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Efficacy of once-weekly MK-8591 in SIV infected rhesus macaques
Jay A. Grobler, Deborah Nicoll-Griffith, Ming-Tain Lai, Kerry Fillgrove, Andreas Lindauer, Matthew L. Rizk, Daria J. HazudaMerck & Co., Inc.
West Point, PA, USA
MK-8591 (EFdA): A Novel Nucleoside with a Unique Mechanism of Action
• MK-8591 (4’-ethynyl-2-fluoro-2’-deoxyadenosine; EFdA) licensed from Yamasa
• Virologic profile and mechanism of action is extensively described in the literature (Mitsuya, Sarafianos, Parniak)
– Non-obligate chain terminator
– Inhibits reverse transcriptase by preventing translocation
– Potent antiviral activity (PBMC EC50 = 0.2 nM) with broad subtype and mutant coverage (HIV-1, HIV-2, MDR strains)
2Michailidis et al. (2009) JBC
MK-8591: Resistance Profile
MK-8591 Zidovudine Tenofovir Lamivudine
M184I (n = 5) 3.9 ± 0.4 0.37 ± 0.04 0.58 ± 0.03 >123
M184V (n = 5) 5.0 ± 0.9 0.44 ± 0.21 0.60 ± 0.11 >79
K65R (n = 7) 0.16 ± 0.04 0.39 ± 0.14 1.7 ± 0.4 11 ± 7
K65R + M184I/V (n = 7) 2.1 ± 0.3 0.42 ± 0.22 1.3 ± 0.3 > 69
L74V (n = 3) 0.21 ± 0.07 0.38 ± 0.10 0.54 ± 0.08 1.6 ± 0.6
L74V + M184V (n = 2) 2.3 ± 0.4 0.20 ± 0.05 0.37 ± 0.11 > 69
Q151M (n = 5) 0.25 ± 0.11 84 ± 78 1.9 ± 0.8 11 ± 8
Q151M + M184I/V (n = 6) 3.1 ± 2.5 71 ± 95 1.1 ± 0.5 > 69
3 TAMs + L74V (n = 4) 1.2 ± 0.4 12 ± 11 1.4 ± 0.5 4.1 ± 1.6
3TAMs + M184I/V (n = 8) 11 ± 5 34 ± 54 1.6 ± 0.7 > 69
• MK-8591 and TFV pro-drugs have complementary resistance profiles
− MK-8591 hyperactive against K65R / TFV hyperactive against M184 mutants
• TAMs confer low level resistance (< 4-fold) to MK-8591
− M184I/V resistance is additive with TAMs3
Prior MK-8591 Rhesus Efficacy and PK Data
MK-85910.4 mg/kg SC BID
TFV 20 mg/kg SC QDKaletra 13 mg/kg PO
AUC0-∞ 1.2 µM.hr
AUC0-24 1.1 µM.hr
Cmax 0.16 µM
Tmax 2.7 hr
4
0.001
0.010
0.100
1.000
0 4 8 12 16 20 24
MK
-8591 C
oncentr
atio
n (
uM
)
Time (Hour)
10-0185
10-R083
10-0163
Mean
• Previously published data in rhesus with end-stage SAIDS (N=2) demonstrates robust suppression with MK-8591
− 0.4 mg/kg SC BID dosing
• Internally PK generated at same dose in satellite animals to inform exposure-response
Murphy-Corb et al. (2012) AAC
1.7x
3.2x
6.6x
29x
100x
Cell growth
MK-8591 Exhibits Long Intracellular Persistence and Antiviral Activity In Vitro
5
0 Time 24 hr 48 hr 72 hr 5 days 7 days
EC50 1.498 5.045 18.16 61.70 106.9 212.8
No Wash 0 Time 24 hr 48 hr
EC50 74.37 125.0 951.9 457.8
MK-8591 3TC
MT4 cells with GFP virus
• In PBMCs, intracellular MK-8591-TP half-life is >24 hrs
• Decrease in MK-8591 EC50 primarily result of compound dilution due to cell division
Intracellular MK-8591-TP PBMC Levels in Monkeys Following a Single Oral 50 mg/kg Dose
Concentration vs time for MK-8591 and
phosphorylated metabolites – 50 mg/kg PO in monkey
• MK-8591 rapidly taken up in PBMCs and converted to triphosphate
• Persistence in rhesus PBMCs suggests potential for once-weekly oral
dosing
6
Time (hr)
Con
ce
ntr
atio
n (
µM
)
Assessing MK-8591 QW Potential in an Adaptive Design
Arm 1
X
X
13 mg/kg
(1xAUC)
1.3 mg/kg
(0.1xAUC)
X
Vir
al R
ed
uc
tio
n R
es
po
nse
0 (Vehicle)
VL reduction on ER curve:
max VL reduction
may not have been
achieved
at 13 mg/kg OW
7
Arm 2
X
X
X
Vir
al R
ed
uc
tio
n R
es
po
nse
18.2 mg/kg
(1.4xAUC)
3.9 mg/kg
(0.3xAUC)
X
X
Doses chosen to better
define maximal response
and EC50
• SIV-infected Rhesus Monkeys– n=3 per group– Randomized by age, weight and VL– Stable viremia established
• MK-8591 dosed on D0 and D7 (OW)– Arm 1: Vehicle, 1.3 and 13 mg/kg
OW– Arm 2: 3.9 and 18.2 mg/kg OW and
0.19 mg/kg QD– VL measurements in plasma– Plasma PK and mutation analysis
at 2 and 24 hr after each dose
SIV-Infected Rhesus Treated with EFdA
Day of Study
No
rmalized
Lo
g10 V
L D
rop
0 7 14 21 28 35
-4
-3
-2
-1
0
1
3.9 mpk ow (D0, D7)0.19 mpk qd (D0-13)
S IV -in fe c te d rh e s u s tre a te d w ith E F d A
D o s e d o n D 0 a n d D 7 P O
D a y o f S tu d y
No
rma
liz
ed
Lo
g1
0 V
L D
rop
0 7 1 4 2 1 2 8 3 5
-3
-2
-1
0
1
V e h ic le
1 3 m p k
1 .3 m p k
1 8 .2 m p k
3 .9 m p k
MK-8591 Efficacious When Administered Once Weekly to SIV-Infected Rhesus Macaques
• Maximal efficacy observed at 3.9 mpk once-weekly (similar to 0.19 mg/kg QD)
• MK-8591-TP C168hr (7 days) target of 0.53 pmol/106 cells based on PK/PD modeling
Means include nonrespondersN=3 for each dose group
8
S IV -in fe c te d rh e s u s tre a te d w ith E F d A
D o s e d o n D 0 a n d D 7 P O
D a y o f S tu d y
No
rma
liz
ed
Lo
g1
0 V
L D
rop
0 7 1 4 2 1 2 8 3 5
-3
-2
-1
0
1
V e h ic le
1 3 m p k
1 .3 m p k
1 8 .2 m p k
3 .9 m p k
MK-8591 dosed on D0 and D7 PO
SIV-Infected Rhesus Treated with EFdA
Day of Study
No
rmalized
Lo
g10 V
L D
rop
0 7 14 21 28 35
-4
-3
-2
-1
0
1
3.9 mpk ow (D0, D7)0.19 mpk qd (D0-13)
MK-8591 OW vs QD Dosing
SIV-Infected Rhesus Treated with 1.3 mg/kg EFdA (OW)Dosed on D0 and D7 PO
Day of Study
Ab
so
lute
Lo
g10 V
L V
alu
es
0 7 14 21 28 35
4
6
8
10
1.3 mpk 05D260
1.3 mpk 05D120
1.3 mpk 01D338
M184M/V
M184V
M184V
SIV-Infected Rhesus Treated with 13 mg/kg EFdA (OW)Dosed on D0 and D7 PO
Day of Study
Ab
so
lute
Lo
g10 V
L V
alu
es
0 7 14 21 28 35
4
6
8
10
13 mpk 05D242
13 mpk 04D279
13 mpk 02D111
M184V
WT
M184M/V
SIV-Infected Rhesus Treated with 18.2 mg/kg EFdA (OW)Dosed on D0 and D7 PO
Day of Study
Ab
so
lute
Lo
g10 V
L V
alu
es
0 7 14 21 28 352
4
6
8 18.2 mpk A5L106
18.2 mpk A5L084
18.2 mpk 05D195M184V
WT
WT
SIV-Infected Rhesus Treated with 3.9 mg/kg EFdA (OW)Dosed on D0 and D7 PO
Day of Study
Ab
so
lute
Lo
g10 V
L V
alu
es
0 7 14 21 28 352
4
6
8
3.9 mpk A5L058
3.9 mpk A6R107
3.9 mpk 00D067
M184V
WT
WT
Individual Results: Impact of Dose, Baseline Viral Load, and Mutation Development upon QW Dosing
9
QW EFdA can suppress M184V virus in vivo
0 7 14 21 28 351
2
3
4
5
6
7
8
1
10
100
1000
10000
Days
Log
VLPlasm
a Conc. (ng/ml)
Log VL
EFdA PK
MK-8591 30 mg/kg
3TC 5 mg/kg
10
WT
WT M184V/M
M184V/MM184V
M184V
MK-8591 PK
Viral Load
MK-8591 Human Phase 1 PK ConfirmsQW Potential
• Well tolerated in healthy adult subjects
• Intracellular MK-8591-TP C168hr target concentration exceeded with 10 mg dose for > 7 days
Concentration-time profile of MK-8591-TP in PBMCs
PK Target – Intracellular
TP @ 7 days
Time (hr)
Week 1
0 24 48 72 96 120 144 168
MK
-8591-T
P C
once
ntr
ation
in
PB
MC
(pm
ol/1
06
ce
lls)
0.1
1
10
100
Time (hr)
Week 3
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336
10 mg
30 mg
100 mg
11Grobler et al. (2016) CROI
-1.64-1.78
MK-8591 is Effective in HIV patients when Dosed Once-Weekly: Results from ongoing Ph1b study
12Friedman et al. (2016) CROI
Ruane PJ, DeJesus E, Berger D, et al. (2013) JAIDS
• A single 10 mg oral dose in HIV-infected patients results in ~1.6 log decrease in viral load at days 7-10
• Intracellular MK-8591-TP t1/2 = 103 hr
• No evidence of resistance out to Day 10
• Greater rate and extent of initial viral load decline with a single MK-8591 dose than with QD TAF or TDF
TDF
TAF
MK-8591
MK-8591 Parenteral Formulations Release Effective Drug Levels for >180 days
• Low dose amenable to extended-duration parenteral formulation
• >180-day extended release from solid formulations after single injection in rat
• Data suggest potential to provide coverage for up to 1 year
• NHP study (ongoing) suggests implants deliver MK-8591 in plasma and MK-8591-TP in PBMCs at therapeutic target
13
Rat Non-human Primates
Summary
• QW administration of MK-8591 was efficacious in SIV-infected rhesus macaques
• Efficacy data from SIV-infected rhesus macaque study used to establish target PBMC MK-8591-TP levels for treatment of HIV in humans
• Interim Phase 1b results in human suggest rhesus-derived target was translatable to human, with robust efficacy observed at 10 mg QW
• Parenteral formulations exhibited >180-day extended release after a single injection in rats
– Ongoing studies suggest the potential to provide coverage for durations up to 1 year
14