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