Transcript Document

Tenofovir Alafenamide (TAF)
in a Single-Tablet Regimen
in Initial HIV-1 Therapy
Combined Primary Results of
Studies GS-US-292-0104 and GS-US-292-0111
David Wohl1, Anton Pozniak2, Melanie Thompson3, Edwin DeJesus4,
Daniel Podzamczer5, Jean-Michel Molina6, Gordon Crofoot7,
Christian Callebaut8, Hal Martin8, Scott McCallister8
1University
of North Carolina, Chapel Hill, NC; 2Chelsea and Westminster Hospital,
NHS Foundation Trust, London, UK; 3AIDS Research Consortium of Atlanta, Atlanta, GA;
4Orlando Immunology Center, Orlando, FL; 5Hospital Universitari de Bellvitge, Barcelona,
Spain; 6Hôpital Saint Louis, Paris, France; 7Gordon Crofoot Research, Houston, TX;
8Gilead Sciences, Foster City, CA
Abstract 113LB
CROI 2015, Seattle
Author Disclosures
 Dr. Wohl has served as an advisor to Gilead Sciences and Janssen,
and the University of North Carolina Chapel Hill has received funding
from Gilead Sciences and Merck
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Background
 Tenofovir disoproxil fumarate (TDF) is included in most recommended
antiretroviral regimens, and although potent and generally well
tolerated, has been associated with clinically significant renal and bone
toxicity1-3
 Relative to TDF 300 mg, tenofovir alafenamide (TAF) 25 mg has 90%
lower circulating plasma TFV, while maintaining high antiviral activity4
 In Phase 2, efficacy of elvitegravir, cobicistat, emtricitabine, and TAF
(E/C/F/TAF) was comparable to E/C/F/TDF, and demonstrated
significant improvements in renal and bone safety5
 We sought to confirm the efficacy of E/C/F/TAF in two fully powered
clinical trials
1. DeJesus E, et al. Lancet 2012;379:2429-38; 2. Gallant JE, et al. J Infect Dis 2013;208:32-9; 3. Sax PE, et al. Lancet
2012;379:2439-48; 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-55; 5. Sax PE, et al. J Acquir Immune
Defic Syndr 2014;67:52-8.
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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
117
114
Median age, years
Sex, %
Race/ethnicity, %
% with HIV-1 RNA >100,000 c/mL
Median estimated GFR*, mL/min
*Cockcroft-Gault.
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Patient Disposition
Studies 104 and 111: Week 48 Combined Analysis
Screened
(N=2,175)
Randomized,
treated with E/C/F/TAF
n=866
5% Discontinued (n=45)
•
•
•
•
•
•
•
Adverse event (8)
Death (1)
Lack of efficacy (2)
Withdrew consent (12)
Lost to follow-up (15)
Subject non-compliance (2)
Protocol violation (5)
95% on Treatment
n=821
Randomized,
treated with E/C/F/TDF
n=867
8% Discontinued (n=71)
•
•
•
•
•
•
•
•
•
Adverse event (13)
Death (2)
Lack of efficacy (3)
Withdrew consent (16)
Lost to follow-up (18)
Subject non-compliance (1)
Protocol violation (6)
Investigator discretion (7)
Pregnancy (5)
92% on Treatment
n=796
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Primary Endpoint: HIV-1 RNA <50 copies/mL at Week 48
Studies 104 and 111: Week 48 Combined Analysis
Treatment Difference (95% CI)
HIV-1 RNA <50 c/mL, %
Virologic Outcome
100
E/C/F/TAF (n=866)
E/C/F/TDF (n=867)
92 90
Favors E/C/F/TDF Favors E/C/F/TAF
80
60
2.0%
‒0.7%
4.7%
40
20
4
4
4
6
0
Success
Failure
No Data
‒12%
0
+12%
 E/C/F/TAF was non-inferior to E/C/F/TDF at Week 48 in each study
– 93% E/C/F/TAF vs 92% E/C/F/TDF (Study 104)
– 92% E/C/F/TAF vs 89% E/C/F/TDF (Study 111)
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Efficacy by Baseline HIV-1 RNA and CD4 Count
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF (n=866)
Viral Load
Overall
Virologic Success (%)
100
92
90
E/C/F/TDF (n=867)
94
91
Cell Count
87
89
171
196
174
195
86
89
93
91
80
60
40
20
0
800
866
784
867
629
670
610
672
≤100,000
>100,000
HIV-1 RNA (c/mL)
96
112
104
117
<200
703
753
680
750
≥200
CD4 (cells/μL)
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Efficacy in Select Subgroups
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF (n=866)
Age
Overall
Virologic Success (%)
100
92
90
E/C/F/TDF (n=867)
92
90
Sex
94
91
92
91
Race
95
94
87
93
88
83
80
60
40
20
0
800
866
784
867
716
777
680
753
84
89
104
114
<50 years ≥50 years
674
733
673
740
Male
126
133
111
127
Female
603
643
607
654
Non-Black
197
223
177
213
Black
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Median Change from Baseline in CD4 Count
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
E/C/F/TDF
Median Change from Baseline in
CD4 Count (cells/μL)
300
211
200
p=0.024
181
100
0
02 4
8
12 16 20 24 28 32 36 40 44 48 52
Weeks
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Resistance Through Week 48
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
n=866
E/C/F/TDF
n=867
16 (1.8)
19 (2.2)
7 (0.8)
5 (0.6)
Study 104, n
3
3
Study 111, n
4
2
Any
7
5
M184V/I
6
3
M184V/I + K65R
1
2
Any
5
3
T66A
1
0
E92Q
2
1
Q148R
0
1
Q148R + T66I/A
1
0
Q148R + E92Q
0
1
N155H
1
0
Patients analyzed for resistance*, n (%)
Any, n (%)
Primary Genotypic
Resistance
NRTI Resistance, n
INSTI Resistance, n
*With 2 consecutive HIV-1 RNA ≥50 c/mL after first achieving <50 c/mL and the second ≥400 c/mL;
or had ≥400 c/mL at Week 48 or last study visit.
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Overall Safety
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
n=866
%
E/C/F/TDF
n=867
%
90
90
40
42
8
9
1
1
8
7
Any drug-related serious AE
0.3
0.2
Any AE-related discontinuation
0.9
1.5
Deaths
0.2*
0.3†
Any AE
Any drug-related AE
Any Grade 3 or 4 AE
Any drug-related Grade 3 or 4 AE
Any serious AE
*Stroke (1), alcohol intoxication (1).
†Alcohol and drug intoxication (1), myocardial infarction (2).
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Adverse Events Leading to Discontinuation
Studies 104 and 111: Week 48 Combined Analysis
% (n)
Type
E/C/F/TAF
n=866
E/C/F/TDF
n=867
0.9% (8)
1.5% (13)
• Blood triglycerides increased
• Cerebral infarction, hemorrhagic
transformation stroke
• Dyspnea, hyperkeratosis, abdominal
distention & pain, back pain,
lipodystrophy acquired
• Dysphagia, pharyngitis
• Erectile dysfunction
• Eye irritation, eye pain, eye pruritus
• Proctalgia, penile pain
• Rash erythematous
• Arthropod bite, dermatitis
• Abdominal pain, temporomandibular joint
syndrome, headache, depression
• Cardiac arrest
• Dysphagia, nausea, vomiting
• Decreased GFR
• Hyperamylasemia
• Immune reconstitution inflammatory
syndrome
• Iridocyclitis
• Nephropathy
• Rash generalized
• Renal failure (2)
• Vomiting, bladder spasm, pyrexia,
headache, myalgia, rash maculopapular
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Common Adverse Events (All Grades)
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
n=866
E/C/F/TDF
n=867
Diarrhea
17
19
Nausea
15
17
Headache
14
13
Upper respiratory tract infection
11
13
Nasopharyngitis
9
9
Fatigue
8
8
Cough
8
7
Vomiting
7
6
Arthralgia
7
5
Back pain
7
7
Insomnia
7
6
Rash
6
5
Pyrexia
5
5
Dizziness
5
4
AEs in ≥5% of patients, %
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Grade 3 or 4 Laboratory Abnormalities
Studies 104 and 111: Week 48 Combined Analysis
E/C/F/TAF
n=866
%
E/C/F/TDF
n=867
%
20
20
Creatine kinase elevation
7
6
LDL elevation (fasting)
5
2
Hypercholesterolemia (fasting)
2
1
Hematuria (quantitative)
2
2
AST elevation
2
2
Serum amylase elevation
2
3
Neutropenia (<1000 cells/µL)
2
2
ALT elevation
1
1
Any grade 3 or 4 lab abnormalities*
*≥1% on E/C/F/TAF arm.
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Conclusions
Studies 104 and 111: Week 48 Combined Analysis
 92% of patients treated with E/C/F/TAF achieved virologic suppression
through Week 48 (combined analysis)
– Virologic response for E/C/F/TAF, 93% (Study 104) and 92% (Study 111)
– E/C/F/TAF was non-inferior to E/C/F/TDF
– High and similar response rates, irrespective of age, sex, race, HIV-1 RNA,
and CD4 cell count
 Low rates of virologic failure, with resistance <1% in both arms
 Both drugs were well tolerated and safe
─ Discontinuations due to AEs were low in both arms
─ 0.9% (8) for E/C/F/TAF vs 1.5% (13) for E/C/F/TDF
─ No proximal tubulopathy cases
─ Common AEs similar between treatment arms
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Additional Data
 Detailed resistance analysis (Margot, Poster #6)
– HIV Drug Resistance Workshop (Feb 21-22)
 Off-target side effects of tenofovir (renal, bone, lipid) (Sax, #143LB)
– Feb 26th Oral Abstract Session: Cardiovascular, Bone, and Kidney Health
 Patients with mild to moderate renal impairment (eGFR 30-69 mL/min)
who switch to E/C/F/TAF, bone mineral density and markers of kidney
function improved 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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