Accepted Manuscript Riociguat: A novel therapeutic option for PAH and CTEPH Lisa M. Mielniczuk, MD, FRCPC John R. Swiston, MD, MPH, FRCPC Sanjay Mehta, MD, FRCPC, FCCP PII:
S0828-282X(14)00280-3
DOI:
10.1016/j.cjca.2014.04.014
Reference:
CJCA 1190
To appear in:
Canadian Journal of Cardiology
Received Date: 15 February 2014 Revised Date:
5 April 2014
Accepted Date: 6 April 2014
Please cite this article as: Mielniczuk LM, Swiston JR, Mehta S, Riociguat: A novel therapeutic option for PAH and CTEPH, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.04.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Authorship: • Lisa M Mielniczuk*, MD, FRCPC University of Ottawa Heart Institute, Ottawa ON John R Swiston*, MD, MPH, FRCPC University of British Columbia, Vancouver BC
•
Sanjay Mehta, MD, FRCPC, FCCP Pulmonary Hypertension Association (PHA) Canada Southwest Ontario PH Clinic, London Health Sciences Centre Division of Respirology, Department of Medicine, Schulich School of Medicine, Western University, London ON
M AN U
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•
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Title: • Riociguat: A novel therapeutic option for PAH and CTEPH
*Co-first author – Both of these authors contributed equally to this publication
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Word Count: 5540
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Short Title: • Riociguat for PAH and CTEPH
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Corresponding Author Information: • Lisa M Mielniczuk University of Ottawa Heart Institute 40 Ruskin St, Room H1295 Ottawa, ON K1Y 4W7 Phone: (613) 761-5000 Fax: (613) 761-4877 [email protected]
1
ACCEPTED MANUSCRIPT
Brief Summary Riociguat, a novel direct-acting soluble guanylate cyclase stimulator, has been
RI PT
approved by Health Canada and the FDA as the first medical therapy for the treatment of chronic thromboembolic pulmonary hypertension and as a novel treatment option for pulmonary arterial hypertension. This paper reviews the
AC C
EP
TE D
M AN U
SC
pivotal trials that led to these approvals and the implications for clinical practice.
2
ACCEPTED MANUSCRIPT
Abstract Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary
RI PT
hypertension (CTEPH) are serious and often fatal diseases. The pathophysiology of both diseases is complex, and in part attributed to alterations in the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway. Riociguat, a novel sGC stimulator, acts on this pathway through a dual
SC
mechanism of action by directly stimulating sGC in a NO-independent manner
M AN U
and also increasing the sensitivity of sGC to NO. Based on benefits from clinical trials for both PAH and CTEPH, riociguat was approved by Health Canada and the FDA as the first medical therapy for patients with CTEPH who are deemed inoperable or those who have residual/recurrent PH post-pulmonary endarterectomy (PEA), and as a novel treatment option for patients with PAH.
TE D
This paper reviews the key findings from the Phase III trials for riociguat that led to these approvals and the implications this has for the treatment of patients with
AC C
EP
PAH and CTEPH.
3
ACCEPTED MANUSCRIPT
Introduction Pulmonary hypertension (PH) is a serious, progressive and often fatal condition
RI PT
which is characterized by an increase in pulmonary artery pressure, right ventricular (RV) dysfunction and death. The pathophysiology of PH is complex, involving abnormalities in many cellular components of the pulmonary arterial
wall including endothelial cells, smooth muscle cells and fibroblasts.1 Endothelial
SC
dysfunction is thought to be one of the most important pathophysiologic
M AN U
abnormalities contributing to PH, characterized by an abnormal pulmonary vasodilatory/vasoconstrictive balance, enhanced thrombosis, and remodelling of the pulmonary vascular wall through fibrosis, endothelial cell proliferation and increased muscularization of the pulmonary arteries.2,3
TE D
Endothelial dysfunction occurs as a result of alterations in many different signalling pathways, including the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway.4 This pathway is
EP
responsible for inducing vasodilation and inhibiting proliferation of smooth muscle cells by increasing the production of the secondary messenger cGMP via NO-
AC C
mediated activation of sGC (Figure 1).5,6 Pulmonary hypertension is associated with impaired NO synthesis which results in insufficient sGC activation and cGMP production, supporting a role for therapeutic interventions which target this pathway.7-9 Phosphodiesterase-5 (PDE-5) inhibitors, which act downstream of NO to reduce the degradation of cGMP, have shown benefits in patients with PH, thus demonstrating the therapeutic potential of this pathway.10 However, PDE-5 4
ACCEPTED MANUSCRIPT
inhibitors are not effective in all patients. This may be due, in part, to the fact that their action is dependent on the presence of endogenous NO synthesis and expression of functional PDE-5, both of which have been found to be impaired in
RI PT
patients with PH.11 Alternative therapies which act directly on sGC would provide a therapeutic option which overcomes the limitations associated with PDE-5 inhibitors.
SC
Riociguat represents the first, direct sGC stimulator to be approved by Health
M AN U
Canada and the FDA for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat is currently under review by the EMA and has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of CTEPH and PAH. Riociguat enhances NO-sGC-cGMP signalling in
TE D
two ways; by directly stimulating sGC in a NO-independent manner and also increasing the sensitivity of sGC to NO.12,13 This dual mechanism of action is supported by in vitro studies where riociguat stimulated recombinant sGC up to
EP
73-fold, and in the presence of a NO-releasing agent, increased the activity of
AC C
sGC 112-fold above baseline.14 Riociguat is rapidly absorbed, reaching maximum concentrations after 1 to 1.5 hours.15 It is excreted through both renal and biliary/fecal routes, with an elimination half life of 7 hours in healthy individuals and 13 hours in patients. Exposure to riociguat is higher in patients with renal impairment, thus caution should be taken during dose titration in patients with creatinine clearance 5
ACCEPTED MANUSCRIPT
between 15 and 80 mL/min, and its use is not recommended for patients with creatinine clearance
S0828-282X(14)00280-3
DOI:
10.1016/j.cjca.2014.04.014
Reference:
CJCA 1190
To appear in:
Canadian Journal of Cardiology
Received Date: 15 February 2014 Revised Date:
5 April 2014
Accepted Date: 6 April 2014
Please cite this article as: Mielniczuk LM, Swiston JR, Mehta S, Riociguat: A novel therapeutic option for PAH and CTEPH, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.04.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Authorship: • Lisa M Mielniczuk*, MD, FRCPC University of Ottawa Heart Institute, Ottawa ON John R Swiston*, MD, MPH, FRCPC University of British Columbia, Vancouver BC
•
Sanjay Mehta, MD, FRCPC, FCCP Pulmonary Hypertension Association (PHA) Canada Southwest Ontario PH Clinic, London Health Sciences Centre Division of Respirology, Department of Medicine, Schulich School of Medicine, Western University, London ON
M AN U
SC
•
RI PT
Title: • Riociguat: A novel therapeutic option for PAH and CTEPH
*Co-first author – Both of these authors contributed equally to this publication
EP
Word Count: 5540
TE D
Short Title: • Riociguat for PAH and CTEPH
AC C
Corresponding Author Information: • Lisa M Mielniczuk University of Ottawa Heart Institute 40 Ruskin St, Room H1295 Ottawa, ON K1Y 4W7 Phone: (613) 761-5000 Fax: (613) 761-4877 [email protected]
1
ACCEPTED MANUSCRIPT
Brief Summary Riociguat, a novel direct-acting soluble guanylate cyclase stimulator, has been
RI PT
approved by Health Canada and the FDA as the first medical therapy for the treatment of chronic thromboembolic pulmonary hypertension and as a novel treatment option for pulmonary arterial hypertension. This paper reviews the
AC C
EP
TE D
M AN U
SC
pivotal trials that led to these approvals and the implications for clinical practice.
2
ACCEPTED MANUSCRIPT
Abstract Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary
RI PT
hypertension (CTEPH) are serious and often fatal diseases. The pathophysiology of both diseases is complex, and in part attributed to alterations in the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway. Riociguat, a novel sGC stimulator, acts on this pathway through a dual
SC
mechanism of action by directly stimulating sGC in a NO-independent manner
M AN U
and also increasing the sensitivity of sGC to NO. Based on benefits from clinical trials for both PAH and CTEPH, riociguat was approved by Health Canada and the FDA as the first medical therapy for patients with CTEPH who are deemed inoperable or those who have residual/recurrent PH post-pulmonary endarterectomy (PEA), and as a novel treatment option for patients with PAH.
TE D
This paper reviews the key findings from the Phase III trials for riociguat that led to these approvals and the implications this has for the treatment of patients with
AC C
EP
PAH and CTEPH.
3
ACCEPTED MANUSCRIPT
Introduction Pulmonary hypertension (PH) is a serious, progressive and often fatal condition
RI PT
which is characterized by an increase in pulmonary artery pressure, right ventricular (RV) dysfunction and death. The pathophysiology of PH is complex, involving abnormalities in many cellular components of the pulmonary arterial
wall including endothelial cells, smooth muscle cells and fibroblasts.1 Endothelial
SC
dysfunction is thought to be one of the most important pathophysiologic
M AN U
abnormalities contributing to PH, characterized by an abnormal pulmonary vasodilatory/vasoconstrictive balance, enhanced thrombosis, and remodelling of the pulmonary vascular wall through fibrosis, endothelial cell proliferation and increased muscularization of the pulmonary arteries.2,3
TE D
Endothelial dysfunction occurs as a result of alterations in many different signalling pathways, including the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway.4 This pathway is
EP
responsible for inducing vasodilation and inhibiting proliferation of smooth muscle cells by increasing the production of the secondary messenger cGMP via NO-
AC C
mediated activation of sGC (Figure 1).5,6 Pulmonary hypertension is associated with impaired NO synthesis which results in insufficient sGC activation and cGMP production, supporting a role for therapeutic interventions which target this pathway.7-9 Phosphodiesterase-5 (PDE-5) inhibitors, which act downstream of NO to reduce the degradation of cGMP, have shown benefits in patients with PH, thus demonstrating the therapeutic potential of this pathway.10 However, PDE-5 4
ACCEPTED MANUSCRIPT
inhibitors are not effective in all patients. This may be due, in part, to the fact that their action is dependent on the presence of endogenous NO synthesis and expression of functional PDE-5, both of which have been found to be impaired in
RI PT
patients with PH.11 Alternative therapies which act directly on sGC would provide a therapeutic option which overcomes the limitations associated with PDE-5 inhibitors.
SC
Riociguat represents the first, direct sGC stimulator to be approved by Health
M AN U
Canada and the FDA for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat is currently under review by the EMA and has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of CTEPH and PAH. Riociguat enhances NO-sGC-cGMP signalling in
TE D
two ways; by directly stimulating sGC in a NO-independent manner and also increasing the sensitivity of sGC to NO.12,13 This dual mechanism of action is supported by in vitro studies where riociguat stimulated recombinant sGC up to
EP
73-fold, and in the presence of a NO-releasing agent, increased the activity of
AC C
sGC 112-fold above baseline.14 Riociguat is rapidly absorbed, reaching maximum concentrations after 1 to 1.5 hours.15 It is excreted through both renal and biliary/fecal routes, with an elimination half life of 7 hours in healthy individuals and 13 hours in patients. Exposure to riociguat is higher in patients with renal impairment, thus caution should be taken during dose titration in patients with creatinine clearance 5
ACCEPTED MANUSCRIPT
between 15 and 80 mL/min, and its use is not recommended for patients with creatinine clearance
