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