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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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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.
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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%)
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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.
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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.
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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.
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
Back-ups
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention17-20 July 2011 Rome, Italy
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.)