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

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

• 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.

• 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.

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.

– 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 phosphodiesterasetype 5 inhibitors were not eligible.

• 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).

• 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.

• 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.

• 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.

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)

• 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.

Results

• 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.

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.

• 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).

• 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.

• 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.

• 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.

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.

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.

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