clinical development programme for second-line treatment anton pozniak world aids conference, july...
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Clinical development programmefor Second-Line treatment
Anton PozniakWorld AIDS Conference,
July 2014
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Current second-line treatment
WHO standard: 2 new NRTIs plus LPV/r or ATV/r
Efficacy of LPV/r + 2NRTIs in EARNEST and SECOND-LINE studies
? Use PI/r with Integrase
Issues:
– overlapping NRTI resistance
– pill count,
– twice daily (LPV/r),
– NRTI safety
– Cost versus first-line treatment
What do the patients look like?Baseline characteristics- Earnest(at randomisation / switch to second-line)
PI/NRTI PI/RAL PImono+ TotalRandomised 426 433 418 1277Female 264 (62%) 263 (61%) 215 (51%) 742 (58%)Age (years)
37 (31-43) 37 (30-43) 38 (32-44) 37 (31-44)Years since started ART
4.0(2.8-5.4)
4.0 (2.9-5.5)
3.9 (2.7-5.4)
4.0(2.8-5.4)
CD4 (cells/mm3) 72 (29-143) 70 (27-142) 70 (33-149) 71 (30-146)Pre-ART CD4 62 (23-144) 63 (23-135) 63 (22-152) 62 (23-145)VL (c/ml) 67515
(23065-175800)74500
(25004-205000)70874
(21584-210000)69782
(23183-194690)
VL ≥100,000 c/ml
168 (40%) 181 (41%) 181 (43%) 530 (42%)
3Note: n(%) or median (IQR)
VL suppression at 96 weeks
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PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88
First-line to second Line
TDF/3TC/EFV400or NRTI /NNRTIs
First-line
DRV/r +DTG
Second-line
VFOption 1
TDF/3TC/DTG
First-line
PI/r+NNRTI
Second-line
VFOption 2
OPTION 1Pill A to Pill B – two single tablet regimens?
Pill A TDF/3TC/EFV400 $100
Pill B DRV400/r/DTG $250
Two pills, used in sequenceSimple treatment rule – task shiftingNo overlapping drug resistanceMass generic production for Universal AccessLow cost: $100 and $250 per person-year
Data for low dose DRV/r Phase 2 trials: %HIV RNA >1 log reduction
at Week 24, by dose and baseline DRV resistance
Katlama C et al AIDS 2007, 21: 395-402Haubrich et al AIDS 2007, 21: F11-F18
1 2 3 40
10
20
30
40
50
60
70
80
90
100
1 2 3 40
10
20
30
40
50
60
70
80
90
100DRV FC <4 (sensitive) DRV FC >4 (resistant)
400/100 800/100 400/100 600/100OD OD BID BID
400/100 800/100 400/100 600/100OD OD BID BID
DRV/r dose group DRV/r dose group
No PK/PD relationship ODIN trial: HIV RNA <50 copies/mL at Week 48, treatment experienced, DRV sensitive patients DRV/r
800/100 mg OD +2NRTIs, by DRV Cmin
1 2 3 40
20
40
60
80
100
84.687.5
83.6
66.1
Quartile of DRV Cmin
HIV RNA<50 c/mL(%)Week48
Kakuda et al, HIV11, Glasgow 2012 [abstr P072]
p=0.004, inverse correlation
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DRV/r 600/100 OD + 2NRTIs: 12 naïve patients ___________________________________________________________________________
Patient RNA BL RNA FU Time DRV Cmin
___________________________________________________________________________
Naïve 85,501 <50 20 months 2866
Naïve 115,853 <50 19 months 3140
Naïve 334,500 <50 10 months 3627
Naïve 154,000 <50 24 months 2553
Naïve 87,350 <50 18 months 3824
Naïve 88,110 <50 19 months 1700
Naïve 34,793 <50 12 months 1268
Naïve 4,526 <50 18 months 3732
Naïve 235,520 <50 20 months 2019
Naïve 7,251 <50 15 months 2818
Naïve 63,244 <50 16 months 4562
Naïve 397,932 <50 5 months no data
____________________________________________________________________
___________________________________________________________________
Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]
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DRV/r 600/100 OD+2NRTIs: 7 pre-treated patients
___________________________________________________________________________
Prior ARV’s RNA BL RNA FU Time DRV Cmin
___________________________________________________________________________
TDF/FTC/FPV/r 33,250 <50 55 months 2143
ZDV/3TC/TDF 15,226 <50 55 months 4518
TDF/FTC/FPV/r 586 <50 43 months 844
TDF/FTC/ATV/r 8,450 <50 38 months no data
TDF/FTC/LPV/r 11,426 <50 38 months no data
TDF/FTC/FPV 119 <50 22 months no data
TDF/FTC/FPV/r 112 <50 20 months no data
____________________________________________________________________
___________________________________________________________________
Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]
Study endpoints– The proportion of patients with HIV-1 RNA <50 c/mL at w48 (ITT).
Non inferiority if lower limit of the 95% CI for d < -15%, 80% power– Changes in CD4+ T cell count
– Changes in DRV Ctrough in plasma
– The proportion of patients with AEs during follow-up– The economic cost derived from ARV drugs
DRV/r 800/100 mg QD+ 2 NRTIs
DRV/r 600/100 mg QD+ 2 NRTIs
Randomisation1 : 1
Open-label
100 HIV+ adultsOn 2 NRTIs + DRV 800mg qd > 4 weeks
HIV-1 RNA < 50 c/mL > 3 monthsNo history of prior virologic failure to
PI-based ARTN = 50
N = 50
W48
DRV600. Study Design
Results w48
0
20
40
60
80
100
% H
IV-1
RN
A <
50
cp
/mL
ITT Observed data
DRV800 DRV600
94%90%
96% 94%
Non inferiority of DRV/r 600/100 mg QD
0-15%
ITT
Observed data
50 50 49 48
95% CI for the difference
ITT -4.0 (-12.9; 4.9)
Observed data -2,2 (-9.6; 5.2)
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Clinical experience with DRV/r + DTG
There is no effect of DTG on DRV/r PK FDA label
DRV/r 600/100 BID lowers DTG Cmin by 38%. This is not considered clinically significant, given the 50mg OD dose of DTG used FDA label.
DRV/r + integrase proof of principle: NEAT (DRV/r + RAL vs DRV/r + TDF/FTC) CROI 2014
DRV/r + DTG was the most common combination used in the SAILING trial. Lancet 2013, 382, 700-708
In the SAILING trial, 72 patients treated with DRV/r + DTG + NRTIs with no primary PI mutations: HIV RNA <50 copies/mL at Week 48 in 69%, versus 70% for DRV/r + RAL + NRTIs.
Pill A, Pill B: Phase 2B-Dose ranging study
Treatment naive
SL2: Second-line, 2 drugsRandomised, 48 weeks24 week interim justifies progression of programme
TDF/FTC + DRV/r 800/100 OD
DTG + DRV/r 800/100 OD
DTG + DRV/r 400/100 OD
Pill A, Pill B: Phase 3 -pivotal study
NNRTI experienced
n=1050
(350 per arm)
Randomised, 96 weeksAfrica, Asia
2NRTI + PI/r (Control)
DTG + DRV/r 800/100 OD
DTG + DRV/r 400/100 OD
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Phase 3 study – design
Inclusion: HIV RNA >1000 on two visits while taking NNRTI based treatment
Primary endpoint: HIV RNA >1000 on two visits, 96 week follow up
Recruitment: Africa, SE Asia, E Europe
Statistics: powered to demonstrate non-inferiority for DRV/r + DTG versus control arm.
Clinical development programmefor Second-Line treatment
Need for FDC second line pill
Low dose Darunavir and DTG attractive option as no overlapping resistance Co formulated as STR so easy to takeComponents well toleratedCost savingsCan Task shift
Phase 2b into phase 3 for patient safety