nuevos fármacos pere domingo malalties infeccioses hospital de la santa creu i sant pau...

Nuevos fármacosNuevos fármacos

Pere DomingoPere Domingo

Malalties InfecciosesMalalties Infeccioses

Hospital de la Santa Creu i Sant PauHospital de la Santa Creu i Sant Pau

BarcelonaBarcelona

[email protected]@santpau.cat

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%


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)


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%


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


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%


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 (%

)


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


Vir

olo

gic

Su

cces

s (%

)

Age (years) RaceSex


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


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.


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


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.


35

Common Adverse Events236-0103

Adverse Eventa Quad(n=353)


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


36

Common Adverse Events Leading to DC236-0103

Adverse Eventa,b Quad(n=353)


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%


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


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


39

1011

688

11

5

23

0

5

10

15

20

25

Total Cholesterol LDL HDL Triglyceride


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)


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


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


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)


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


● 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


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


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


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.


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 )


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


● 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


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.


● 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

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