Riociguat is an investigational, oral treatment that was discovered and developed by Bayer to
target a key molecular mechanism underlying pulmonary hypertension (PH). Riociguat is being
investigated as a new and specific approach to treat different types of PH.1, 2 PH is a severe,
progressive, life-changing and life-threatening disorder of the heart and lungs in which the
blood pressure in the pulmonary arteries is above normal and which can lead to heart failure
There are five types of PH; each can affect the patient in a different way and every patient may
have a different etiology and manifestation of PH.5-7 Riociguat is the first and only drug that has
consistently demonstrated robust clinical efficacy in two separate PH indications: chronic
thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension
The novel science of riociguat
Riociguat is a soluble guanylate cyclase (sGC) stimulator, the first member of a novel class of
compounds.1, 2 sGC is an enzyme found in the cardiopulmonary system and the receptor for
nitric oxide (NO). When NO binds to sGC, the enzyme enhances synthesis of the signaling
molecule cyclic guanosine monophosphate (cGMP). cGMP plays an important role in
regulating vascular tone, proliferation, fibrosis, and inflammation.10
PH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient
stimulation of sGC.1 Riociguat has a unique mode of action: it sensitizes sGC to endogenous
NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different
binding site, independently of NO.1, 2, 10 Riociguat, as a stimulator of sGC, addresses the issue
of NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of
Riociguat aims to address areas of high unmet medical need
Although the prognosis for patients with PH has improved in recent years, there is still a high
unmet need for more efficient therapies.11 With its novel mode of action, riociguat has the
potential to overcome a number of limitations of currently approved PAH therapies, including
NO dependence, and is the first drug which has shown clinical benefits in CTEPH, where no
pharmacological treatment is approved.* 1, 8
Positive results for riociguat in PH Chronic thromboembolic pulmonary hypertension (CTEPH) and riociguat
CHEST (Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial) is a Phase
III program which assessed the efficacy and safety of oral riociguat in the treatment of patients
with either inoperable CTEPH or PH which persisted or reoccurred after pulmonary
endarterectomy (PEA). CHEST is a multi-center, multi-national program with active centers in
26 countries. The program includes a randomized, double-blinded, placebo-controlled pivotal
trial phase (CHEST-1) and an open label long-term extension trial phase (CHEST-2).
In the CHEST-1 study, 261 patients with inoperable CTEPH or with persistent or recurrent
pulmonary hypertension after PEA were randomized and treated with either riociguat or
placebo orally for 16 weeks. Riociguat was titrated, over a period of eight weeks in doses of
0.5 mg increments, from 1.0 mg up to 2.5 mg, three times a day. After the titration phase,
patients were followed up for another eight weeks on their last dose to complete CHEST-1.
Patients from both arms then had the option of participating in the open label long term
extension study (CHEST-2), starting with an eight-week double-blinded sham titration. The
ongoing CHEST-2 study is investigating the sustainability of the efficacy results, as well as
longer term safety aspects of riociguat for CTEPH patients.
CHEST-1 met its primary endpoint, with riociguat shown to be the first ever drug to
significantly improve exercise capacity in patients with CTEPH. In the study, riociguat
demonstrated a statistically significant improvement in the six-minute walk test (6MWT) from
baseline after 16 weeks compared with placebo.8 A statistically significant improvement in
exercise capacity with riociguat was observed as early as four weeks after treatment initiation
and improved further in the long term extension study, CHEST-2, whilst the safety profile was
Riociguat also showed statistically significant improvements in relevant secondary endpoints,
including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic
peptide (NT-proBNP) and WHO functional class (FC).12 The improvements in 6MWD and
* Please note that riociguat has already been approved and launched under the brand name Adempas® in some countries for the treatment of PAH and/or CTEPH.
WHO FC observed during the pivotal 16-week CHEST-1 study were sustained during long-
term extension in the CHEST-2 study for a further 12 weeks and data suggests sustained
improvements over one year of observation.13
Pulmonary arterial hypertension (PAH) and riociguat
PATENT (Pulmonary Arterial Hypertension sGC-Stimulator Trial) is a Phase III program to
assess the efficacy and safety of oral riociguat in the treatment of treatment naïve and pre-
treated patients with symptomatic PAH. PATENT is a multi-center, multi-national program with
active centers in 30 countries. The program includes a randomized, double-blinded, placebo-
controlled pivotal trial phase (PATENT-1) and an open label long-term extension trial phase
In the PATENT-1 study, 443 patients with symptomatic PAH were randomized and treated
with either placebo or two different dose titration arms (an individual and a capped dose
titration arm) of riociguat orally over a period of 12 weeks. Riociguat was titrated over a period
of eight weeks in doses of 0.5 mg increments, from 1.0 mg up to 2.5 mg three times daily or up
to 1.5 mg in an exploratory arm. After the titration phase, patients were followed up for an
additional four weeks on their last dose to complete PATENT-1.
Patients from all three arms then had the option of participating in the open label long term
extension study (PATENT-2), starting with an eight-week double-blinded sham titration. The
ongoing PATENT-2 study is investigating the sustainability of the efficacy results as well as
longer term safety aspects of riociguat for PAH patients. PATENT included both treatment-
naïve patients and those pre-treated with an endothelin receptor antagonist (ERA) or an oral,
inhaled or subcutaneous prostanoid monotherapy.
PATENT-1 met its primary end point, with riociguat shown to significantly improve exercise
capacity in treatment-naïve and pre-treated patients with symptomatic PAH from baseline after
12 weeks compared with placebo. In the study, riociguat demonstrated a statistically
significant improvement in the 6MWT, a marker of disease severity and a predictor of survival.9
A statistically significant improvement in exercise capacity with riociguat was observed as
early as four weeks after treatment initiation and further improved in the long term extension
study, PATENT-2, whilst the safety profile was sustained and confirmed.9, 14
Riociguat is the first and only oral treatment to show significant and sustained clinical efficacy
in PAH in treatment-naïve as well as in patients pre-treated with ERAs or oral, inhaled or
subcutaneous prostanoid monotherapy. So far no other drugs, including phosphodiesterase
type 5 inhibitors (PDE5-inhibitors), have been able to show this.5, 9, 11
Additionally, statistically significant improvements were observed consistently across
secondary endpoints, including PVR, NT-pro BNP, WHO FC, TTCW and Borg dyspnea score.9
The improvements in 6MWD and WHO FC observed during the pivotal 12-week PATENT-1
study were sustained during long-term extension in the PATENT-2 study for a further 12
weeks and data suggests sustained improvements over one year of observation.9, 14
Riociguat was shown to be a well-tolerated, with a good safety profile in both the CHEST and
PATENT trials. Riociguat-related adverse events mostly occurring in either trial were mild or
Based on the findings of CHEST and PATENT, riociguat is the first and only drug that has
consistently demonstrated robust clinical efficacy in two separate PH indications: CTEPH and
Taken together, the positive results of both trials, CHEST and PATENT, underline the potential
of riociguat, with its unique mode of action, as an effective and well-tolerated treatment for
Riociguat enables personalized oral dosing that is well supported and simply managed. It is
individually titrated over the first two months of treatment, which ensures an optimized dosing
scheme for patients.15 In both CHEST-1 and PATENT-1, 90% of patients received the two
highest dosages of riociguat using the individual dosing scheme. Improvements were rapidly
observed within the first two weeks of treatment demonstrating that even the 1 mg dose is
Riociguat and Bayer HealthCare
Riociguat’s development program across different forms of PH demonstrates Bayer’s
commitment to understanding this severe and life-threatening condition with the high unmet
medical need to improve the lives of people with PH. Bayer is dedicated to the research and
development of new, innovative treatments targeting pulmonary hypertension, building on
more than 15 years’ experience with Ventavis® (iloprost) and more than a century in
1. Ghofrani HA, Voswinckel R, Gall H et al. Riociguat for pulmonary hypertension. Future
2. Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble
guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33(4):785-792.
3. Rosenkranz S. Pulmonary hypertension: current diagnosis and treatment. Clin Res
4. Macchia A, Marchioli R, Marfisi R et al. A meta-analysis of trials of pulmonary
hypertension: a clinical condition looking for drugs and research methodology. Am Heart J 2007;153(6):1037-1047.
5. Galie N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of
pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30(20):2493-2537.
6. Ali JM, Hardman G, Page A, Jenkins DP. Chronic thromboembolic pulmonary
hypertension: an underdiagnosed entity? Hosp Pract (1995 ) 2012;40(3):71-79.
7. Armstrong I, Rochnia N, Harries C, Bundock S, Yorke J. The trajectory to diagnosis with
pulmonary arterial hypertension: a qualitative study. BMJ Open 2012;2(2):e000806.
8. Ghofrani HA, D'Armini AM, Grimminger F et al. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension. N Engl J Med 2013;369(4):319-329.
9. Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary
arterial hypertension. N Engl J Med 2013;369(4):330-340.
10. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging
therapeutic target in cardiopulmonary disease. Circulation 2011;123(20):2263-2273.
11. Girgis RE. Emerging drugs for pulmonary hypertension. Expert Opin Emerg Drugs
12. Ghofrani HA, D'Armini AM, Grimminger F et al. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension. N Engl J Med 2013;369(4):319-329.
13. Simonneau G, D'Armini AM, Ghofrani HA et al. Riociguat for the treatment of chronic
thromboembolic pulmonary hypertension (CTEPH): a phase III long-term extension study (CHEST-2). 5th World Sympsoium on Pulmonary Hypertension, Nice, France, 27 February - 1 March; 2013.
14. Rubin LJ, Galie N, Grimminger F et al. Safety and efficacy of riociguat for the long-term
treatment of pulmonary arterial hypertension (PAH) in the phase III PATENT-2 long-term extension study. American Thoracic Society International Conference, Philadelphia, PA, USA, 17-22 May; 2013.
15. Bayer. Adempas Summary of Product Characteristics. 2013.
16. Camerini F, Alberti E, Klugmann S, Salvi A. Primary pulmonary hypertension: effects of
nifedipine. Br Heart J 1980;44(3):352-356.
17. Olschewski H, Ghofrani HA, Schmehl T et al. Inhaled iloprost to treat severe pulmonary
hypertension. An uncontrolled trial. German PPH Study Group. Ann Intern Med 2000;132(6):435-443.
Novel Integrated Water Management Systems Southern European Regions Novel Integrated Water Management Systems Southern European Regions 27 JAP ACTION - Development of upgraded bioprocesses in order to cope with tetracycline and methyl parathion. It will be studied the treatment of the selected emerging contaminants in a simulated and controlled wastewater using aerobic and aerobic sequencin
Overview This lesson focuses on the many products that are derived from beef cattle beyond just meat and meat products. Students will see that animal agriculture is an important part of their everyday lives. Suggested Grade Level 6 - 8 Estimated Time One-half a class period plus time at home or in the community. Objectives Students will be able to: 1. identify products they use every d