Post on 14-Jan-2016
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FármacoFármaco CompañíaCompañía FamiliaFamilia Nº abstractNº abstract
LEDFG/P75LEDFG/P75 PfizerPfizer INIINI 9898
QuadQuad GileadGilead INIINI 101, 627101, 627
DolutegravirDolutegravir ViiVViiV INIINI 102LB102LB
GS-7340GS-7340 GileadGilead ITIANITIAN 103103
CenicrivirocCenicriviroc TobiraTobira CCR5CCR5 600600
NitazoxanidaNitazoxanida U. MilanU. Milan ?? 583583
FármacoFármaco CompañíaCompañía FamiliaFamilia Nº abstractNº abstract
LEDFG/P75LEDFG/P75 PfizerPfizer INIINI 9898
QuadQuad GileadGilead INIINI 101, 627101, 627
DolutegravirDolutegravir ViiVViiV INIINI 102LB102LB
GS-7340GS-7340 GileadGilead ITIANITIAN 103103
CenicrivirocCenicriviroc TobiraTobira CCR5CCR5 600600
NitazoxanidaNitazoxanida U. MilanU. Milan ?? 583583
The Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF
(“Quad”) Compared to Efavirenz/Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects: Primary Results of
Study GS-US-236-0102
Paul Sax1, Edwin DeJesus2, Anthony Mills3, Andrew Zolopa4, Calvin Cohen5, David Wohl6, Joel Gallant7, Hui C Liu8, Kirsten White8, Erin Quirk8, and Brian Kearney8
1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US; 2Orlando Immunology Center, Orlando, FL, US; 3Anthony Mills MD, Inc., Los Angeles, US; 4Stanford University, Palo Alto, CA, US; 5Community Research Initiative of New England, Boston, MA, US; 6University of North Carolina, Chapel Hill, NC, US; 7Johns Hopkins School of Medicine, Baltimore, MD, US; 8Gilead Sciences, Foster City, CA, US
19th Conference on Retroviruses and Opportunistic InfectionsMarch 7, 2012 Paper #: 101
Study Design: 236-0102
Treatment- naive (N = 700 planned)
Quad QD
EFV/FTC/TDF QHS Placebo
EFV/FTC/TDF QHS
Quad Placebo QD
• Randomized 1:1• Stratification by HIV-1 RNA (>100,000 c/mL)
n=350
n=350
Primary Endpoint: Proportion with HIV-1 RNA < 50 copies/mL at Week 48 – FDA snapshot analysis, 12% noninferiority margin
– HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5
Week 48 Week 192
Conducted in parallel with Study 236-0103 comparing Quad to FTC/TDF + ATV/r (DeJesus et al, Poster #627)
Conducted in parallel with Study 236-0103 comparing Quad to FTC/TDF + ATV/r (DeJesus et al, Poster #627)
Baseline Characteristics Study 236-0102
CharacteristicQuad
(n=348)EFV/FTC/TDF
(n=352)
Age (years), Mean 38 38
Male (%) 88% 90%
Non-white (%)
Black or African descent (%)
39%
31%
36%
26%
Asymptomatic HIV Infection (%) 83% 84%
HBV – HCV seropositive (%) 1% - 5% 3% - 4%
HIV-1 RNA (log10 copies/mL), Median 4.75 4.78
>100,000 (%) 34% 33%
CD4 count (cells/mm3), Mean (%) 391 382
≤200 cells/mm3 12% 14%
200 to ≤350 32% 27%
351 to ≤500 32% 39%
>500 23% 20%
Subject Disposition Through Week 48 Study 236-0102
11% Discontinued (N=37)
Screened(N=917)
Randomized and TreatedEFV/FTC/TDF (N=352)
Randomized and TreatedQuad (N=348)
13% Discontinued (N=46)
89% Continued (N=311)
87% Continued(N=306)
• Adverse event 12• Death 1• Pregnancy 1• Lack of efficacy 5• Investigator’s discretion 1• Withdrew consent 3• Lost to follow-up 10• Subject non-compliance 3• Protocol violation 1
• Adverse event 12• Death 1• Pregnancy 1• Lack of efficacy 5• Investigator’s discretion 1• Withdrew consent 3• Lost to follow-up 10• Subject non-compliance 3• Protocol violation 1
• Adverse event 18• Death 1• Lack of efficacy 4• Withdrew consent 5• Lost to follow-up 12• Subject non-compliance 6
• Adverse event 18• Death 1• Lack of efficacy 4• Withdrew consent 5• Lost to follow-up 12• Subject non-compliance 6
Primary Endpoint: HIV-1 RNA < 50 copies/mL Study 236-0102
Quad was non-inferior to EFV/FTC/TDF at Week 48Quad was non-inferior to EFV/FTC/TDF at Week 48
95% CI for Difference
12%
-1. 6 8.8
FavorsEFV/FTC/TDF
3.6
FavorsQuad
0 -12%
Percent Difference in Response by Subgroups Study 236-0102
Overall
Age (years)<40≥40
SexMale
Female
RaceWhite
Non-white
Baseline HIV-1 RNA Level≤100,000 c/mm3
>100,000 c/mm3
Baseline CD4 Count≤350 (cells/µL)>350 (cells/µL)
Study Drug Adherence (%)<95≥95
Differences in Percentages (95% CI)
-20 -15 -10 -5 0 5 10 15 20 25
Favors Quad Favors EFV/FTC/TDF
FDA Snapshot Week 48, HIV-1 RNA <50 copies/mL
Efficacy in Baseline HIV-RNA and CD4 Subgroups Study 236-0102
90%84% 83%
91%85% 82% 84% 84%
≤100,000 >100,000 CD4 ≤350 CD4 >350
Quad EFV/FTC/TDF
Vir
olo
gic
Su
cces
s (<
50 c
/mL
)V
iro
log
ic S
ucc
ess
(<50
c/m
L)
Mean Change from Baseline in CD4 Count Study 236-0102
P =.009
Ch
ang
e fr
om
Bas
elin
e in
CD
4 (c
ells
/mm
3 )
300
200
100
0BL 2 4 8 12 16 24 32 40 48
WeekQuad (n=): 348 340 343 342 337 335 326 323 325 325EFV/FTC/TDF (n=): 352 339 344 339 333 325 322 317 314 315
a Anova P value.
EFV/FTC/TDF, 206
Quad, 239
Integrase & NNRTI Resistance Through Week 48 Study 236-0102
Quad(n=348)
EFV/FTC/TDF(n=352)
Subjects Analyzed for Resistance*, n (%) 14 (4) 17 (5)
Subjects with Resistance to ARV Regimen, n (%) 8 (2) 8 (2)
Any Primary Integrase-R, n 7
E92Q 7
T66I 1
Q148R 1
N155H 1
Any Primary NNRTI-R n 8
K103N 7
V108I 2
Y188Y/F/H/L 1
G190A 1
Any Primary NRTI-R, n 8 2
M184V/I 8 2
K65R 3 2
*Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and <1 log10 below baseline after Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit.
Quad(n=348)
EFV/FTC/TDF(n=352)
Treatment Emergent Adverse Events in ≥ 10% of subjects (%)
Diarrhea 23% 19%
Nausea * 21% 14%
Abnormal Dreams ^ 15% 27%
Upper Respiratory Infection 14% 11%
Headache 14% 9%
Fatigue 12% 13%
Insomnia * 9% 14%
Depression 9% 11%
Dizziness ^ 7% 24%
Rash # 6% 12%
Adverse Events Leading to Study Drug Discontinuation in > 1 subject (n)
Depression 1 3
Abnormal Dreams 0 2
Blood Creatinine Increased 2 0
Fatigue 1 1
Paranoia 1 1
Rash 0 2
Renal Failure 2 0
Common Adverse Events and Discontinuations due to Adverse Event
Study 236-0102
* p < 0.05^ p < 0.001# p=0.009
Grade 3 and 4 Laboratory Abnormalities Study 236-0102
Grade 3-4 Labs *Quad
(n = 348)EFV/FTC/TDF
(n = 352)
Creatine Kinase 5% 11%
AST 2% 3%
ALT 1% 3%
GGT 2% 5%
Neutrophils 2% 3%
Amylase 2% 2%
Hematuria 2% 1%
*>5 subjects in any treatment group
Median Change from Baseline in Serum Creatinine
Median change at Week 48: 0.14 mg/dL vs. 0.01 mg/dL (Quad vs. EFV/FTC/TDF group, p<0.001)
Quad (n=): 348 341 345 345 337 335 328 323 320 320EFV/FTC/TDF (n=): 352 340 340 336 327 323 317 313 309 307\\\\\\\\\\
BL 2 4 8 12 16 24 32 40 48BL 2 4 8 12 16 24 32 40 48
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08Ch
an
ge
fro
m B
L i
n S
eru
m C
rea
tin
ine
(m
g/d
L)
(IQ
R)
Ch
an
ge
fro
m B
L i
n S
eru
m C
rea
tin
ine
(m
g/d
L)
(IQ
R)
WeekWeek
10 10
5
7
19
17
87
0
2
4
6
8
10
12
14
16
18
20
Quad EFV/FTC/TDF
Ch
ang
e F
rom
BL
at
Wee
k 48
(m
g/d
L )
Total Cholesterol LDL HDL Triglycerides
Median Change from Baseline in Fasting Lipids through Week 48
Study 236-0102
P <0.001 P =0.001 P =0.001 P =0.44
Conclusions Study 236-0102
• High and comparable efficacy in Quad and EFV/FTC/TDF– Non-inferior virologic suppression rates across protocol-specified
subgroups, including HIV-1 RNA >100,000 copies/mL at baseline
• Quad was well tolerated– Similar low-rates of treatment discontinuation– Fewer reports of abnormal dreams, insomnia, dizziness, and rash– Higher rate of Grade 1 (not Grade 2 or higher) nausea– Median 0.14 mg/dL increase in serum creatinine, with 5/348 (1.4%)
discontinuing due to renal events – Smaller increases in total cholesterol and LDL
20
Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF
“Quad” Compared to Ritonavir-boosted Atazanavir plus Emtricitabine/Tenofovir DF in
Treatment Naïve HIV-1 Infected Subjects
E DeJesus1, JK Rockstroh2, K Henry3, J-M Molina4, J Gathe5, S Ramanathan6, X Wei6, J Szwarcberg6, M
Rhee6, A Cheng6
1Orlando Immunology Center, Orlando, FL, US; 2Department of Medicine I, University of Bonn, Bonn, Germany; 3Hennepin County Medical Center, Minneapolis, MN, US; 4Saint Louis Hospital, Paris,
France; 5Therapeutic Concepts P.A., Houston, TX, US; 6Gilead Sciences, Foster City, CA, US
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012
Seattle, WAPoster #: 627
22
• Randomized, double-blind, double-dummy, active-controlled, non-inferiority study
• Eligibility criteria– Treatment naïve
– Genotypic sensitivity to ATV, FTC, and TDF
– HIV-1 RNA > 5,000 c/mL
– eGFR ≥ 70 mL/min (Cockcroft-Gault equation)
• Primary endpoint– HIV-1 RNA < 50 c/mL at Week 48
(Amplicor HIV-1 Monitor Test, version 1.5)
– FDA snapshot algorithm
– Prespecified primary analysis of non-inferiority margin 12%
• Exploratory analysis of PK/PD relationship
Study Design236-0103
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
23
Study Design236-0103
Treatment naive(N = 700 planned)
Quad QD
ATV/r+FTC/TDF Placebo QD
ATV/r + FTC/TDF QD
Quad Placebo QD
• International • Randomized 1:1• Stratification by HIV-1 RNA
(>100,000 c/mL)
(n=350)
(n=350)
Primary Endpoint: Proportion with HIV-1 RNA < 50 c/mL at Week 48 – FDA snapshot analysis, 12% non-inferiority margin
– HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5
Week 48 Week 192
Conducted in parallel with Study 236-0102 comparing Quad to EFV/FTC/TDFConducted in parallel with Study 236-0102 comparing Quad to EFV/FTC/TDFDeJesus E, et al., CROI 2012; Seattle. Poster 627.
24
Baseline Characteristics236-0103
CharacteristicQuad
(n=353)ATV/r + FTC/TDF
(n=355)
Age (years), Mean 38 39
Male 92% 89%
Non-White
Black or African Descent
29%
20%
22%
13%
Asymptomatic HIV Infection 81% 83%
HBV – HCV Seropositive 1% – 5% 2% – 3%
HIV-1 RNA (log10c/mL), Median 4.88 4.86
HIV-1 RNA > 100,000 c/mL 43% 40%
CD4 count (cells/mm3), Mean 364 375
< 200 15% 11%
201 to ≤ 350 35% 35%
351 to ≤ 500 35% 34%
> 500 16% 20%
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
25
Subject Disposition Through Week 48236-0103
9% Discontinued (N = 33)
Adverse event 13
Pregnancy 1
Lack of efficacy 4
Investigator’s discretion
1
Withdrew consent
1
Lost to follow-up 7
Subject non-compliance
5
Protocol violation
1
Screened (N = 1017)
QUADRandomized and Treated
(N = 353)
ATV/r + FTC/TDFRandomized and Treated
(N = 355)
91% Continuing (N = 320)
11% Discontinued (N = 40)
Adverse event 18
Lack of efficacy 1
Investigator Discretion
3
Withdrew consent 6
Lost to follow-up 7
Subject non-compliance
5
89% Continuing (N = 315)
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
26
Primary Endpoint: HIV-1 RNA < 50 c/mL236-0103
QUAD was non-inferior to ATV/r + FTC/TDF at Week 48QUAD was non-inferior to ATV/r + FTC/TDF at Week 48
95% CI for Difference
12%
-1.9 7.8
FavorsATV/r + FTC/TDF
3.0
FavorsQuad
0 -12%
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
27-25 -20 -15 -10 -5 0 5 10 15 20 25
OVERALL
AGE <40 years≥40 years
SEXMale
Female
RACEWhite
Non-white
BASELINE CD4 COUNT≤350 cells/mm3
>350 cells/mm3
BASELINE HIV-1 RNA LEVEL≤100,000 c/mL>100,000 c/mL
STUDY DRUG ADHERENCE<95%≥95%
Favors QUAD Favors ATV/r + FTC/TDF
Differences in Percentages (95% CI)
Virologic Success1 by Subgroups236-0103
1FDA snapshot at Week 48
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
28
HIV-1 RNA < 50 c/mL through Week 48 (M=F)236-0103
100
90
80
70
60
50
40
30
20
10
0
Su
bje
cts
wit
h H
IV-1
RN
A <
50 c
/mL
(%
)
BL 2 4 8 12 16 24 32 40 48
WeekQUAD (n=): 353 353 353 353 353 353 353 353 353 353ATV/r (n=): 355 355 355 355 355 355 355 355 355 354
Diff: 3.5% (95% CI: -1.0 to 8.0)
Quad: 92%
ATV/r + FTC/TDF: 88%
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
29
Efficacy in Baseline HIV-1 RNA and CD4 Subgroups236-0103
9385 89 9090
8288 86
0
20
40
60
80
100
≤100,000 c/mL >100,000 c/mL CD4≤350 CD4>350
QUAD ATV/r + FTC/TDF
Vir
olo
gic
Su
cces
s (%
)
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
30
Efficacy by Baseline Demographics236-0103
88 92 9083
90 888590 87
8287 87
0
20
40
60
80
100
<40 ≥40 Male Female White Non-white
QUAD ATV/r + FTC/TDF
Vir
olo
gic
Su
cces
s (%
)
Age (years) RaceSex
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
31
Mean Change from Baseline in CD4 Cells (cells/mm3)236-0103
300
200
100
0
Mea
n C
han
ge
fro
m B
asel
ine
in C
D4
(cel
ls/m
m3 )
BL 2 4 8 12 16 24 32 40 48Week
QUAD (n=): 353 347 343 344 334 338 334 331 328 334ATV/r (n=): 355 344 341 336 331 325 333 326 319 321
(P=0.61)
Quad, 207
ATV/r+FTC/TDF, 211
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
32
Integrase, PI, NRTI Resistance Through Week 48236-0103
Quad(n=353)
ATV/r + FTC/TDF(n=355)
Subjects Analyzed for Resistancea, n (%) 12 (3) 8 (2)
Subjects with Resistance to ARV Regimen, n (%) 5 (1) 0
Any Primary Integrase-R, n 4 -
E92Q 1 -
T66I 1 -
Q148R 2 -
N155H 2 -
Any Primary PI-R, n - 0
Any Primary NRTI-R, n 4 0
M184V/I 4
K65R 1a. Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and <1
log10 below baseline after Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit.
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
33
Virologic Success by EVG Exposure – Quad236-0103
Q1 Q2 Q3 Q40
20
40
60
80
100
Median (ng/mL) 172.3 323.0 515.8 880.9
EVG Ctrough Quartile
Vir
olo
gic
Su
cces
s (%
)96 94 98
90
PK/PD Analysis Set, n=192
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
34
Summary of Adverse Events (AE)236-0103
Quad
(n=353)
ATV/r + FTC/TDF
(n=355)
Grade 3 or 4 AE 13% 14%
Drug-related AE 45% 57%
SAE 7% 9%
Drug-related SAE 1% 1%
AE leading to DC of study drug 4% 5%
Death, (n) 0 1% (3)a
aCauses of death included septic shock, Pneumocystis jiroveci pneumonia, and cardiopulmonary arrest after overdose of recreational drugs.
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
35
Common Adverse Events236-0103
Adverse Eventa Quad(n=353)
ATV/r + FTC/TDF(n=355)
Diarrhea 22% 27%
Nausea 20% 19%
Upper respiratory infection 15% 16%
Headache 15% 12%
Fatigue 14% 13%
Ocular icterus 1% 14%a > 10% in either treatment group
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
36
Common Adverse Events Leading to DC236-0103
Adverse Eventa,b Quad(n=353)
ATV/r + FTC/TDF(n=355)
Overall 4% 5%
Diarrhea 1% <1%
Pyrexia 1% 0%
Nausea <1% 1%
Vomiting <1% 1%
Fatigue <1% 1%
Ocular Icterus 0% 1%
Jaundice 0% 1%
Dizziness 0% 1%
Drug Eruption 0% 1%
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
aAt least 2 subjects in either treatment groupbOne subject from each treatment group discontinued due to renal adverse event; one subject in Quad group due to blood creatinine increased, one subject in ATV/r+FTC/TDF group due to nephropathy toxic.
37
Grade 3 and 4 Laboratory Abnormalities236-0103
Grade 3 or 4 LabsaQuad
(n=353)
ATV/r + FTC/TDF
(n=355)
Creatine Kinase 6% 7%
Hematuria 4% 2%
AST 2% 3%
Amylase 2% 3%
ALT 2% 2%
Hyperbilirubinemia 1% 58%aAt least 2% in either treatment group
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
38
Change from Baseline in Serum Creatinine236-0103
Median change W48: 0.12 mg/dL vs. 0.08 mg/dL (Quad vs. ATV/r + FTC/TDF group, p<0.001)
BL 2 4 8 12 16 24 32 40 48BL 2 4 8 12 16 24 32 40 48
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08Ch
an
ge
fro
m B
as
eli
ne
in
Se
rum
Cre
ati
nin
e (
mg
/dL
)C
ha
ng
e f
rom
Ba
se
lin
e i
n S
eru
m C
rea
tin
ine
(m
g/d
L)
WeekWeek
QUAD (n=): 353 346 344 344 340 337 334 325 324 323ATV/r +FTC/TDF (n=):355 344 342 339 335 332 329 323 316 314
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
39
1011
688
11
5
23
0
5
10
15
20
25
Total Cholesterol LDL HDL Triglyceride
QUAD ATV/r + FTC/TDF
Change from Baseline in Fasting Lipids at Week 48236-0103
P =.006
Med
ian
Ch
ang
e F
rom
BL
at
Wee
k 4
8 (m
g/d
L)
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
40
Bone Mineral Density at Week 48236-0103
Quad
(n=353)
ATV/r + FTC/TDF (n=355)
P value
Fracture events, (n) 1% (3) 2% (6) 0.51
Me
dia
n B
MD
ch
an
ge
fro
m B
L,
% Spine Hip
Me
dia
n B
MD
ch
an
ge
fro
m B
L,
%Week Week
-2.87%
-3.59%
P=0.12
-2.45%
-3.46%
P=0.25
-6
-4
-2
0
2
BL 24 48
QUAD (n=54)
ATV/r + FTC/TDF (n=66)
-6
-4
-2
0
2
BL 24 48
QUAD (n=54)ATV/r + FTC/TDF (n=66)
DEXA Analysis Set, n=120
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
41
Conclusions236-0103
• High and comparable efficacy in Quad and ATV/r + FTC/TDF – Robust, durable, and consistent efficacy on all endpoints
– High virologic suppression rates in all subgroups, including those with baseline HIV-1 RNA > 100,000 c/mL
• Quad was well-tolerated– Similar low rates of treatment discontinuation
– Smaller increases in triglyceride in Quad
– Discontinuations due to renal adverse events were
0.3% in ATV/r + FTC/TDF and 0.3% in Quad
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Shionogi-ViiV Healthcare LLC
Hans-Juergen Stellbrink,1 Jacques Reynes,2 Adriano Lazzarin,3 Eugene Voronin,4 Federico Pulido,5 Franco Felizarta,6 Steve Almond,7 Marty St. Clair,8 Nancy Flack,8 and Sherene Min,8 on behalf of the extended SPRING-1 Team1ICH Study Center, Hamburg, Germany; 2Hopital Gui de Chauliac, Montpellier, France; 3Fondazione Centro San Raffaele del Monte Tabor, Milano, Italy; 4Hospital of Infectious Diseases, St. Petersburg, Russia; 5Hospital 12 Octubre, Madrid, Spain; 6Office of Franco Felizarta, Bakersfield, CA; 7,8GlaxoSmithKline, 7Mississauga, Canada, 8Research Triangle Park, NC, USA
Dolutegravir (DTG; S/GSK1349572) in Combination Therapy Exhibits Rapid and Sustained Antiviral Response in Antiretroviral-Naïve Adults: 96-Week Results from SPRING-1 (ING112276)
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Dolutegravir Attributes
● Once daily, unboosted1
● Low PK variability and predictable exposure-response relationship2
● Low potential for drug interactions2
● Distinct in vitro resistance profile including higher barrier to resistance3
● Highly potent antiviral activity in monotherapy1
– At 50mg DTG, 90% were <400 c/mL and 70% <50 c/mL after 10d of monotherapy
Dosing period Follow-up period
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1(BL)
2 3 4 7 8 9 1011 14 21(FU)Day
Mea
n C
ha
ng
e fr
om
Bas
elin
e i
n H
IV-1
RN
A
(lo
g1
0 c
/mL
)
2 mg10 mg50 mgPBO
1.Min, S. et al. AIDS. 2011; 25:1737–1745.2.Min, S. et al. AAC. 2010; 54: 254–258.3.Kobayashi, M et al. AAC. 2011; 55(2):813-821.
Antiviral Activity in Phase IIa Study1
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
● Phase IIb dose-ranging, partially blinded, N~200 ART-naïve patients
● All arms include 2 NRTI backbone given once daily
● Primary endpoint: % <50 c/mL at 16 weeks (TLOVR), for Ph3 dose selection
● Planned analysis: % <50 c/mL at 96 weeks (TLOVR)
ING112276 Study Design
HIV-1 RNA >1000 c/mL
CD4 ≥200 cells/mm3
1:1:1:1 Randomization
EFV 600 mg
DTG 50 mg
DTG 25 mg
DTG 10 mg
Stratified by• HIV RNA >100,000 or ≤100,000 c/mL• Epzicom/Kivexa or Truvada
Week 96
DTG 50 mg
Selected Dose
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
DTG10 mg(N=53)
DTG25 mg(N=51)
DTG50 mg(N=51)
EFV600 mg(N=50)
Total(N=205)
Age, median (range), years 32 (21-61) 38 (20-64) 37 (22-55) 40 (20-79) 37 (20-79)
Male gender 42 (79%) 46 (90%) 45 (88%) 44 (88%) 177 (86%)Race African American/African heritage
7 (13%) 6 (12%) 8 (16%) 4 (8%) 25 (12%)
White 41 (77%) 42 (82%) 38 (75%) 43 (86%) 164 (80%) Other 5 (10%) 3 (6%) 5 (10%) 4 (8%) 17 (8%)Baseline HIV-1 RNA Mean (log10 c/mL) 4.42 4.38 4.58 4.46 4.46
>100,000 c/mL 11 (21%) 10 (20%) 12 (24%) 11 (22%) 44 (21%)Baseline CD4+ (cells/mm3) Mean 309.4 333.8 327.2 327.5 324.3 <300 30 (57%) 20 (39%) 24 (47%) 24 (48%) 98 (48%)Investigator-selected NRTIs TDF/FTC 36 (68%) 34 (67%) 34 (67%) 34 (68%) 138 (67%) ABC/3TC 17 (32%) 17 (33%) 17 (33%) 16 (32%) 67 (33%)
Baseline Characteristics
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Dolutegravir Dose Selection
DTG demonstrated low PK variability. DTG trough levels on 50mg remain19-fold
above antiviral target, PA-IC90.
0.1
1
10
0 5 10 15 20 25
PA-IC90 0.064 ug/mL
Post-dose Time (hour)
Mea
n D
TG
co
nce
ntr
atio
n (
ug
/mL
)
DTG 10mg once dailyDTG 25mg once dailyDTG 50mg once daily
• A priori, maximum tolerated dose to be selected for use in phase III trials based on data from 16 and 24 weeks
• May simplify dosing in the presence of modest drug interactions
• Comparable virologic responses, safety and tolerability were seen across all three DTG doses at 16 and 24 weeks of therapy
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Dolutegravir: Rapid and Durable Antiviral ActivityWeek 96 Efficacy Analysis (<50 c/mL)
95% confidence intervals are derived using the normal approximation.
88%
78%79%
72%
Pe
rce
nt
Su
bje
cts
wit
h H
IV-1
RN
A <
50
c/m
L (
TL
OV
R)
Week
1. van Lunzen, Lancet ID, 2012;12: 111–18.
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Primary Outcomes: <50 c/mL (TLOVR) at Week 96
Outcome
DTG10 mg(N=53)
DTG25 mg(N=51)
DTG50 mg(N=51)
EFV600 mg(N=50)
Responder 42 (79%) 40 (78%) 45 (88%) 36 (72%)
Virologic nonresponders
Rebound by TLOVR 7 (13%) 4 (8%) 2 (4%)* 4 (8%)
Re-suppressed by Week 96 3 2 1 3
Other nonresponders
Adverse event 0 1 (2%) 1 (2%) 5 (10%)
Protocol deviation 1 (2%) 2 (4%) 1 (2%) 0
Subject reached protocol-defined stopping criteria 0 0 0 1 (2%)
Lost to follow-up/decision by subject 2 (4%) 3 (6%) 2 (4%) 2 (4%)
Death 1 (2%)** 0 0 0
Not discontinued but no data at Week 96 and beyond 0 1 (2%) 0 2 (4%)
*Includes one subject discontinued from study drug due to Burkitt’s lymphoma prior to retest**By motor vehicle accident
19th Conference on Retroviruses and Opportunistic Infections05-08 March 2012 Seattle, Washington
Protocol Defined Virologic Failure
● PDVF = confirmed HIV-1 RNA >400 c/mL OR < 1.0 log10 c/mL decrease by Week 4
● Amongst DTG-treated subjects (N=155), no integrase mutations were detected through Week 96
● No subjects in 50 mg arm had confirmed VL ≥400 c/mL through Wk 96
*Non-adherence in DTG 10mg (n=1) and DTG 25mg subjects by report/pill count at time of PDVF**<1.0 log10 decrease by Wk 4
Outcome
DTG10mg
(N=53)
DTG25mg
(N=51)
DTG50mg
(N=51)
EFV600mg(N=50)
Protocol-defined Virologic Failure 2 * 1 * 0 1**
Genotype/phenotype Determinable 2 0 0 1
INI Mutations Present 0 0 0 0
NNRTI Mutations Present 0 0 0 0
NRTI Mutations PresentM184V
(1) 0 0 0
19th Conference on Retroviruses and Opportunistic Infections05-08 March 2012 Seattle, Washington
Median (95% CI) Change from BaselineCD4+ Cell Count (cells/mm3)
Week 24 p=0.008; Week 48 p=0.076; Week 96 p=0.155Wilcoxon two-sample test, EFV vs. DTG total
Ch
ang
e fr
om
Bas
elin
e C
D4+
Cel
l C
ou
nt
(cel
ls/m
m3 )
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
DTG10 mg(N=53)
DTG25 mg(N=51)
DTG50 mg(N=51)
DTGSubtotal(N=155)
EFV600 mg(N=50)
Number of Subjects with any Grade 2-4 Drug-Related Event
4 (8%) 5 (10%) 8 (16%) 17 (11%) 12 (24%)
Gastrointestinal 1 (2%) 2 (4%) 1 (2%) 4 (3%) 2 (4%)
Psychiatric disorders 0 0 0 0 3 (6%)
Metabolic disorders 0 3 (6%) 1 (2%) 4 (3%) 0
Skin disorders 0 0 0 0 3 (6%)
Infections 2 (4%) 0 0 2 (1%) 0
General disorders 1 (2%) 1 (2%) 1 (2%) 3 (2%) 1 (2%)
Laboratory Abnormalities 0 1 (2%) 1 (2%) 2 (1%) 1 (2%)
Nervous system disorders 0 0 1 (2%) 1 (<1%) 1 (2%)
Serious Adverse Events (all) 5 (9%) 5 (10%) 7 (14%) 17 (11%) 7 (14%)
AEs Leading to WD/IP Discontinuation
1 (2%) 1 (2%) 2 (4%) 4 (3%) 5 (10%)
● Fewer AEs leading to withdrawal on DTG vs EFV– DTG (4/155, 3%): dyspepsia, Burkitt’s lymphoma, death due to motor vehicle accident, lipoatrophy– EFV (5/50, 10%): abnormal dreams, suicide attempt, drug intolerance, drug hypersensitivity, insomnia
AEs (by System Organ Class) Reported in >1 Subject on Investigational Product
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
● Clinically significant liver chemistry abnormalities were rare– 1 Gr3 ALT (DTG 25 mg, Acute HCV infection), 1 Gr4 ALT (EFV, Acute HCV infection)
● No subject with elevated bilirubin had corresponding ALT elevation
Laboratory Results: ALT and BilirubinMaximum Treatment Emergent Toxicity
DTG 10mg(N=53)
DTG 25mg(N=51)
DTG 50mg(N=51)
DTG Subtotal(N=155)
EFV600mg(N=50)
Alanine Amino Transferase (ALT)
Grade 2 1 (2%) 3 (6%) 1 (2%) 5 (3%) 6 (12%)
Grade 3 0 1 (2%) 0 1 (<1%) 0
Grade 4 0 0 0 0 1 (2%)
Total Bilirubin
Grade 2 0 1 (2%) 1 (2%) 2 (1%) 0
Grade 3 0 0 0 0 0
Grade 4 0 0 0 0 0
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Laboratory Results: Creatinine & Urine Protein
● Small changes in mean serum creatinine (0.1 – 0.15 mg/dL) observed– Observed with both NRTI backbones, did not progress over time
– No effect of DTG on GFR (as measured by iohexol clearance)1
● At Week 96, no evidence for higher urine protein in DTG arms
.
1Koteff J, et al. 51st ICAAC; September 17-20, 2011: Chicago, Illinois. Abstract A1-1728.
Arm n (Wk 96)
Mean Urine Alb/Cr ratio (mg/mmol Cr) at Wk96 (SD)
Min/Max
DTG 10mg 38 1.06 (1.699) 0.2 / 9.4
DTG 25mg 33 0.91 (0.95) 0.3 / 5.2
DTG 50mg 38 0.97 (1.113) 0.3 / 6.2
EFV 600mg 34 1.56 (2.908) 0.2 / 16.3
In vitro and clinical data are consistent with non-significant inhibition of the renal transporter (OCT2) responsible for tubular secretion of creatinine.
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
● DTG administered once daily with two NRTIs was associated with good treatment response at all doses
– Proportion with HIV RNA <50 c/mL for selected 50mg dose (88%) compares favorably with EFV (72%) through 96 weeks
– No INI mutations detected through 96 weeks, consistent with high barrier to resistance demonstrated in vitro
● Fewer subjects treated with DTG discontinued therapy due to adverse events when compared to EFV
● Data through 96 weeks continue to support 50mg once daily for INI-naïve subjects, and provide evidence for durable efficacy and tolerability for DTG in combination therapy
Conclusions
GS-7340 25 mg and 40 mg Demonstrate Greater Antiviral Activity Compared with
TDF 300 mg in a 10-Day Monotherapy Study of HIV-1 Infected Patients
PJ Ruane1, E DeJesus2, D Berger3, M Markowitz4, UF Bredeek5, C Callebaut6, L Zhong6,
S Ramanathan6, MS Rhee6, K Yale6
1Peter J Ruane MD Inc., Los Angeles, CA; 2Orlando Immunology Center, Orlando, FL; 3Northstar Healthcare, Chicago, IL; 4Aaron Diamond AIDS
Research Center, New York, NY; 5Metropolis Medical, San Francisco, CA; 6Gilead Sciences, Foster City, CA
19th Conference on Retroviruses and Opportunistic InfectionsMarch 7, 2012 Paper #: 103
58
N
N
N
N
NH2
OP
O
HOOH
N
N
N
N
NH2
OP
O
OO
O
O
O
OO
O
Compound
EC50HIV-1 [M]
MT-2s PBMCs Macrophages
Tenofovir 3.5 1.2 0.9
TDF 0.05 0.015 0.06
GS-7340 0.008 0.003 0.014
Tenofovir TDF GS-7340
Lee et al. Antimicrob Agents Chemother 2005.
GS-7340: Novel Prodrug of Tenofovir (TFV)Greater in vitro Potency
ON
NN
NH2
N
P
O
O
HN
O
O
60
• Randomized, double-blind, active controlled study– HIV-1 infected, treatment naïve subjects
– HIV-1 RNA ≥ 15,000 c/mL
– GS-7340 150 mg, GS-7340 50 mg, TDF 300 mg
– Once-daily monotherapy for 14 days
• GS-7340 (50 mg or 150 mg) led to significantly greater decreases in HIV-1 RNA, compared with TDF 300 mg
• 50 mg of GS-7340 had 88% lower plasma TFV exposures, and 4-fold higher intracellular TFV-DP concentrations, compared with TDF 300 mg
Markowitz M et al. CROI 2011; Paper#152LB.
First Proof-of-Concept Study (GS-US-120-1101)
61
Study Design (GS-US-120-0104)
Primary objective– To evaluate the antiviral activity of 3 different doses of GS-7340
Primary endpoint– Time-weighted average change in HIV-1 RNA (DAVG11)
Randomized, partially-blinded, placebo and active controlled10-day monotherapy study
Treatment naïve adultsHIV-1 RNA ≥ 2,000 c/mL
CD4 ≥ 200 cells/mm³
(N = 38)
TDF 300 mg QD
GS-7340 8 mg QD
GS-7340 25 mg QD
GS-7340 40 mg QD
GS-7340 Placebo QD
62
All subjects (n=38)
Age (mean) 38
Sex (males) 97%
Race
White 53%
African American 37%
Others 11%
Median HIV-1 RNA (log10 c/mL) 4.6
Median CD4 cell count (cells/mm3) 444
Baseline Characteristics
63
Treatment Group
NMedian DAVG11
[log10 c/mL]P value vs.TDF 300 mg
Placebo 7 -0.01 0.038
TDF 300 mg 6 -0.48 -
GS-7340 8 mg 9 -0.76 0.216
GS-7340 25 mg 8 -0.94 0.017
GS-7340 40 mg 8 -1.08 0.01
Primary Efficacy Endpoint
64
0 10 20-2.0
-1.5
-1.0
-0.5
0.0
0.5
GS-7340 8 mg
GS-7340 25 mg
GS-7340 40 mg
TDF 300 mg
Placebo
Dosing
Day
Me
dia
n H
IV-1
RN
A c
ha
ng
e (
log 1
0c
/mL
)Viral Dynamics
65
Treatment Group
Median ΔVLDay 11
[log10 c/mL]
P value vs.
TDF 300 mg
Median first phase decay
slope
P value vs.
TDF 300 mg
Placebo -0.07 0.038 0.036 0.027
TDF 300 mg -0.97 -- -0.183 --
GS-7340 8 mg -1.08 0.768 -0.305 0.175
GS-7340 25 mg -1.46 0.024 -0.455 0.012
GS-7340 40 mg -1.73 0.003 -0.511 0.006
Viral Dynamics Summary
66
0 6 12 18 24
1
10
100
1000
GS-7340 8 mgGS-7340 25 mgGS-7340 40 mgTDF 300 mg
79% 86%
96%
AUC
TDF 300 mg
89% 94%
98%
Cmax
Time (hr)
TF
V P
lasm
a C
on
cen
trat
ion
(n
g/m
l)GS-7340: Lower Plasma TFV
67
TDF GS-7340 GS-7340 GS-73400
50
100
X ~1X
~7X
>20X
300 mg 40 mg25 mg8 mg
Intr
acel
lula
r T
FV
-DP
(µ
M*h
)
GS-7340: Higher Intracellular (PBMC) TFV-DP
68
• No study drug discontinuations• No drug-related serious adverse events• No clinically significant laboratory abnormalities• Most adverse events were mild to moderate • No mutations associated with TDF resistance
Safety and Viral Resistance
69
• GS-7340 25 mg, compared to TDF (Viread®) 300 mg, achieves
– Greater antiviral activity in 10-day monotherapy
– Higher intracellular TFV-DP by ~7-fold
– Lower circulating plasma TFV by ~90%
• At 1/10th the mass of TDF 300 mg, GS-7340 offers the possibility to formulate new single-tablet regimens (STRs)
Conclusion
70
GS-7340 Phase 2 ProgramTwo Novel STRs in Treatment Naïve Patients
QUAD Placebo
GS-7340 QUAD
GS-7340 QUAD Placebo
QUAD
DRV + COBI + FTC/TDF Placebo
DRV/COBI/FTC/GS-7340
DRV/COBI/FTC/GS-7340 Placebo
DRV + COBI + FTC/TDF
292-0102
299-0102
Currently Enrolling
Screening to be started
soon