6 th ias conference on hiv pathogenesis, treatment and prevention 17-20 july 2011 rome, italy...

6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy

Shionogi-ViiV Healthcare LLC

Rapid, Robust and Sustained Antiviral Response with Once-daily (QD) Dolutegravir (DTG, S/GSK1349572), a Next Generation Integrase Inhibitor (INI) in Combination Therapy in Antiretroviral-naïve Adults 48 Week Results from SPRING-1 (ING112276) Jan van Lunzen1, Franco Maggiolo2, Bao Phung3, Olga Tsybakova4, Benjamin Young5,6, Jose Gatell7, Steve Almond8, Marty St Clair9, Cindy Brothers9 and Sherene Min9 on behalf of the extended SPRING-1 team1University Medical Center, Hamburg-Eppendorf, Germany; 2Ospedali Riuniti de Bergamo, Bergamo, Italy; 3Hôpital Bichat-Claude Bernard, Paris, France; 4AIDS Center, Smolensk, Russian Federation5Rocky Mountain CARES/DIDC, Denver, CO, 6Health Connections International, Amsterdam, Netherlands; 7University of Barcelona, Barcelona, Spain; 8GlaxoSmithKline, Missisauga, Canada and 9RTP, USA


ING112276 Study Design

● 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)

● Planned interim analysis: % <50 c/mL at 48 weeks (TLOVR)

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 mg50 mg DTG

Selected Dose

EFV 600 mg

Wk 48 interim

analysis

Stratified by• HIV RNA >100,000 or ≤ 100,000• Epzicom/Kivexa or Truvada

*Post hoc analysis using bioMONTR HIV-1 EQ SuperLow Assay LLOD=2 c/mL at Weeks 16, 24 and 48

Wk 96


DTG10mg

(N=53)

DTG25mg

(N=51)

DTG50mg

(N=51)

EFV600mg(N=50)

Total

(N=205)

Age (Median and range in 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 <350 36 (68%) 29 (57%) 35 (69%) 30 (60%) 130 (63%)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


DTG: Rapid and Sustained Antiviral ActivityWeek 48 Efficacy Analysis (%<50 c/mL)

Pro

po

rtio

n (

%)

<5

0 c

/mL

(T

LO

VR

)

91%

88%90%

82%

DTG 10mgDTG 25mg

DTG 50mgEFV 600mg

95% confidence intervals are derived using the normal approximation


Primary Outcomes: % <50 c/mL (TLOVR) at Week 48

Outcome

DTG10mg

(N=53)

DTG25mg

(N=51)

DTG50mg

(N=51)

EFV600mg(N=50)

Responder 48 (91%) 45 (88%) 46 (90%) 41 (82%)

Reason for non-response (virologic)

Rebound or virologic non-response 4 (8%) 3 (6%) 2 (4%)* 3 (6%)

Never suppressed through Week 48 0 0 1 (2%) 1 (2%)

Reason for non-response(discontinuation or change in ART)

Adverse event 0 1 (2%) 0 4 (8%)

Protocol deviation 1 (2%) 1 (2%) 1 (2%) 0

Lost to follow-up 0 0 1 (2%) 0

Decision to discontinue study by subject 0 0 0 1 (2%)

Non-permitted change in ART 0 1 (2%) 0 0

*Includes one subject discontinued from study drug due to Burkitt’s lymphoma


Protocol Defined Virologic Failure (>400c/mL)

● SPRING-1 (n=150 on DTG)– Week 48, 3/150 (2%) DTG protocol-defined virologic failures (>400 c/mL

HIV-1 RNA) 10 mg DTG, Wk 4: M184V only. No IN mutations or phenotypic

changes 25 mg DTG, Wk 24: 404 c/mL. No geno/pheno determined 10 mg DTG, Wk 40: No RT, Pro, or IN mutations or phenotypic

changes

– No subjects in 50 mg arm had confirmed VL >400 c/mL through Wk 48

– No integrase mutations through week 48

● Merck P004 (n=160 on RAL)1

– Week 48, 5/160 (3%) virologic failures (>400 c/mL HIV-1 RNA) 2/5 (40%) had RAL resistance mutations (N155H)

1. Markowitz, M et al. JAIDS 2007: 46.


Response to 50 mg DTG vs 600 mg EFV <50 c/mL and <2 c/mL

Abbott RealTime HIV-1 Assay (lower limit of detection 40 c/mL) and a modified BioMerieux EasyQ HIV-1 SuperLow assay (lower limit of detection 2 c/mL)

100

90

80

70

60

50

40

30

20

10

0

0

Per

cen

t

605040302010

Weeks

50 mg DTG <50 c/mL

600 mg EFV <50 c/mL

50 mg DTG <2 c/mL

600 mg EFV <2 c/mL


Median Change from BaselineCD4+ Cell Counts (cells/mm3)

Week 24 p=0.008; Week 48 p=0.076Wilcoxon two-sample test, EFV vs. DTG total


AEs (by System Organ Class) Reported in >1 Subject on Investigational Product

● No SAEs judged related to DTG● One SAE judged related to EFV (suicide attempt)● No clear dose-response relationship in DTG AEs● Events leading to withdrawal:

– DTG (n=2): dyspepsia and Burkitt’s lymphoma– EFV (n=4): abnormal dreams, suicide attempt, drug intolerance, drug hypersensitivity

DTG10mg

(N=53)

DTG25mg

(N=51)

DTG50mg

(N=51)

DTGSubtotal(N=155)

EFV600mg(N=50)

Grade 2-4 Drug Related (all) 5 (9%) 4 (8%) 4 (8%) 13 (8%) 10 (20%)

Gastrointestinal 1 (2%) 1 (2%) 1 (2%) 3 (2%) 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 2 (4%)

Infections 2 (4%) 0 0 2 (1%) 0

General disorders 1 (2%) 0 1 (2%) 2 (1%) 1 (2%)

Serious Adverse Events (all) 3 (6%) 1 (2%) 4 (8%) 8 (5%) 4 (8%)

AEs Leading to WD/IP Discontinuation

0 1 (2%) 1 (2%) 2(1%) 4 (8%)


Laboratory Findings

● > Grade 3 lab abnormalities were rare (DTG 12% vs. EFV 14%)● No Grade 3 or 4 ALT elevations in any subject● Small changes in serum creatinine (0.1 – 0.15 mg/dL) were

observed1

– Observed with both NRTI backbones, did not progress over time

– No effect of DTG on GFR (as measured by iohexol clearance)

– In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine

DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidine

1. Min S et al. Safety Profile of Dolutegravir (DTG, S/GSK1349572), a Next Generation Integrase Inhibitor (INI) in Combination Therapy in Antiretroviral (ART)-naïve and ART-experienced Adults from Phase 2b Studies. IAS. July 17-20, 2011. Rome. Abstract TUPE238.


DTG: Lower Impact on Plasma Lipids than EFV

DTG Total EFV 600 mg

Lip

id P

aram

eter

Week 48 Change from Baseline (95% CI)

-20 -10 0 10 20 30 40

Chol

HDL

Chol/HDL

LDL

Trig

Note: Individual lipids are expressed in mg/dL; Chol/HDL is a unitless ratio.


DTG Week 2 Pharmacokinetic Data

Dose (mg)

Tablet Cmax

(µg/mL) AUC(0-)

(hr.µg/mL) C

(µg/mL)

IQ

10

10mg 1.10 (37)

16.0 (40)

0.30 (71)

4.7

25

25mg 1.71

(43) 23.1 (48)

0.54 (67)

8.4

50

2x 25mg

3.40 (27)

48.1 (40)

1.20 (62)

19

Values shown are geometric mean (CV%) IQ = C/PA-IC90

DTG demonstrated low pharmacokinetic variability and drug exposure increased with dose.

IQ values ranged 5-19 fold

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


Conclusions

● DTG administered once-daily without a PK booster showed a rapid and sustained response at all doses explored through Week 48– No IN resistance mutations detected through 48 weeks

● DTG was well tolerated with fewer discontinuations than EFV and less impact on lipid parameters – Grade 3/4 lab abnormalities were uncommon

– Small increases in creatinine noted early without progression or safety-related withdrawals1

likely due to non-pathologic inhibition of creatinine secretion

● These data provide longer term efficacy and safety data for DTG in combination therapy– Subjects continue on their randomized regimen until Week 96

1. Min S et al. Safety Profile of Dolutegravir (DTG, S/GSK1349572), a Next Generation Integrase Inhibitor (INI) in Combination Therapy in Antiretroviral (ART)-naïve and ART-experienced Adults from Phase 2b Studies. IAS. July 17-20, 2011. Rome. Abstract TUPE238.


Acknowledgments

We thank everyone who has contributed to the success of this study, including:

All of our study participants and their families

The SPRING-1 Clinical Investigators and their staff:

France: J Reynes, L Cotte, F Raffi, C Katlama, P Yeni, J-M Molina

Germany: J van Lunzen, H-J Stellbrink, M Stoll, T Lutz

Italy: G Carosi, F Maggiolo, G Rizzardini, A Lazzarin

Russia: O Tsybakova, E Voronin, A Rakhmanova

Spain: F Pulido, J Arribas, S Moreno-Guillen, J Gatell, B Clotet

United States: E DeJesus, F Felizarta, T Hawkins, J Lalezari, L McCurdy, G Richmond, S Schneider, L Sloan, J Torres, B Young, T Vanig, M Mustafa, A LaMarca

And the extended ViiV Healthcare-Shionogi-GlaxoSmithKline SPRING-1 study team


Back-ups


Laboratory Findings

● > Grade 3 lab abnormalities were rare (DTG 12% vs. EFV 14%)● No Grade 3 or 4 ALT elevations in any subject● Changes (+/- SD) in serum creatinine over time

Note: no clinically relevant events nor discontinuations related to creatinineSee also abstract TUPE238 (Min et. al.)

6 th ias conference on hiv pathogenesis, treatment and prevention 17-20 july 2011 rome, italy...

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