Riociguat
Encyclopedia
Riociguat is a novel drug that is currently in clinical development by Bayer
. It is a stimulator of soluble guanylate cyclase (sGC). At the moment Phase III clinical trials investigate the use of riociguat as a new approach to treat two forms of pulmonary hypertension
(PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of a novel class of sGC stimulators.
(NO) 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.
and pharmacodynamics
of single oral doses of riociguat (0.25–5 mg). 58 healthy male subjects were given riociguat orally (oral solution or immediate-release tablet) in a randomised, placebo-controlled trial. Doses of riociguat were increased stepwise, and riociguat was well tolerated up to 2.5 mg.
An open-label, non-controlled phase II trial of riociguat in 75 adult patients (42 with CTEPH and 33 with PAH, all in World Health Organization
(WHO) 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 (PH-ILD). First results from this study are expected in 2011.
, a register of studies maintained by the National Institutes of Health
(NIH).
(20 mg thrice daily) in a non-randomized uncontrolled trial. The study has been completed in Aug 2009, results are outstanding .
. NO binds to soluble guanylate cyclase (sGC) and mediates the synthesis of the secondary messenger cyclic guanosine monophosphate
(cGMP). 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
(protein kinase G) to regulate cytosolic calcium
ion concentration. This changes the actin
–myosin
contractility
, which results in vasodilation. In patients with pulmonary arterial hypertension endothelial NO synthase, the enzyme that is responsible for the production of NO, is expressed to reduced levels. 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.
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
. It is a stimulator of soluble guanylate cyclase (sGC). At the moment Phase III clinical trials investigate the use of riociguat as a new approach to treat two forms of pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of a novel class of sGC stimulators.
Discovery
The first nitric oxideNitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO) independent, haem-dependent sGC stimulator YC-1, a synthetic benzylindazole
Indazole
Indazole, also called benzpyrazole or isoindazone, is a heterocyclic aromatic organic compound.Indazole derivatives display a broad variety of biological activities....
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, pharmacokineticsPharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
and pharmacodynamics
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
of single oral doses of riociguat (0.25–5 mg). 58 healthy male subjects were given riociguat orally (oral solution or immediate-release tablet) 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 (in 4 PAH patients) 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 (42 with CTEPH and 33 with PAH, all in World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO) 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 (PH-ILD). 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 (CHEST-1 and PATENT-1), and open-label extensions of these studies (CHEST-2 and PATENT-2). Details of these studies are reported on ClinicalTrials.govClinicalTrials.gov
ClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine at the National Institutes of Health, and is the largest clinical trials database, currently holding registrations from over 93,000 trials from more than 170 countries in the...
, a register of studies maintained by the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH).
CHEST
The Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial (CHEST) 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 (6-MWT). Patients having completed CHEST-1 will be invited to enter the extension trial, CHEST-2. The trial is ongoing .PATENT
The Pulmonary Arterial Hypertension sGC-Stimulator Trial (PATENT) 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 .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 (IR)-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 sildenafilSildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(20 mg thrice daily) in a non-randomized uncontrolled trial. The study has been completed in Aug 2009, results are outstanding .
Chemistry and mechanism of action
In healthy individuals nitric oxide (NO) acts as a signalling molecule on vascular smooth muscle cells to induce vasodilationVasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
. NO binds to soluble guanylate cyclase (sGC) and mediates the synthesis of the secondary messenger cyclic guanosine monophosphate
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
(cGMP). 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
CGMP-dependent protein kinase
cGMP-dependent protein kinase or Protein Kinase G is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell...
(protein kinase G) to regulate cytosolic calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ion concentration. This changes the actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
–myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
contractility
Contractility
Myocardial contractility is the intrinsic ability of the heart to contract independent of preload and afterload. Changes in the ability to produce force during contraction result from different degrees of binding between myosin and actin filaments...
, which results in vasodilation. In patients with pulmonary arterial hypertension endothelial NO synthase, the enzyme that is responsible for the production of NO, is expressed to reduced levels. 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
Cinaciguat
Cinaciguat is an experimental drug for the treatment of acute decompensated heart failure.-Mechanism of action:Cinaciguat activates the soluble guanylate cyclase which is a receptor for nitric oxide...
, 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.See also
- CinaciguatCinaciguatCinaciguat is an experimental drug for the treatment of acute decompensated heart failure.-Mechanism of action:Cinaciguat activates the soluble guanylate cyclase which is a receptor for nitric oxide...
, a sGC activator (not sCG stimulator). - PDE5 inhibitorPDE5 inhibitorA phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis...
s act downstream in the nitric oxide signalling pathway, reducing cyclic GMP degradation.