N

N

NHS

O

O

OH

O

O O

N

N

N

N

NHS

NH

O

O

O O

N

N

Br

Br

Macitentan – A novel sulfamide

MacitentanBosentan

Bolli M, et al. J Med Chem 2012; 55:7849-61.

Tissue penetration requires drugs to cross from the bloodstream through the lipophilic cell membrane

• The ability of a drug to cross the bilipid membrane depends on

– Ionisation properties - drugs cross the membrane in the non-ionised, lipophilic form1

– Affinity for the lipid vs the aqueous phase1

– Size of the molecule1

1. Rowland M and Tozer TN. Clinical Pharmacokinetics: Concepts and applications. Lippincott Williams & Wilkins, 1995.

Optimisation of the physicochemical properties compared to Bosentan may favour macitentan’s penetration into tissues: pKa

A higher pKa corresponds to greater lipophilicity and thus greater tissue targeting potential

Adapted from Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45. pKa: ionisation dissociation constant

Optimisation of the physicochemical properties compared to Bosentan may favour macitentan’s penetration into tissues: Log D

Macitentan800:1

Bosentan20:1

Ambrisentan1:2.5

Blood

Tissue

Membrane

Log D (Distribution coefficient)

Lipid:Aqueous

• The distribution coefficient (Log D) defines the distribution of a compound between an aqueous and a lipid phase

• A greater affinity for the lipid phase may favour tissue penetration

• Macitentan may have a greater affinity for the lipid phase compared with other ERAs*

Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.

In vitro data

*To date, no head-to-head trials in humans have been performed.

Macitentan displays sustained binding to its target receptors

Experimental system: Determination of changes in inhibitory potency after antagonist wash-out (calcium flux in PASMC)

Macitentan displays a 15-fold increased receptor residence time (t1/2) compared to ambrisentan and bosentan

*p < 0.05

* * * *

*

**

Bosentan

0.1

Kb a

fter

was

ho

ut

(nM

)

1

10

100

1000

0 20 40 60

t1/2~70 sec

0 20 40 60

**

* * *

*

*

Ambrisentan

t1/2~40 sec

Time after wash-out (minutes)

Time after wash-out (minutes)

*

*

*

Macitentan

6040200

t1/2~17 min

Time after wash-out (minutes)

In vitro data

Gatfield J, et al. PloS One 2012; 7(10):e47662.

In contrast to ambrisentan and bosentan, macitentan remains potent at elevated ET-1 concentrations

Experimental system: ET-1-induced signalling in human PASMCs measuring IP1

ET-1 concentration-response curves in presence of different concentrations of antagonists

XProtection against

high ET-1

Bosentan

10000 nM1000 nM100 nM10 nM1 nM0 nM

No

rma

lise

d I

P1

con

c. (

%)

0

20

40

60

80

100

120

-11 -10 -9 -8 -7 -6 -5ET-1 (log M)

20 nM 3000 nM InactiveIC50

xx x

X

Ambrisentan

-11 -10 -9 -8 -7 -6 -5ET-1 (log M)

2 nM 500 nM Inactive

x

x x

Macitentan

-11 -10 -9 -8 -7 -6 -5ET-1 (log M)

1 nM 5 nM 5 nM

x

x x

In vitro data

Gatfield J, et al. PloS One 2012; 7(10):e47662.

Chronic† macitentan administration reduced mPAP at a dose 10-fold lower than bosentan in the MCT rat model

Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.†Administered for 4 weeks

MCT + bosentan

MCT + macitentan

MCT (monocrotaline)

Control

Veh 0.3 3 10 30 100 300

Dose (mg/kg/day)

40

30

20

10

mP

AP

(m

mH

g)

+++

*

*****

***

*** ***

***

+++ p < 0.001 vs. control

** p < 0.01 vs. MCT + vehicle

* p < 0.05 vs. MCT + vehicle

*** p < 0.001 vs. MCT + vehicle

Animal model

Chronic† macitentan administration reduced RV hypertrophy at a dose 10-fold lower than bosentan in the MCT rat model

Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.RV: right ventricular†Administered for 4 weeks

MCT + bosentan

MCT + macitentan

MCT (monocrotaline)

Control

+++ p < 0.001 vs. control

** p < 0.01 vs. MCT + vehicle

* p < 0.05 vs. MCT + vehicle

*** p < 0.001 vs. MCT + vehicle

Veh 0.3 3 10 30 100 300

Dose (mg/kg/day)

0.5

0.4

0.3

0.2

RV

/LV

+S

Animal model

+++

*** **

*********

Effect of macitentan on survival in the MCT rat model of PAH

00

20

40

60

80

100

Su

rviv

al (

%)

7 14 21 28 35 42

Time (days)

Control

Monocrotaline (MCT) + vehicle

50%

*macitentan was administered at 30 mg/kg/day

MCT + macitentan*

83%

p = 0.002

Animal model

Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45.Raja SG. Curr Opin Investig Drugs 2010;11:1066-73.

Macitentan added to ambrisentan leads to a further reduction in MAP

**p < 0.05 vs. Ambrisentan then vehicle

Ambrisentanthen

vehicle

Ambrisentanthen

Macitentan

-50

-40

-30

-20

-10

0

Del

ta M

AP

(m

mH

g)

**

Ambrisentanthen

Ambrisentan

p = ns

Animal model

Dahl-S rats (n = 5), telemetry equippedDose: 30 mg/kg (ambrisentan or macitentan) by gavage Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

Addition of ambrisentan to macitentan did not lead to further reductions in MAP

Dahl-S rats (n = 5), telemetry equippedDose: 30 mg/kg (ambrisentan or macitentan) by gavage

Macitentanthen

vehicle

Macitentanthen

Ambrisentan

-50

-40

-30

-20

-10

0D

elta

MA

P (

mm

Hg)

p = ns

Animal model

Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

Macitentan added to bosentan leads to a further reduction in MAP

-50

-40

-30

-20

-10

0D

elta

MA

P (

mm

Hg)

Bosentanthen

vehicle

Bosentanthen

macitentan

Bosentanthen

bosentan

Dahl-Salt rat model of systemic hypertension (n = 4 to 9)Measurements in conscious animals (telemetry)Dose (by gavage): bosentan 100 mg/kg; macitentan 30 mg/kg

p = ns

**

Animal model **p < 0.05 vs. Bosentan then vehicle

Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

Addition of bosentan to macitentan did not lead to further reductions in MAP

Macitentanthen

vehicle

Macitentanthen

bosentan

-50

-40

-30

-20

-10

0

Animal model

p = ns

Del

ta M

AP

(m

mH

g)

Iglarz M, et al. Eur Respir J 2012; 40: Suppl. 56:717s.

Dahl-Salt rat model of systemic hypertension (n = 4 to 9)Measurements in conscious animals (telemetry)Dose (by gavage): bosentan 100 mg/kg; macitentan 30 mg/kg

Pre-clinical, in vitro data and hepatic safety for macitentan

• Inhibition of BSEP, resulting in the disruption of bile salt homeostasis, is a key mechanism that may cause hepatic cholestasis and liver damage1

• Macitentan and its active metabolite do not have significant inhibitory effects on bile salt transport2,3

• In vitro studies suggest that hepatic disposition of macitentan is mainly driven by passive diffusion rather than OATP-mediated uptake4

1. Fattinger K, et al. Clin Pharmacol Ther 2001; 69:223-31.2. Raja SG. Curr Opin Investig Drugs 2010; 11:1066-73.

3. Bolli M, et al. J Med Chem 2012; 55:7849-61.4. Bruderer S, et al. AAPS 2012; 14:68-78.

Macitentan – Summary

• Macitentan is a newly developed molecule displaying:

– Optimised physicochemical properties that facilitate penetration

into the tissue

– High affinity for the ET receptors and sustained receptor binding

resulting in more effective receptor antagonism

• Pre-clinical data suggest that macitentan may have the

potential for favourable potency and efficacy

• In vitro and pre-clinical data suggests that macitentan has the

potential for favourable safety and tolerability