New class of therapeutic agents called soluble guanylate cyclase (sGC) stimulators. Impairment of NO synthesis and signaling through the NO-sGC–cGMP pathway is involved in the pathogenesis of pulmonary hypertension. Dual mode of action, Directly stimulating sGC independently of NO, and Increasing the sensitivity of sGC to NO. vasorelaxation , antiproliferative and antifibrotic effects

2. Introduction
• PAH
– life-threatening disease
– Increased pulmonary vascular resistance owing to
progressive vascular remodeling, which can ultimately
lead to right heart failure and death.
• Current treatments - phosphodiesterase type 5
inhibitors, prostanoids, and endothelin-receptor
antagonists.
• However - mortality remains high despite
treatment

3. RIOCIGUAT
(BAY 63-2521, trade name Adempas)
• New class of therapeutic agents called soluble
guanylate cyclase (sGC) stimulators.
• Impairment of NO synthesis and signaling
through the NO-sGC–cGMP pathway is involved
in the pathogenesis of pulmonary hypertension.
• Dual mode of action,
– Directly stimulating sGC independently of NO, and
– Increasing the sensitivity of sGC to NO.
– vasorelaxation , antiproliferative and antifibrotic
effects

4. • Rapidly absorbed, and maximum plasma concentration
is reached between 0.5–1.5 h
• Metabolism in liver- CYP1A1, CYP3A, CYP2C8 and
CYP2J2
• The mean elimination half-life appears to be 5–10
hours.
• Dosage – 0.5mg to 2.5mg TID
• Adverse effects
• Headache, Hypotension , headache,
and gastrointestinal disorders.

5. • Present the results of the phase 3 Pulmonary Arterial
Hypertension Soluble Guanylate Cyclase–Stimulator
Trial 1 (PATENT-1).
• In this study, they investigated the efficacy and side-
effect profile of riociguat in patients with symptomatic
pulmonary arterial hypertension, both those who were
receiving no other treatment the disease and those
who were receiving treatment with endothelin-
receptor antagonists or nonintravenous prostanoids.

6. Methods
• Study Design : 12-week, double-blind, randomized,
placebo-controlled trial at 124 centers in 30 countries.
• Selection of Patients
• Patients with symptomatic PAH (idiopathic, familial, or
associated with connective-tissue disease, congenital
heart disease, portal hypertension with liver cirrhosis,
or anorexigen or amphetamine use) were included if
they had a
– pulmonary vascular resistance greater than 300 dyn · sec ·
cm–5,
– a mean pulmonary-artery pressure of at least 25 mm Hg,
and
– a 6-minute walk distance of 150 to 450 m.

7. – Patients who were receiving no other treatment
for PAH and patients who were receiving
treatment with endothelin-receptor antagonists
or prostanoids (excluding intravenous prostanoids)
at doses that had been stable for at least 90 days
were eligible
– Oral anticoagulant agents, as well as diuretics and
supplemental oxygen at stable doses, were also
permitted.
– Patients who were receiving phosphodiesterase
type 5 inhibitors were not eligible.

8. • Study Procedures
• Eligible patients were randomly assigned, in a
2:4:1 ratio, to one of three regimens:
• Placebo
• Oral riociguat
– 2.5 mg three times daily (2.5 mg–maximum group
– 1.5 mg three times daily (1.5 mg–maximum
group).

9. • The 1.5 mg–maximum group was included for
exploratory purposes, to provide information
about lower riociguat doses, and data from that
group were not included in the efficacy analyses.
• Patients were seen at weeks 2, 4, 6, and 8 (during
the dose-adjustment phase) and at week 12 (at
the end of the maintenance phase).
• At each visit, clinical assessments and blood tests
were performed.

10. • Riociguat - initiated at a dose of 1 mg three times daily,
and the dose was adjusted according to the patient’s
systolic systemic arterial blood pressure and signs or
symptoms of hypotension (final range, 0.5 mg to 2.5
mg three times daily).
• Patients were seen at weeks 2, 4, 6, and 8 (during the
dose-adjustment phase) and at week 12 (at the end of
the maintenance phase).
• Outcome Measures
• The primary end point was the change from baseline to
the end of week 12 in the distance walked in 6
minutes.

11. • Secondary efficacy end points included changes from baseline to
the end of week 12 in
– Pulmonary vascular resistance,
– N-terminal pro–brain natriuretic peptide (NT-proBNP) levels,
– World Health Organization (WHO) functional class
– The time to clinical worsening
– Borg dyspnea score (which ranges from 0 to 10, with 0 representing
no dyspnea and 10 maximal dyspnea),
– Score on the EuroQol Group 5-Dimension Self-Report Questionnaire
(EQ-5D, in which scores range from –0.6 to 1.0, with higher scores
indicating better quality of life), and
– The Living with Pulmonary Hypertension (LPH) questionnaire (an
adaptation of the Minnesota Living with Heart Failure Questionnaire,
with scores ranging from 0 to 105 and higher scores indicating worse
quality of life).
• Adverse events and laboratory variables were assessed throughout
the study and during the safety follow-up period.

12. Results
• Patients
• December 2008 - February 2012
• 443 patients were randomly assigned to
receive
– Placebo (126 patients),
– Riociguat at individually adjusted doses up to 2.5
mg three times daily (254 patients), or
– Riociguat at individually adjusted doses capped at
1.5 mg three times daily (63 patients)

15. • Dosing
• 2.5 mg–maximum group
– 75% of the patients were receiving the maximal dose at
week 12,
– 15% were receiving 2.0 mg three times daily,
– 6% 1.5 mg three times daily,
– 3% 1.0 mg three times daily, and
– 2% 0.5 mg three times daily.
• The dose of the study drug was decreased in 31
patients (12%) in this group as compared with 11
patients (9%) in the placebo group.
• In the 1.5 mg– maximum group, 96% of the patients
were receiving 1.5 mg three times daily at week 12.

16. Results

19. • Long-Term Extension Study
• 396 patients (98% of the patients who completed the study) entered the
long-term extension study PATENT-2
• Treatment was open-label thereafter.
• Of these patients, 363 patients (308 of whom were still receiving
treatment at a median of 441 days) were included in an interim analysis of
data collected up to April 2012.
• An exploratory analysis of the first 12 weeks of PATENT-2 showed further
increases in the 6-minute walk distance in the 215 patients receiving up to
2.5 mg of riociguat three times daily.
• A mean (±SD) increase of 53±62 m over the baseline distance in PATENT-1
among these 215 patients was observed at week 12 of PATENT-2.
• The same group had had an increase of 36±54 m at week 12 of PATENT-1.

20. Discussion
• Riociguat significantly improved exercise capacity
• Benefit - patients who were receiving endothelin-
receptor antagonists or prostanoids and in those who
were receiving no other treatment for the disease.
• Riociguat also significantly and consistently improved a
range of secondary efficacy end points, including
pulmonary hemodynamics, WHO functional class, and
time to clinical worsening.

21. • Although some studies suggest that the 6-minute walk
distance has modest validity as a surrogate end point for
clinical events,
• it is the most frequently used primary end point in
randomized, controlled trials involving patients with
pulmonary arterial hypertension, is an independent
predictor of death, and correlates with changes in
functional status and hemodynamic variables and with
survival.
• The overall difference in the 6-minute walk distance with
riociguat as compared with placebo (36 m) at 12 weeks is
consistent with the increases observed in previous studies
of other medications for the treatment of pulmonary
arterial hypertension (16 to 59 m).

22. • Furthermore, these improvements were maintained
during the first 12 weeks of the long-term extension
study.
• The improvement in the 6-minute walk distance with
riociguat as compared with placebo is also within the
range of thresholds that have previously been reported
to represent a clinically relevant change (31 to 42 m).
• However, a large proportion of patients in PATENT-1
had WHO functional class II symptoms at baseline and
a baseline 6-minute walk distance that was relatively
long; thus, this population had less advanced illness
than did the population in many previous studies.

23. • Indeed, there was statistical evidence from a
subgroup analysis that WHO functional class
influenced the beneficial effect of riociguat on
the 6-minute walk distance
• A finding that was anticipated from previous
observations- suggesting that the benefit with
riociguat is more likely to be clinically important
in patients with WHO functional class III or IV
symptoms than in those with class I or II
symptoms.

24. • Another study, the Pulmonary Arterial Hypertension and
Response to Tadalafil (PHIRST) study, closely resembled
PATENT-1 with respect to both the patient population and
the study design
• However, in the PHIRST study, patients receiving
background endothelin-receptor–antagonist therapy did
not have significant improvements in the 6-minute walk
distance
• In PATENT-1, riociguat improved the 6-minute walk
distance in both patients who were receiving no therapy for
the disease and patients who werereceiving endothelin-
receptor antagonists or prostanoids.

25. limitation
• lack of follow-up efficacy measurements in patients
• The exclusion of patients with pulmonary arterial
hypertension associated with human
immunodeficiency virus infection, schistosomiasis, and
chronic hemolytic anemia.
• Patients who were receiving treatment with
phosphodiesterase type 5 inhibitors or intravenous
prostanoids were also excluded from PATENT-1, and
the effect of riociguat in such patients is unknown.

26. Conclusion
• Riociguat significantly improved the 6-minute
walk distance, as well as pulmonary vascular
resistance and several other secondary
efficacy end points, in patients with
symptomatic pulmonary arterial hypertension
who were receiving no other treatment for
the disease or who were receiving endothelin-
receptor antagonists or prostanoids.

27. Modified Borg Rating Scale for Perceived Dyspnea
0 Nothing at all
0.5 Very, very slight shortness of breath
1 Very mild shortness of breath
2 Mild shortness of breath
3 Moderate shortness of breath or breathing difficulty
4 Somewhat severe
5 Strong or hard breathing
6 -
7 Severe shortness of breath or very hard breathing
8 -
9 Extremely severe
10 Shortness of breath so severe you need to stop