Transcript Renal and Bone Safety of Tenofovir Alafenamide vs

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 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
CROI 2015, Seattle
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
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Tenofovir Alafenamide (TAF, GS-7340)
Novel Prodrug of Tenofovir
Tenofovir
(TFV)
GUT
TFV
TDF
Tenofovir
disoproxil fumarate
(TDF)
PLASMA
LYMPHOID CELL
X
TFV
TFV
TAF
TFV
TFV-MP
Tenofovir
alafenamide (TAF)
TFV-DP
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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. 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
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Study Design: Studies 104 and 111
Primary Endpoint
Week 0
n=866
Tx-Naïve Adults
HIV-1 RNA ≥1000 c/mL
eGFR ≥50 mL/min
48
96
144
E/C/F/TAF QD
1:1
n=867
E/C/F/TDF QD (Stribild, STB)
 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
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Baseline Characteristics
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
n=866
E/C/F/TDF
n=867
33
35
Male
85
85
Female
15
15
Black or African descent
26
25
Hispanic/Latino ethnicity
19
19
Median HIV-1 RNA, log10 c/mL
4.58
4.58
23
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
10
Median age, year
Sex, %
Race/ethnicity, %
% with HIV-1 RNA >100,000 c/mL
*Cockcroft-Gault.
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Plasma TFV and Intracellular TFV-DP Levels
Studies 104 and 111: Week 48 Combined Analysis
Intracellular TFV-DP
500
20
E/C/F/TDF
E /C /F /T D F (n(n=29)
=29)
E /C /F /T A F (n(n=36)
=36)
E/C/F/TAF
100
10
TFV Exposure (μM*h)
TFV Concentration, ng/mL (SD)
Mean
M e a n T F V C o n c e n tr a tio n , n g /m L ( S D )
Plasma TFV
5
0
6
12
18
24
Geometric mean (95% CI)
15
4.1 X
10
5
X
0
E/C/F/TDF
(n=14)
E/C/F/TAF
(n=21)
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
T im e (h )
Time (h)
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Change in eGFR (Cockcroft-Gault)
Studies 104 and 111: Week 48 Combined Analysis
(SD) Change
Mean Mean
(SD) change
from baseline
Baseline eGFR*
from
eGFR
Cockroft-Gault
(mL/min)
20
E/C/F/TAF
E/C/F/TDF
10
0
-6.6
p <0.001
-10
-11.2
-20
0
*Cockroft-Gault (mL/min).
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Time (Weeks)
Time (Weeks)
36
48
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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
Renal adverse events leading to discontinuation
0
4 (0.5)*
Tubulopathy/Fanconi syndrome
0
0
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)
0
2 (0.2)
2 (0.2)
2 (0.2)
n (%)
Events
Laboratory
Abnormalities
Normoglycemic glycosuria (≥1 grade increase
urine glucose; serum glucose ≤100 mg/dL)
Proteinuria (≥2 grade increase)
*Renal failure (2), decreased GFR (1), nephropathy (1).
†Confirmed abnormality in any 2 categories at 2 consecutive post-baseline visits.
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Changes in Quantitative Proteinuria at Week 48
Studies 104 and 111: Week 48 Combined Analysis
Median % Change from Baseline (Q1, Q3)
Urine [protein]:Creatinine Ratio
Protein
(UPCR)
Albumin
(UACR)
Retinol Binding
Protein
76
75
Beta2microglobulin
133
168
E/C/F/TAF
E/C/F/TDF
51
50
24
20
25
7
9
0
-3
-5
p <0.001
for all
-25
-32
-50
Baseline
57
44
mg/g
44
mg/g
5
mg/g
5
mg/g
64
μg/g
67
μg/g
101
μg/g
103
μg/g
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Changes in Spine and Hip BMD Through Week 48
Studies 104 and 111: Week 48 Combined Analysis
Mean (SD) % Change
from Baseline
Spine
Hip
p <0.001
2
2
p <0.001
0
0
‒0.66
‒1.30
-2
-2
‒2.86
‒2.95
-4
-4
-6
-6
0
24
48
0
Week
24
48
Week
E/C/F/TAF, n
845
797
784
836
789
780
E/C/F/TDF, n
850
816
773
848
815
767
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BMD Categorical Changes at Week 48
Studies 104 and 111: Week 48 Combined Analysis
BMD Change
≥3% gain
Spine
Hip
Gain or loss <3%
≥3% loss
7%
7%
17%
26%
E/C/F/TAF (N=845)
68%
76%
3%
3%
45%
50%
E/C/F/TDF (N=850)
51%
46%
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Fasting Lipids at Week 48
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
Baseline
Week 48
200
E/C/F/TDF
Baseline
Week 48
5
189
Median Values (mg/dL)
177
150
160
4
163
115
100
101
114
109
104
50
95
51
48
44
44
108
100
3.7
3.7
3.6
3.6
3
2
1
0
0
Total Cholesterol
LDL
HDL
Triglycerides
TC:HDL Ratio
p <0.001
p <0.001
p <0.001
p=0.027
p=0.84
Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42).
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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
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Additional Data
 Study 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 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
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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 SantanaBagur, L Santiago, R Sarmento e Castro, P Sax, B Schmied, T Schmidt, S Schrader, A Scribner, S SegalMaurer, 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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