Transcript Slide 1

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 team
1University
Medical Center, Hamburg-Eppendorf, Germany; 2Ospedali Riuniti de Bergamo, Bergamo,
Italy; 3Hôpital Bichat-Claude Bernard, Paris, France; 4AIDS Center, Smolensk, Russian Federation
5Rocky Mountain CARES/DIDC, Denver, CO, 6Health Connections International, Amsterdam,
Netherlands; 7University of Barcelona, Barcelona, Spain; 8GlaxoSmithKline, Missisauga, Canada
and 9RTP, USA
Shionogi-ViiV Healthcare LLC
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 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)
DTG 10 mg
HIV-1 RNA >1000 c/mL
CD4 ≥200 cells/mm3
1:1:1:1 Randomization
Stratified by
• HIV RNA >100,000
or ≤ 100,000
• Epzicom/Kivexa
or Truvada
50 mg DTG
Selected Dose
DTG 25 mg
DTG 50 mg
EFV 600 mg
EFV 600 mg
Wk 48 interim
Wk 96
analysis
*Post hoc analysis using bioMONTR HIV-1 EQ SuperLow Assay LLOD=2 c/mL at Weeks 16, 24 and 48
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy
Baseline Characteristics
Age (Median and range in years)
Male gender
Race
African American/African Heritage
White
Other
Baseline HIV-1 RNA
Mean (log10 c/mL)
>100,000 c/mL
Baseline CD4+ (cells/mm3)
Mean
<350
Investigator-selected NRTIs
TDF/FTC
ABC/3TC
DTG
10mg
(N=53)
DTG
25mg
(N=51)
DTG
50mg
(N=51)
EFV
600mg
(N=50)
(N=205)
32 (21 – 61)
38 (20-64)
37 (22 – 55)
40 (20 – 79)
37 (20 – 79)
42 (79%)
46 (90%)
45 (88%)
44 (88%)
177 (86%)
7 (13%)
41 (77%)
5 (10%)
6 (12%)
42 (82%)
3 (6%)
8 (16%)
38 (75%)
5 (10%)
4 (8%)
43 (86%)
4 (8%)
25 (12%)
164 (80%)
17 (8%)
4.42
11 (21%)
4.38
10 (20%)
4.58
12 (24%)
4.46
11 (22%)
4.46
44 (21%)
309.4
36 (68%)
333.8
29 (57%)
327.2
35 (69%)
327.5
30 (60%)
324.3
130 (63%)
36 (68%)
17 (32%)
34 (67%)
17 (33%)
34 (67%)
17 (33%)
34 (68%)
16 (32%)
138 (67%)
67 (33%)
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy
Total
DTG: Rapid and Sustained Antiviral Activity
Week 48 Efficacy Analysis (%<50 c/mL)
Proportion (%) <50 c/mL (TLOVR)
91%
90%
88%
82%
DTG 10mg
DTG 25mg
95% confidence intervals are derived using the normal approximation
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy
DTG 50mg
EFV 600mg
Primary Outcomes:
% <50 c/mL (TLOVR) at Week 48
DTG
10mg
(N=53)
DTG
25mg
(N=51)
DTG
50mg
(N=51)
EFV
600mg
(N=50)
48 (91%)
45 (88%)
46 (90%)
41 (82%)
Rebound or virologic non-response
4 (8%)
3 (6%)
2 (4%)*
3 (6%)
Never suppressed through Week 48
0
0
1 (2%)
1 (2%)
0
1 (2%)
0
4 (8%)
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
Outcome
Responder
Reason for non-response (virologic)
Reason for non-response
(discontinuation or change in ART)
Adverse event
Protocol deviation
*Includes one subject discontinued from study drug due to Burkitt’s lymphoma
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 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 Prevention
17-20 July 2011 Rome, Italy
Response to 50 mg DTG vs 600 mg EFV
<50 c/mL and <2 c/mL
100
90
80
Percent
70
60
50 mg DTG <50 c/mL
50
600 mg EFV <50 c/mL
40
50 mg DTG <2 c/mL
30
600 mg EFV <2 c/mL
20
10
0
0
10
20
30
40
50
60
Weeks
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)
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy
Median Change from Baseline
CD4+ Cell Counts (cells/mm3)
Week 24 p=0.008; Week 48 p=0.076
Wilcoxon two-sample test, EFV vs. DTG total
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy
AEs (by System Organ Class) Reported in
>1 Subject on Investigational Product
DTG
10mg
(N=53)
DTG
25mg
(N=51)
DTG
50mg
(N=51)
DTG
Subtotal
(N=155)
EFV
600mg
(N=50)
5 (9%)
4 (8%)
4 (8%)
13 (8%)
10 (20%)
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%)
3 (6%)
1 (2%)
4 (8%)
8 (5%)
4 (8%)
0
1 (2%)
1 (2%)
2(1%)
4 (8%)
Grade 2-4 Drug Related (all)
Gastrointestinal
Serious Adverse Events (all)
AEs Leading to WD/IP Discontinuation
●
●
●
●
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
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 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 Prevention
17-20 July 2011 Rome, Italy
DTG:
Lower Impact on Plasma Lipids than EFV
Lipid Parameter
Chol
HDL
Chol/HDL
LDL
Trig
-20
-10
0
10
20
30
Week 48 Change from Baseline (95% CI)
DTG Total
Note: Individual lipids are expressed in mg/dL; Chol/HDL is a unitless ratio.
EFV 600 mg
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy
40
DTG Week 2 Pharmacokinetic Data
DTG 10mg once daily
DTG 25mg once daily
DTG 50mg once daily
Mean DTG concentration (ug/mL)
10
Dose
Tablet
(mg)
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
PA-IC90 0.064 ug/mL
0
5
10
15
20
IQ
10
1
0.1
Cmax
AUC(0-)
C
(µg/mL) (hr.µg/mL) (µg/mL)
25
Post-dose Time (hour)
DTG demonstrated low pharmacokinetic variability and
drug exposure increased with dose.
IQ values ranged 5-19 fold
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 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 safetyrelated 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 Prevention
17-20 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 Prevention
17-20 July 2011 Rome, Italy
Back-ups
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 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 creatinine
See also abstract TUPE238 (Min et. al.)
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
17-20 July 2011 Rome, Italy