Riociguat is a novel drug that is a stimulator of soluble guanylate cyclase.
Clinical trials have looked at riociguat as a new approach to treat two forms of
pulmonary hypertension: chronic thromboembolic pulmonary hypertension
and pulmonary arterial hypertension. Riociguat constitutes the first drug of
a novel class of sGC stimulators. Contraindications
Riociguat can cause fetal harm and is therefore contraindicated in pregnant
women. Adverse effects
Serious adverse effects in clinical trials included bleeding. Hypotension,
headache, and gastrointestinal disorders also occurred.
Interactions Nitrates and phosphodiesterase
inhibitors increase the hypotensive effect of riociguat. Combining such
drugs is therefore contraindicated. Riociguat levels in the blood are
reduced by tobacco smoking and strong inducers of the liver enzyme CYP3A4, and
increased by strong cytochrome inhibitors.
Chemistry and mechanism of action In healthy individuals nitric oxide acts
as a signalling molecule on vascular smooth muscle cells to induce
vasodilation. NO binds to soluble guanylate cyclase and mediates the
synthesis of the secondary messenger cyclic guanosine monophosphate. sGC
forms heterodimers consisting of a larger alpha-subunit and a smaller
haem-binding beta-subunit. The synthesised cGMP acts as a secondary
messenger and activates cGMP-dependent protein kinase to regulate cytosolic
calcium ion concentration. This changes the actin–myosin contractility, which
results in vasodilation. NO is produced by the enzyme endothelial nitric oxide
synthetase NO synthase. In patients with pulmonary arterial hypertension eNOS
levels are reduced. This results in overall lower levels of endothelial
cell-derived NO and reduced vasodilation of smooth muscle cells. NO also reduces
pulmonary smooth muscle cell growth and antagonises platelet inhibition, factors
which play a key role in the pathogenesis of PAH. In contrast to NO-
and haem-independent sGC activators like cinaciguat, the sGC stimulator riociguat
directly stimulates sGC activity independent of NO and also acts in
synergy with NO to produce anti-aggregatory, anti-proliferative,
and vasodilatory effects. Pharmacology
Riociguat at concentration between 0.1 and 100 mmol stimulates in a
dose-dependent manner sGC activity up to 73-fold. In addition, it acts
synergistically with diethylamine/NO, the donor of NO, to increase sGC
activity in vitro up to 112-fold. A phase I study showed that riociguat is
rapidly absorbed, and maximum plasma concentration is reached between 0.5–1.5
h. The mean elimination half-life appears to be 5–10 hours. Riociguat
plasma concentrations have been also shown to be quite variable between
patients, indicating that for clinical use it is probably necessary to titrate
the drug specifically for each individual.
History = Discovery =
The first nitric oxide independent, haem-dependent sGC stimulator YC-1, a
synthetic benzylindazole derivative, was described in 1978. The characterisation
20 years later demonstrated that as well as increasing sGC activity, YC-1 acted
in synergy with NO to stimulate sGC. However, YC-1 was a relatively weak
vasodilator and had side effects. Therefore, the search began for novel
indazole compounds that were more potent and more specific sGC stimulators. The
result was the identification of BAY 41-2272 and BAY 41-8543. Both compounds
were tested in various preclinical studies on different animal models and
appeared to improve systemic arterial oxygenation. To improve the
pharmacologic and pharmacokinetic profile an additional 1000 compounds
were screened leading to the discovery of riociguat. Riociguat was tested in
mouse and rat disease models, where it effectively reduced pulmonary
hypertension and reversed the associated right heart hypertrophy and ventricular
remodelling. Several clinical trials have been
undertaken to investigate and evaluate diverse aspects of riociguat and some of
them are still ongoing. = Phase I clinical trials =
One of the first studies was designed to test the safety profile,
pharmacokinetics and pharmacodynamics of single oral doses of riociguat. 58
healthy male subjects were given riociguat orally in a randomised,
placebo-controlled trial. Doses of riociguat were increased stepwise, and
riociguat was well tolerated up to 2.5 mg.
= Phase II clinical trials = A proof-of-concept study, reported by
the University of Gießen Lung Center, was the first small study to investigate
safety, tolerability, pharmacokinetics and efficacy parameters. The drug was
well-tolerated and superior to NO in efficacy and duration.
An open-label, non-controlled phase II trial of riociguat in 75 adult patients
functional class II or III) evaluated the safety and tolerability, and the
effects on hemodynamics, exercise capacity and functional class. Riociguat
was given three times daily for 12 weeks. Doses were titrated at 2-week
intervals from 1.0 mg three times daily to a maximum of 2.5 mg three times
daily. Riociguat had a favourable safety profile, and also significantly improved
exercise capacity and hemodynamic parameters such as pulmonary vascular
resistance, cardiac output and pulmonary arterial pressure compared to baseline
values. In addition, a phase II study of
riociguat is underway in patients suffering from other forms of PH such as
associated with interstitial lung disease. First results from this study
are expected in 2011. = Phase III clinical trials =
The phase III trials on riociguat are multi-center studies. The study program
includes large randomized, double-blind, placebo-controlled pivotal trial phase,
and open-label extensions of these studies. Details of these studies are
reported on ClinicalTrials.gov, a register of studies maintained by the
National Institutes of Health. CHEST
The Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial is a
randomized, placebo-controlled trial that is aimed to analyse the efficacy
and safety of riociguat in CTEPH patients. After a 16 week riociguat
treatment the patient’s exercise capacity will be evaluated by measuring
the change in the six-minute walk test. Patients having completed CHEST-1 will
be invited to enter the extension trial, CHEST-2. The trial is ongoing as of
December 2009. PATENT
The Pulmonary Arterial Hypertension sGC-Stimulator Trial is a randomized,
placebo-controlled trial that investigates the efficacy and safety of
riociguat in PAH patients. After a 12 week treatment the patient’s exercise
capacity will be evaluated by measuring the change in the 6-MWT. Patients having
completed PATENT-1 will be invited to enter the extension trial, PATENT-2. The
trial is ongoing as of December 2009. = Other studies =
Effect of riociguat on bone metabolism This randomized, double blind, placebo
controlled Phase I study investigates the effect of riociguat, administered as
2.5 mg immediate-release-tablets twice daily over 14 days, on the bone
metabolism. Final data collection is expected in December 2009.
Interaction study with sildenafil This study investigates safety,
tolerability, pharmacokinetics and the impact on pulmonary and systemic
haemodynamics of single doses of 0.5 and 1 mg of riociguat in patients with PAH
and stable treatment of sildenafil in a non-randomized uncontrolled trial. The
study has been completed in Aug 2009, results are outstanding as of December
2009. See also
Cinaciguat, a sGC activator. PDE5 inhibitors act downstream in the
nitric oxide signalling pathway, reducing cyclic GMP degradation.
Endothelin receptor antagonist, another class of drugs used in PAH
Weblinks Bibliography on HOP
References