Riociguat directly stimulates the native sGC independently of NO

Riociguat increases the sensitivity of native soluble guanylate cyclase

(sGC) to NO

Both actions lead to vasodilatation (and anti-proliferation)

Effect of riociguat is not limited by low NO levels (unlike PDE-5-I)

Riociguat: Mode of action

Constricted

Pressure

Flow rate

Relaxed

Pressure

Flow rate

sGC*Riociguat cGMP

* native (intact)

NO

PDE-5-I = phosphodiesterase-5-inhibitor NO = mitroc oxide

2

Anti-remodeling effects of riociguat

in a rat model of PH

MCTRiociguat

N P M

––

N P M

+–

N P M

+–

N P M

++

Vessel muscularization

MCT21 days

MCT35 days

††

*

**

*0

20

40

60

80

100

Rat

s20

–70

µm

per

cent

age

ofto

tal v

esse

l cou

nt

†*

*p < 0.05 versus control animals without PH; †p < 0.05 versus untreated animals with PH at day 35.N, non-muscularized; P, partially muscularized; M, fully muscularized.Schermuly et al., ERJ 2008

3

Haemodynamic effects of BAY 63-2521:

decrease in vascular resistanceBAY 63-2521

iNO

*p < 0.05

‡p < 0.001

§p < 0.0001

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

1 mg study group(n = 5)

2.5 mg study group(n = 10)

Pulmonary vascular resistance

Po

int

esti

mat

e o

f d

ecre

ase

fro

m b

asel

ine

(%)

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

1 mg study group(n = 5)

2.5 mg study group(n = 10)

Systemic vascular resistance

Po

int

esti

mat

e o

f d

ecre

ase

fro

m b

asel

ine

(%)

‡§

§

§*‡

§

§

Grimminger et al., ERJ 2009

Haemodynamic effects of BAY 63-2521:

increase in cardiac indexBAY 63-2521

iNO

§p < 0.0001

0

5

10

15

20

25

30

35

40

45

50

1 mg study group(n = 5)

2.5 mg study group(n = 10)

Cardiac index

Po

int

esti

mat

e o

f in

crea

se f

rom

bas

elin

e (%

)

§ §

§§

Grimminger et al., ERJ 2009

5

Riociguat phase 2 study• Multicenter, open-label, individual dose-

titration study

• Primary objective: to investigate the safety, tolerability and feasibility of individual titration of riociguat according to peripheral systolic blood pressure

• Secondary objectives: to assess the pharmacodynamics and pharmacokinetics of riociguat

6

Dose titration scheme• If trough SBP > 100 mmHg, increase dose (+0.5 mg t.i.d.)

• If trough SBP 90–100 mmHg, maintain dose

• If trough SBP < 90 mmHg without symptoms of hypotension, reduce dose (–0.5 mg t.i.d.)

• If trough SBP < 90 mmHg with symptoms of hypotension, restart after 24 hours with reduced dose (–0.5 mg t.i.d.)

2.5 mg t.i.d.

2.0 mg t.i.d.

1.5 mg t.i.d.

1 mg t.i.d.

Week 2 Week 4 Week 6 Week 8 Week 12Day 1

7

Baseline demographicsDemographic variable n (%) or mean

Total patients 75 (100%)

PAH 33 (44%)

CTEPH 42 (56%)

Age (years) 60.3 (range: 19–76)

Race

White 75 (100%)

Sex

Men 34 (45%)

Women 41 (55%)

Body mass index (kg/m2) 26.1 (SD: 4.4)

8

Baseline hemodynamic and functional parameters

Parameter n (%) or mean ± SD

mPAP (mmHg) 45.3 ± 10.8

CO (L/min) 4.1 ± 1.1

RAP (mmHg) 6.6 ± 4.3

PCWP (mmHg) 8.0 ± 4.2

PVR/SVR 45.7 ± 15.7

NYHA class:IIIIIIIV

0 (0%)15 (21%)56 (78%) 1 (1%)

6-minute walking distance (m)

354.4 ± 111.0

9

Six-minute walking distance: all patients

Baseline valuesPAH: 316.7 127.4; CTEPH: 382.9 88.1; All: 354.4 111.0

0

20

40

60

80

100

Baseline 2 4 6 8 10 12

Duration of treatment (weeks)

Ch

ang

e i

n 6

-min

ute

w

alki

ng

dis

tan

ce (

m)

AllPAH CTEPH

Titration phase

n = 72n = 31 n = 41

10

Pulmonary arterial pressure and pulmonary vascular resistance

*p < 0.05; ***p < 0.001

–14

–12

–10

–8

–6

–4

–2

0PAH CTEPH All

Me

an

de

cre

as

e f

rom

ba

se

lin

e i

n

pu

lmo

na

ry a

rte

ria

l p

res

su

re (

mm

Hg

)

–500

–450

–400

–350

–300

–250

–200

–150

–100

–50

0PAH CTEPH All

Me

an

de

cre

as

e f

rom

ba

se

lin

e i

n

pu

lmo

na

ry v

as

cu

lar

res

ista

nc

e (

dy

n.s

/cm

5 )

n = 20 n = 30 n = 50 n = 19 n = 29 n = 48

*

******

***

***

***

11

Functional class

CTEPH, chronic thromboembolic pulmonary hypertension; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Baseline 12 weeks Baseline 12 weeks Baseline 12 weeks

PAH CTEPH Total

Pro

po

rtio

n o

f p

atie

nts

(%

)

NYHA class IV NYHA class III NYHA class II NYHA class In = 31n = 41n = 72

Riociguat phase III clinical program: PATENT -1 and -2

PATENT: Pulmonary Arterial Hypertension sGC-Stimulator Trial

•Change from baseline in 6 Minute Walk Test after 16 weeks*

*Secondary outcome in extension, ** primary outcome in extension;

p.o.: per os - oral; TID: three times daily; NT-pro BNP: N-terminal pro brain natriuretic peptide; EQ-5D: quality-of-life measures; MLHF-Q: Minnesota Living with Heart Failure Questionnaire

Primary Outcome Measure

• Change from baseline in Pulmonary Vascular Resistance (PVR), change from baseline in WHO functional class, change from baseline in NT-pro BNP, change from baseline in Borg dyspnea, change from baseline in EQ-5D and MLHF-Q, time to clinical worsening  

• Safety**

Secondary Outcome Measures

CHEST: Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial

Riociguat phase III clinical program: CHEST -1 and -2

• Change from baseline in 6 Minute Walk Test after 16 weeks*

*Secondary outcome in extension, ** primary outcome in extension; p.o.: per os - oral; TID: three times daily; NT-pro BNP: N-terminal pro brain natriuretic peptide; EQ-5D: quality-of-life measures; MLHF-Q: Minnesota Living with Heart Failure Questionnaire

Primary Outcome Measure

• Change from baseline in Pulmonary Vascular Resistance (PVR), change from baseline in WHO functional class, change from baseline in NT-pro BNP, change from baseline in Borg dyspnea, change from baseline in EQ-5D and MLHF-Q, time to clinical worsening  

• Safety**

Secondary Outcome Measures