Riociguat the first drug to show efficacy in two potentially fatal forms of pulmonary hypertension in Phase III studies (1,2)
CHEST-1 study shows riociguat to be the first ever drug to demonstrate clinical efficacy in patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH) (1)
Riociguat significantly improved exercise capacity in both treatment-naïve and pre-treated patients with pulmonary arterial hypertension (PAH) in PATENT-1 study (2)
Riociguat was well tolerated with a good safety profile (1,2)
BERLIN, Germany I July 24, 2013 I Data from two pivotal, global Phase III studies published today in the New England Journal of Medicine confirm the robust clinical efficacy and the good safety and tolerability profile of the oral investigational drug riociguat in two life-threatening pulmonary hypertension indications.(1,2) The Phase III studies investigated safety and efficacy of riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH, CHEST-1 study) (1) and in patients with pulmonary arterial hypertension (PAH, PATENT-1 study).(2) Both studies met their primary endpoint by demonstrating a statistically significant improvement in the six-minute walk test (6MWT), a marker of disease severity3 and a predictor of survival in patients suffering from pulmonary hypertension, (4,5) after 16 and 12 weeks respectively.(1,2)
“Riociguat is the first drug to demonstrate efficacy in two distinct forms of pulmonary hypertension, namely PAH and inoperable CTEPH. The extent and consistency of improvements across both the primary and the multiple secondary endpoints as shown in the treatment with riociguat are impressive,” said Principal Investigator Professor Ardeschir Ghofrani, University Hospital Giessen and Marburg, Germany. “CHEST-1 and PATENT-1 provide comprehensive information with regard to endpoints that form the basis for therapeutic decisions and are relevant to daily clinical practice, as e.g. 6MWT, cardiopulmonary hemodynamics, WHO Functional Class and a disease-related biomarker.”
In the CHEST-1 study, patients treated with riociguat showed an improvement of 46 meters (95%-CI [25-67 meters] p<0.0001) from baseline in the 6MWT after 16 weeks compared with placebo.(1) The CHEST-1 study enrolled both inoperable CTEPH patients and patients whose disease persists or is recurrent after a surgical intervention.1 Results from PATENT-1 demonstrate that both treatment-naïve patients and patients pre-treated with endothelin receptor antagonists (ERAs) or non-iv prostanoid monotherapy benefit from treatment with riociguat, as patients improved 36 meters (95%-CI [20-52 meters] p<0.0001) from baseline in the 6MWT after 12 weeks compared with placebo.(2)
In addition, riociguat also demonstrated statistically significant improvements over a broad range of parameters in secondary endpoints in both studies, including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-proBNP) and WHO functional class (FC).(1,2) Furthermore, PATENT-1 also showed statistically significant improvements with regard to the secondary endpoints time to clinical worsening (TTCW) and Borg dyspnea score.(2)
Both pivotal studies also showed that riociguat was well tolerated with a good safety profile.(1,2) The most frequent treatment emergent adverse events with riociguat were headache, dizziness, peripheral edema, and gastrointestinal symptoms such as dyspepsia and nausea.(1,2)
At the beginning of February 2013, Bayer HealthCare submitted riociguat, the first drug to demonstrate efficacy in two distinct forms of pulmonary hypertension, namely inoperable CTEPH and pulmonary arterial hypertension (PAH) for regulatory approval in the United States and in the European Union. In April, the U.S. Food and Drug Administration (FDA) granted priority review to the New Drug Application (NDA) in both indications.
About Pulmonary Arterial Hypertension (PAH)
PAH is a rare and life-threatening disease in which the pressure in the pulmonary arteries is above normal.(6) PAH is characterized by morphological changes to the endothelium of the arteries of the lungs causing remodeling of the tissue, vasoconstriction and thrombosis-in-situ.6 As a result of these changes, the blood vessels in the lungs are narrowed, making it difficult for the heart to pump blood through to the lungs. PAH affects an estimated 52 people per million globally.(7) It is more prevalent in younger women than men.(7) In most cases, PAH has no known cause and, in some cases, it can be inherited.(7)
Despite the availability of several approved therapies, the prognosis for patients with PAH remains poor.
About Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
CTEPH is a rare and life-threatening disease in which it is believed that thromboembolic occlusion (organized blood clots) of pulmonary vessels gradually lead to an increased pressure in the pulmonary arteries, resulting in an overload of the right heart.(8,9) CTEPH may evolve after prior episodes of acute pulmonary embolism, but the pathogenesis is not yet completely understood.9 The standard treatment for CTEPH is pulmonary endarterectomy (PEA), a surgical procedure in which the blood vessels of the lungs are cleared of clot and scar material. However, a considerable number of patients with CTEPH are not operable and in some patients the disease persists or reoccurs after PEA.(9,10) Currently, there are no approved pharmacological treatments available for CTEPH.
About Riociguat
Riociguat (BAY 63-2521) is a soluble guanylase cyclase (sGC) stimulator, the first member of a novel class of compounds being investigated as a new and specific approach to treat different types of PH. 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.(11)
PH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of sGC.12 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.(11,12,13) Riociguat, as a stimulator of sGC, addresses NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of cGMP.(12)
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.(12,14,15)
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55,300 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at http://www.healthcare.bayer.com.
References
1. Ghofrani, HA. et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.
N Engl J Med 2013;369:319-29.
2. Ghofrani, HA. et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013;369:330-40.
3. Reesink HJ, et al. Six-minute walk distance as parameter of functional outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg. 2007: 133: 2: 510-516.
4. Vachiéry J-L, et al. How to detect disease progression in pulmonary arterial hypertension. Eur Respir Rev. 2012: 21: 12: 40-47.
5. Saouti N, et al. Predictors of mortality in inoperable chronic thromboembolic pulmonary hypertension. Respir Med. 2009: 7: 1013-1019.
6. Rosenkranz, S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol 2007;96:527.
7. Peacock AJ et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104-109.
8. Galiè, N 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;30:2493-2537.
9. Ali JM, et al Chronic Thromboembolic Pulmonary Hypertension: An Underdiagnosed Entity? Hosp Pract 2012; 40: 71-9.
10. Mayer E. Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2010;19:64-67.
11. Stasch J-P et al. Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease. Circulation. 2011; 123: 2263-73.
12. Ghofrani, HA. et al. Riociguat for pulmonary hypertension. Future Cardiol. 2010;6(10):155-166.
13. Grimminger F et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33:785-792.
14. Ghofrani, HA. et al. Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, placebo-controlled study (CHEST-1). ACCP 2012, Atlanta,
USA. Oral abstract 1462924.
15. Simonneau G et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH): A Phase III long-term extension study (CHEST-2). 5th World Symposium of Pulmonary Hypertension (WSPH) 2013
SOURCE: Bayer HealthCare Pharmaceuticals
Post Views: 105
Riociguat the first drug to show efficacy in two potentially fatal forms of pulmonary hypertension in Phase III studies (1,2)
CHEST-1 study shows riociguat to be the first ever drug to demonstrate clinical efficacy in patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH) (1)
Riociguat significantly improved exercise capacity in both treatment-naïve and pre-treated patients with pulmonary arterial hypertension (PAH) in PATENT-1 study (2)
Riociguat was well tolerated with a good safety profile (1,2)
BERLIN, Germany I July 24, 2013 I Data from two pivotal, global Phase III studies published today in the New England Journal of Medicine confirm the robust clinical efficacy and the good safety and tolerability profile of the oral investigational drug riociguat in two life-threatening pulmonary hypertension indications.(1,2) The Phase III studies investigated safety and efficacy of riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH, CHEST-1 study) (1) and in patients with pulmonary arterial hypertension (PAH, PATENT-1 study).(2) Both studies met their primary endpoint by demonstrating a statistically significant improvement in the six-minute walk test (6MWT), a marker of disease severity3 and a predictor of survival in patients suffering from pulmonary hypertension, (4,5) after 16 and 12 weeks respectively.(1,2)
“Riociguat is the first drug to demonstrate efficacy in two distinct forms of pulmonary hypertension, namely PAH and inoperable CTEPH. The extent and consistency of improvements across both the primary and the multiple secondary endpoints as shown in the treatment with riociguat are impressive,” said Principal Investigator Professor Ardeschir Ghofrani, University Hospital Giessen and Marburg, Germany. “CHEST-1 and PATENT-1 provide comprehensive information with regard to endpoints that form the basis for therapeutic decisions and are relevant to daily clinical practice, as e.g. 6MWT, cardiopulmonary hemodynamics, WHO Functional Class and a disease-related biomarker.”
In the CHEST-1 study, patients treated with riociguat showed an improvement of 46 meters (95%-CI [25-67 meters] p<0.0001) from baseline in the 6MWT after 16 weeks compared with placebo.(1) The CHEST-1 study enrolled both inoperable CTEPH patients and patients whose disease persists or is recurrent after a surgical intervention.1 Results from PATENT-1 demonstrate that both treatment-naïve patients and patients pre-treated with endothelin receptor antagonists (ERAs) or non-iv prostanoid monotherapy benefit from treatment with riociguat, as patients improved 36 meters (95%-CI [20-52 meters] p<0.0001) from baseline in the 6MWT after 12 weeks compared with placebo.(2)
In addition, riociguat also demonstrated statistically significant improvements over a broad range of parameters in secondary endpoints in both studies, including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-proBNP) and WHO functional class (FC).(1,2) Furthermore, PATENT-1 also showed statistically significant improvements with regard to the secondary endpoints time to clinical worsening (TTCW) and Borg dyspnea score.(2)
Both pivotal studies also showed that riociguat was well tolerated with a good safety profile.(1,2) The most frequent treatment emergent adverse events with riociguat were headache, dizziness, peripheral edema, and gastrointestinal symptoms such as dyspepsia and nausea.(1,2)
At the beginning of February 2013, Bayer HealthCare submitted riociguat, the first drug to demonstrate efficacy in two distinct forms of pulmonary hypertension, namely inoperable CTEPH and pulmonary arterial hypertension (PAH) for regulatory approval in the United States and in the European Union. In April, the U.S. Food and Drug Administration (FDA) granted priority review to the New Drug Application (NDA) in both indications.
About Pulmonary Arterial Hypertension (PAH)
PAH is a rare and life-threatening disease in which the pressure in the pulmonary arteries is above normal.(6) PAH is characterized by morphological changes to the endothelium of the arteries of the lungs causing remodeling of the tissue, vasoconstriction and thrombosis-in-situ.6 As a result of these changes, the blood vessels in the lungs are narrowed, making it difficult for the heart to pump blood through to the lungs. PAH affects an estimated 52 people per million globally.(7) It is more prevalent in younger women than men.(7) In most cases, PAH has no known cause and, in some cases, it can be inherited.(7)
Despite the availability of several approved therapies, the prognosis for patients with PAH remains poor.
About Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
CTEPH is a rare and life-threatening disease in which it is believed that thromboembolic occlusion (organized blood clots) of pulmonary vessels gradually lead to an increased pressure in the pulmonary arteries, resulting in an overload of the right heart.(8,9) CTEPH may evolve after prior episodes of acute pulmonary embolism, but the pathogenesis is not yet completely understood.9 The standard treatment for CTEPH is pulmonary endarterectomy (PEA), a surgical procedure in which the blood vessels of the lungs are cleared of clot and scar material. However, a considerable number of patients with CTEPH are not operable and in some patients the disease persists or reoccurs after PEA.(9,10) Currently, there are no approved pharmacological treatments available for CTEPH.
About Riociguat
Riociguat (BAY 63-2521) is a soluble guanylase cyclase (sGC) stimulator, the first member of a novel class of compounds being investigated as a new and specific approach to treat different types of PH. 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.(11)
PH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of sGC.12 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.(11,12,13) Riociguat, as a stimulator of sGC, addresses NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of cGMP.(12)
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.(12,14,15)
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55,300 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at http://www.healthcare.bayer.com.
References
1. Ghofrani, HA. et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.
N Engl J Med 2013;369:319-29.
2. Ghofrani, HA. et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013;369:330-40.
3. Reesink HJ, et al. Six-minute walk distance as parameter of functional outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg. 2007: 133: 2: 510-516.
4. Vachiéry J-L, et al. How to detect disease progression in pulmonary arterial hypertension. Eur Respir Rev. 2012: 21: 12: 40-47.
5. Saouti N, et al. Predictors of mortality in inoperable chronic thromboembolic pulmonary hypertension. Respir Med. 2009: 7: 1013-1019.
6. Rosenkranz, S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol 2007;96:527.
7. Peacock AJ et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104-109.
8. Galiè, N 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;30:2493-2537.
9. Ali JM, et al Chronic Thromboembolic Pulmonary Hypertension: An Underdiagnosed Entity? Hosp Pract 2012; 40: 71-9.
10. Mayer E. Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2010;19:64-67.
11. Stasch J-P et al. Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease. Circulation. 2011; 123: 2263-73.
12. Ghofrani, HA. et al. Riociguat for pulmonary hypertension. Future Cardiol. 2010;6(10):155-166.
13. Grimminger F et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33:785-792.
14. Ghofrani, HA. et al. Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, placebo-controlled study (CHEST-1). ACCP 2012, Atlanta,
USA. Oral abstract 1462924.
15. Simonneau G et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH): A Phase III long-term extension study (CHEST-2). 5th World Symposium of Pulmonary Hypertension (WSPH) 2013
SOURCE: Bayer HealthCare Pharmaceuticals
Post Views: 105
