n=867
Two Phase 3 randomized, double-blind,
double-dummy, active-controlled studiesStudy 104 (North America, EU, Asia), Study 111 (North America, EU, Latin America)Stratified by HIV-1 RNA, CD4 cell count, geographic regionPrimary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL (Taqman 2.0)Non-inferiority (12% margin) based on Week 48 FDA snapshot analysisCombined efficacy analysis pre-specifiedPre-specified Week 48 safety endpoints: serum creatinine, proteinuria, hip BMD, spine BMD
Primary Endpoint
48
144
96
0
Week
Slide6Baseline CharacteristicsStudies 104 and 111: Week 48 Combined AnalysisE/C/F/TAF
n=866
E/C/F/TDF
n=867
Median age, year
33
35
Sex, %
Male
85
85
Female
15
15
Race/ethnicity, %
Black or African descent
26
25
Hispanic/Latino ethnicity
19
19
Median HIV-1 RNA, log
10
c/mL
4.58
4.58
% with HIV-1 RNA >100,000 c/mL23
23Median CD4 count, cells/μL
404406
% with CD4 count ≤200
13
14
Median estimated GFR*, mL/min
117
114
Dipstick proteinuria (any grade), %
10
10
*Cockcroft-
Gault
.
6
Slide7Plasma TFV and Intracellular TFV-DP LevelsStudies 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)
TFV Exposure
(
M
*h)
Time (h)
Steady State TFV PK
E/C/F/TDF
n=29
E/C/F/TAF
n=36
% Reduction
Mean
AUC
tau
, ng*h/mL (%CV)
3,410 (25)
297(20)
91
Slide8Change 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
*
Slide9n (%)
E/C/F/TAF
n=866
E/C/F/TDF
n=867
Events
Renal adverse events leading to discontinuation
0
4 (0.5)*
Tubulopathy
/
Fanconi
syndrome
0
0
Laboratory Abnormalities
Subclinical
tubulopathy
†
0
1 (0.1)
Serum creatinine (≥0.4 mg/dL increase)0
0
Hypophosphatemia (≥1 grade decrease)
3 (0.3)4 (0.5)
Normoglycemic
glycosuria (≥1 grade increase urine glucose; serum glucose ≤100 mg/dL)
02 (0.2)
Proteinuria (≥2 grade increase)2 (0.2)
2 (0.2)
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
Slide10Changes in Quantitative Proteinuria at Week 48Studies 104 and 111: Week 48 Combined Analysis 10Median % 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
f
or all
Urine [protein]:Creatinine Ratio
Baseline
44
mg/g
44
mg/g
5mg/g5mg/g
64μg/g 67μg/g 101μg/g
103μg/g 76133
16857
Slide11Changes in Spine and Hip BMD Through Week 48Studies 104 and 111: Week 48 Combined Analysis 11E/C/F/TAF, n845
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
Hip
Spine
Mean (SD)
%
Change from Baseline
2448Week0
2448Week0
Slide1212E/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
Slide13Fasting Lipids at Week 48
Studies 104 and 111: Week 48 Combined Analysis
13
Total Cholesterol
LDL
HDL
Triglycerides
TC: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
18917711510951
481083.71143.7
E/C/F/TAFBaseline
Week 48E/C/F/TDFBaseline
Week 48
Slide14ConclusionsStudies 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 TAFCompared with TDF, TAF demonstrated:No discontinuations due to renal AEsSignificantly smaller decreases in eGFRSignificantly less proteinuria, albuminuria, and tubular proteinuria Significantly less impact on spine and hip BMDGreater increases in fasting lipids, TC:HDL sameThe most likely explanation for these findings is the 90% lower tenofovir plasma exposure with TAF vs TDF14
Slide15Additional DataStudy 104+111 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 armsBoth drugs well tolerated through 48 weeksPatients 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 publicationHealth authority filings submitted and under review in multiple countries
15
Slide16AcknowledgmentsWe extend our thanks to the patients, their partners and families, and all participating Study 104 & 111 investigatorsC 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 ZurawskiThis study was funded by Gilead Sciences, Inc.16