Novel drug improved walk distance in pulmonary hypertension patients

Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.

Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.

The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.

The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.

The CHEST-1 trial

In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.

The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.

The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).

Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.

In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).

In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.

Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.

There were two deaths in the riociguat group and three in the placebo group.

A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.

The PATENT-1 trial

The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.

In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.

A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.

These study subjects were randomly assigned to receive high-dose riociguat capped at 2.5 mg three times daily (254 patients), low-dose riociguat capped at 1.5 mg three times daily (63 patients), or placebo (126 patients) for 12 weeks. The analysis of data from the low-dose group was considered exploratory and was reported separately.

The primary endpoint – change from baseline in 6-minute walk distance – increased by a mean of 30 m in the high-dose group but decreased by a mean of 6 m in the placebo group in the intention-to-treat analysis. The results were similar in the per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209655]).

This treatment benefit was consistent across several subgroups of patients. In addition, the active drug significantly decreased pulmonary vascular resistance, improved mean pulmonary artery pressure and cardiac output, lengthened the interval to clinical worsening, improved NT-proBNP levels, improved WHO functional class, and improved scores on the Borg dyspnea scale.

In exploratory analyses, riociguat did not improve scores on one measure of QOL but did so on a disease-specific QOL tool.

Drug-related serious adverse events occurred in 1.4 % of patients receiving high-dose riociguat and 1% of those receiving placebo. A total of 3% of patients in the riociguat group and 7% of those in the placebo group discontinued the study drug because of adverse events.

Serious or drug-related adverse events in both groups included increased hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, hypoxemia, dyspnea, and worsening of pulmonary hypertension. There were two deaths in the riociguat group and three in the placebo group, none of which were considered to be related to the study drug.

A total of 396 of the subjects in the PATENT-1 study elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the PATENT-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed a further mean increase of 53 m in 6-minute walk distance with high-dose riociguat.

CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.

Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.

Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.

The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.

The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.

The CHEST-1 trial

In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.

The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.

The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).

Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.

In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).

In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.

Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.

There were two deaths in the riociguat group and three in the placebo group.

A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.

The PATENT-1 trial

The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.

In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.

A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.

These study subjects were randomly assigned to receive high-dose riociguat capped at 2.5 mg three times daily (254 patients), low-dose riociguat capped at 1.5 mg three times daily (63 patients), or placebo (126 patients) for 12 weeks. The analysis of data from the low-dose group was considered exploratory and was reported separately.

The primary endpoint – change from baseline in 6-minute walk distance – increased by a mean of 30 m in the high-dose group but decreased by a mean of 6 m in the placebo group in the intention-to-treat analysis. The results were similar in the per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209655]).

This treatment benefit was consistent across several subgroups of patients. In addition, the active drug significantly decreased pulmonary vascular resistance, improved mean pulmonary artery pressure and cardiac output, lengthened the interval to clinical worsening, improved NT-proBNP levels, improved WHO functional class, and improved scores on the Borg dyspnea scale.

In exploratory analyses, riociguat did not improve scores on one measure of QOL but did so on a disease-specific QOL tool.

Drug-related serious adverse events occurred in 1.4 % of patients receiving high-dose riociguat and 1% of those receiving placebo. A total of 3% of patients in the riociguat group and 7% of those in the placebo group discontinued the study drug because of adverse events.

Serious or drug-related adverse events in both groups included increased hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, hypoxemia, dyspnea, and worsening of pulmonary hypertension. There were two deaths in the riociguat group and three in the placebo group, none of which were considered to be related to the study drug.

A total of 396 of the subjects in the PATENT-1 study elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the PATENT-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed a further mean increase of 53 m in 6-minute walk distance with high-dose riociguat.

CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.

Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.

Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.

The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.

The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.

The CHEST-1 trial

In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.

The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.

The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).

Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.

In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).

In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.

Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.

There were two deaths in the riociguat group and three in the placebo group.

A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.

The PATENT-1 trial

The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.

In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.

A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.

These study subjects were randomly assigned to receive high-dose riociguat capped at 2.5 mg three times daily (254 patients), low-dose riociguat capped at 1.5 mg three times daily (63 patients), or placebo (126 patients) for 12 weeks. The analysis of data from the low-dose group was considered exploratory and was reported separately.

The primary endpoint – change from baseline in 6-minute walk distance – increased by a mean of 30 m in the high-dose group but decreased by a mean of 6 m in the placebo group in the intention-to-treat analysis. The results were similar in the per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209655]).

This treatment benefit was consistent across several subgroups of patients. In addition, the active drug significantly decreased pulmonary vascular resistance, improved mean pulmonary artery pressure and cardiac output, lengthened the interval to clinical worsening, improved NT-proBNP levels, improved WHO functional class, and improved scores on the Borg dyspnea scale.

In exploratory analyses, riociguat did not improve scores on one measure of QOL but did so on a disease-specific QOL tool.

Drug-related serious adverse events occurred in 1.4 % of patients receiving high-dose riociguat and 1% of those receiving placebo. A total of 3% of patients in the riociguat group and 7% of those in the placebo group discontinued the study drug because of adverse events.

Serious or drug-related adverse events in both groups included increased hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, hypoxemia, dyspnea, and worsening of pulmonary hypertension. There were two deaths in the riociguat group and three in the placebo group, none of which were considered to be related to the study drug.

A total of 396 of the subjects in the PATENT-1 study elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the PATENT-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed a further mean increase of 53 m in 6-minute walk distance with high-dose riociguat.

CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.