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PAH treatment

hypertension (CTEPH), PH associated with interstitial lung disease) showed that sGC stimulation had the expected favourable haemodynamic effects in PH population. Riociguat decreased mean pulmonary arterial pressure (mPAP), and PVR and increased cardiac index to a significantly greater extent than inhaled NO at doses of 1 and 2.5mg. Neither dose produced any deterioration in gas exchange, indicating that ventilation/perfusion matching was maintained. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110mmHg. In a Phase II study,18

riociguat was tested in 78

subjects with the PH subforms of PAH (n=33) and CTEPH (n=42). In this 12-week, multicentre, open-label, uncontrolled Phase II study, patients received oral riociguat 1.0–2.5mg three times a day, titrated according to systemic systolic blood pressure. Median six- minute walking distance (6MWD) increased significantly in patients with CTEPH and PAH. Riociguat treatment led to a decrease in PVR by 215

. In PAH In PATENT-1,19 a randomised, double-

blind, placebo-controlled, multi-centre study, the efficacy and safety of oral riociguat was tested in 443 patients with symptomatic PAH (treatment-naïve and pre-treated with an endothelin receptor antagonist or a prostacyclin analogue) over 12 weeks. During the eight-week titration phase, the dose of study medication was adjusted every two weeks based on the subject’s monitoring of systolic blood pressure and wellbeing. Riociguat was given in individually adjusted doses of up to 2.5mg three times a day (2.5mg–maximum group), or riociguat in individually adjusted doses that were capped at 1.5mg three times a day (1.5mg–maximum group). By week 12, the 6MWD had increased by a mean of 30 metres in the 2.5mg–maximum group and had decreased by a mean of six metres in the placebo group (p<0.001). There were significant improvements in PVR (p<0.001), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (p<0.001), World Health Organization (WHO) functional class (p=0.003), time to clinical worsening (p=0.005) and Borg dyspnoea score (p=0.002). One of the main features of the study was the significant benefit in treatment-naive and pre-treated patients. The most common

serious adverse event in the placebo group and the 2.5mg–maximum group was syncope (4% and 1%, respectively). The dose of the study drug was decreased in 31 patients (12%) in the riociguat group. The long-term safety, tolerability and

efficacy of riociguat were assessed in 396 patients completing PATENT-1 and entering the PATENT-2 open label extension study.20

A total of 62% had

idiopathic PAH, and the majority of patients were in WHO FC II and III (97%). At the cut-off date (March 2013), 324 patients were still receiving ongoing treatment and 84% were longer than one year on treatment. In the observed population at the one-year time point, 6MWD had increased by 51±74m and WHO functional class had improved in 33%, stabilised in 61% and worsened in 6% of the patients. Long-term riociguat was well tolerated in patients with PAH, and led to sustained improvements in exercise capacity and functional capacity for up to one year.

The adverse event profiles in PATENT-1 and PATENT-2 were in agreement with those observed in previous clinical trials with riociguat, reflecting the vasodilator mode of action of the drug and the fact that effects of the drug on smooth muscles may lead to gastrointestinal symptoms. Bleeding cases (mostly not drug-related) occurred during both studies including three cases with fatal outcomes. PATENT PLUS21

evaluated the safety

and efficacy of riociguat in combination with sildenafil in PAH patients. Patients receiving sildenafil (20mg three times daily) were randomised to placebo or riociguat (up to 2.5mg three-times daily) for 12 weeks. Combination therapy showed no favourable effects on exploratory clinical parameters, including haemodynamics and exercise capacity. There were potentially unfavourable safety signals with sildenafil plus riociguat (discontinuation due to hypotension and three deaths) and no evidence of a positive benefit/risk ratio.

In PAH associated with congenital heart disease

PAH is a common complication in patients with congenital heart disease (CHD) and is currently most common associated form of PAH in adults. PAH can develop due to an incomplete or delayed repair of the cardiac defect or late diagnosis of CHD. The efficacy and safety of riociguat was explored in the post hoc

analysis of 35 patients with persistent/ recurrent PAH following complete repair of CHD in PATENT-1 and PATENT-2.22

PATENT-1, riociguat increased 6MWD from baseline to week 12 by 39±60m versus 0±4m for placebo. Riociguat also improved PVR (−250±410



NT-proBNP (−164±317 pg/ml) and WHO FC (21%/79%/0% improved/stabilised/ worsened) compared with placebo. Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes.


was a randomised, double-

blind, placebo-controlled, multicentre, study assessing the efficacy and safety of oral riociguat in 261 patients with either inoperable CTEPH (n=189) or recurrent or persisting PH after pulmonary endarterectomy (PEA) (n=72). Riociguat at doses of 1.0–2.5mg as a titration regimen for 16 weeks resulted in a statistically significant and clinically meaningful improvement in 6MWD (mean increase of 39m in the riociguat group compared with a mean decrease of six metres in the placebo group; p<0.001). In CHEST-1, consistent with the effects observed for the 6MWD, riociguat had superior effects over placebo on the predefined secondary efficacy variables PVR (decrease by 226 in the riociguat group, and increase by 23


the placebo group; p<0.001), NT-proBNP (p<0.001) and WHO functional class (p=0.003). Both CTEPH groups showed a similar response to riociguat treatment. The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). CHEST-224

was an open-label

extension study evaluating the long-term safety and efficacy of riociguat in 237 patients from CHEST-1 receiving riociguat individually adjusted up to a maximum dose of 2.5mg three times daily. During CHEST-2, the clinical benefit and safety profile observed in CHEST-1 were maintained and patients previously treated with placebo improved to a similar extent as subjects on riociguat during the pivotal study. In the observed population at one year, 6MWD had changed by +51±62m, and WHO FC had improved/ stabilised/worsened in 47/50/3% of patients. Serious cases of haemoptysis and pulmonary haemorrhage occurred during both studies. Haemoptysis occurred in


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