CHEST-1 Study: Riociguat Shows Efficacy in CTEPH

ATLANTA – Riociguat, a novel first-in-class soluble guanylate cyclase stimulator, significantly improved 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension in the randomized, placebo-controlled phase III CHEST-1 study.

The overall 46-m improvement in 6-minute walk distance at 16 weeks in the study population was largely attributable to improvements in the 173 patients randomized to receive riociguat treatment, as opposed to improvements in 88 patients who received placebo, Dr. Hossein A. Ghofrani reported at the annual meeting of the American College of Chest Physicians.

The improvement in the treatment group was progressive and had not reached a plateau at 16 weeks after treatment initiation. Meanwhile, an initial improvement in the placebo group was followed by a constant decline in the placebo group, said Dr. Ghofrani of University Hospital Giessen and Marburg in Germany.

Treatment also was associated with consistent, significant improvements in a number of secondary end points, including change in pulmonary vascular resistance (PVR), change in World Health Organization functional class, time to clinical worsening, change in Borg dyspnea score, and quality of life assessments, he said.

Hemodynamics were robustly improved, he added, noting that treatment was associated with a 32% reduction in PVR, which translated into a highly significant 246-dyne reduction.

Patients enrolled in the multicenter CHEST-1 study – the largest placebo-controlled study to date of chronic thromboembolic pulmonary hypertension (CTEPH), for which there are currently no approved medical treatments – were aged 18-80 years with either inoperable disease or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. They had a mean PVR of greater than 480 dyn.s/cm⁵.

Treatment with riociguat was initiated at an oral dose of 1 mg three times daily titrated up to a maximum of 2.5 mg three times daily as tolerated according to systolic blood pressure; 90% achieved the highest dose, attesting to the tolerability of the drug, Dr. Ghofrani said.

In fact, the adverse event rate was very low, and side effects were similar to those seen in the PATENT-1 trial of riociguat for pulmonary arterial hypertension (PAH), which also was reported at the meeting.

These included headache, dizziness, peripheral edema (which occurred more often in the placebo group), cough, dyspnea, nasopharyngitis, nausea, diarrhea, and vomiting.

The findings are encouraging given the lack of medical treatments for CETPH patients who either are ineligible for surgical treatment or have persistent pulmonary hypertension after surgery, Dr. Ghofrani said.

The study of riociguat for CETPH is ongoing. CHEST-1 completers were allowed to enroll in a long-term extension study (CHEST-2), and results of that study will be reported next year, Dr. Ghofrani said.

As for how it is that a single molecule appears to have efficacy for two distinct pulmonary hypertension subgroups (PAH and CETPH), which are believed to have differing pathophysiological mechanisms, he explained that the disease might have some "common denominators."

"After a certain level of severity, they have a lot of commonalities, and the progressive component, for instance for pulmonary vascular remodeling beyond a certain point of no return, becomes very much alike in the different disease entities. The lack of the endogenous [nitric oxide] signaling pathway has been proven for many of these diseases. ... I think there may be a common denominator for the disease, even if the underlying pathophysiology may be different," he explained.

This is not to say riociguat is a "magic bullet" for all pulmonary hypertension subgroups, he added.

The drug’s efficacy "has to be proven in each single indication with a proper randomized controlled trial," he said.

In addition to the PATENT-1 and CHEST-1 studies showing efficacy in PAH and CETPH, respectively, studies of other pulmonary hypertension disease subgroups are underway, including one involving patients with left heart systolic disorders and PAH; phase II data from that study will be presented at an upcoming meeting of the American Heart Association, he said.

The PATENT and CHEST trials are supported by Bayer, the maker of riociguat. Dr. Ghofrani disclosed that he has received grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and German Ministry for Education and Research; and from Bayer HealthCare, Aires, and other companies. He also has received payment for consulting and serving on speakers bureaus or advisory committees of several pharmaceutical companies.

ATLANTA – Riociguat, a novel first-in-class soluble guanylate cyclase stimulator, significantly improved 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension in the randomized, placebo-controlled phase III CHEST-1 study.

The overall 46-m improvement in 6-minute walk distance at 16 weeks in the study population was largely attributable to improvements in the 173 patients randomized to receive riociguat treatment, as opposed to improvements in 88 patients who received placebo, Dr. Hossein A. Ghofrani reported at the annual meeting of the American College of Chest Physicians.

The improvement in the treatment group was progressive and had not reached a plateau at 16 weeks after treatment initiation. Meanwhile, an initial improvement in the placebo group was followed by a constant decline in the placebo group, said Dr. Ghofrani of University Hospital Giessen and Marburg in Germany.

Treatment also was associated with consistent, significant improvements in a number of secondary end points, including change in pulmonary vascular resistance (PVR), change in World Health Organization functional class, time to clinical worsening, change in Borg dyspnea score, and quality of life assessments, he said.

Hemodynamics were robustly improved, he added, noting that treatment was associated with a 32% reduction in PVR, which translated into a highly significant 246-dyne reduction.

Patients enrolled in the multicenter CHEST-1 study – the largest placebo-controlled study to date of chronic thromboembolic pulmonary hypertension (CTEPH), for which there are currently no approved medical treatments – were aged 18-80 years with either inoperable disease or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. They had a mean PVR of greater than 480 dyn.s/cm⁵.

Treatment with riociguat was initiated at an oral dose of 1 mg three times daily titrated up to a maximum of 2.5 mg three times daily as tolerated according to systolic blood pressure; 90% achieved the highest dose, attesting to the tolerability of the drug, Dr. Ghofrani said.

In fact, the adverse event rate was very low, and side effects were similar to those seen in the PATENT-1 trial of riociguat for pulmonary arterial hypertension (PAH), which also was reported at the meeting.

These included headache, dizziness, peripheral edema (which occurred more often in the placebo group), cough, dyspnea, nasopharyngitis, nausea, diarrhea, and vomiting.

The findings are encouraging given the lack of medical treatments for CETPH patients who either are ineligible for surgical treatment or have persistent pulmonary hypertension after surgery, Dr. Ghofrani said.

The study of riociguat for CETPH is ongoing. CHEST-1 completers were allowed to enroll in a long-term extension study (CHEST-2), and results of that study will be reported next year, Dr. Ghofrani said.

As for how it is that a single molecule appears to have efficacy for two distinct pulmonary hypertension subgroups (PAH and CETPH), which are believed to have differing pathophysiological mechanisms, he explained that the disease might have some "common denominators."

"After a certain level of severity, they have a lot of commonalities, and the progressive component, for instance for pulmonary vascular remodeling beyond a certain point of no return, becomes very much alike in the different disease entities. The lack of the endogenous [nitric oxide] signaling pathway has been proven for many of these diseases. ... I think there may be a common denominator for the disease, even if the underlying pathophysiology may be different," he explained.

This is not to say riociguat is a "magic bullet" for all pulmonary hypertension subgroups, he added.

The drug’s efficacy "has to be proven in each single indication with a proper randomized controlled trial," he said.

In addition to the PATENT-1 and CHEST-1 studies showing efficacy in PAH and CETPH, respectively, studies of other pulmonary hypertension disease subgroups are underway, including one involving patients with left heart systolic disorders and PAH; phase II data from that study will be presented at an upcoming meeting of the American Heart Association, he said.

The PATENT and CHEST trials are supported by Bayer, the maker of riociguat. Dr. Ghofrani disclosed that he has received grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and German Ministry for Education and Research; and from Bayer HealthCare, Aires, and other companies. He also has received payment for consulting and serving on speakers bureaus or advisory committees of several pharmaceutical companies.

ATLANTA – Riociguat, a novel first-in-class soluble guanylate cyclase stimulator, significantly improved 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension in the randomized, placebo-controlled phase III CHEST-1 study.

The overall 46-m improvement in 6-minute walk distance at 16 weeks in the study population was largely attributable to improvements in the 173 patients randomized to receive riociguat treatment, as opposed to improvements in 88 patients who received placebo, Dr. Hossein A. Ghofrani reported at the annual meeting of the American College of Chest Physicians.

The improvement in the treatment group was progressive and had not reached a plateau at 16 weeks after treatment initiation. Meanwhile, an initial improvement in the placebo group was followed by a constant decline in the placebo group, said Dr. Ghofrani of University Hospital Giessen and Marburg in Germany.

Treatment also was associated with consistent, significant improvements in a number of secondary end points, including change in pulmonary vascular resistance (PVR), change in World Health Organization functional class, time to clinical worsening, change in Borg dyspnea score, and quality of life assessments, he said.

Hemodynamics were robustly improved, he added, noting that treatment was associated with a 32% reduction in PVR, which translated into a highly significant 246-dyne reduction.

Patients enrolled in the multicenter CHEST-1 study – the largest placebo-controlled study to date of chronic thromboembolic pulmonary hypertension (CTEPH), for which there are currently no approved medical treatments – were aged 18-80 years with either inoperable disease or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. They had a mean PVR of greater than 480 dyn.s/cm⁵.

Treatment with riociguat was initiated at an oral dose of 1 mg three times daily titrated up to a maximum of 2.5 mg three times daily as tolerated according to systolic blood pressure; 90% achieved the highest dose, attesting to the tolerability of the drug, Dr. Ghofrani said.

In fact, the adverse event rate was very low, and side effects were similar to those seen in the PATENT-1 trial of riociguat for pulmonary arterial hypertension (PAH), which also was reported at the meeting.

These included headache, dizziness, peripheral edema (which occurred more often in the placebo group), cough, dyspnea, nasopharyngitis, nausea, diarrhea, and vomiting.

The findings are encouraging given the lack of medical treatments for CETPH patients who either are ineligible for surgical treatment or have persistent pulmonary hypertension after surgery, Dr. Ghofrani said.

The study of riociguat for CETPH is ongoing. CHEST-1 completers were allowed to enroll in a long-term extension study (CHEST-2), and results of that study will be reported next year, Dr. Ghofrani said.

As for how it is that a single molecule appears to have efficacy for two distinct pulmonary hypertension subgroups (PAH and CETPH), which are believed to have differing pathophysiological mechanisms, he explained that the disease might have some "common denominators."

"After a certain level of severity, they have a lot of commonalities, and the progressive component, for instance for pulmonary vascular remodeling beyond a certain point of no return, becomes very much alike in the different disease entities. The lack of the endogenous [nitric oxide] signaling pathway has been proven for many of these diseases. ... I think there may be a common denominator for the disease, even if the underlying pathophysiology may be different," he explained.

This is not to say riociguat is a "magic bullet" for all pulmonary hypertension subgroups, he added.

The drug’s efficacy "has to be proven in each single indication with a proper randomized controlled trial," he said.

In addition to the PATENT-1 and CHEST-1 studies showing efficacy in PAH and CETPH, respectively, studies of other pulmonary hypertension disease subgroups are underway, including one involving patients with left heart systolic disorders and PAH; phase II data from that study will be presented at an upcoming meeting of the American Heart Association, he said.

The PATENT and CHEST trials are supported by Bayer, the maker of riociguat. Dr. Ghofrani disclosed that he has received grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and German Ministry for Education and Research; and from Bayer HealthCare, Aires, and other companies. He also has received payment for consulting and serving on speakers bureaus or advisory committees of several pharmaceutical companies.