FDA panel backs riociguat for two types of pulmonary hypertension patients

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended that riociguat, an orally administered potent vasodilator, should be approved for treating patients with pulmonary arterial hypertension (World Health Organization Group 1) and with chronic thromboembolic pulmonary hypertension (WHO Group 4), based on two phase-III international studies that found the drug was associated with significant improvements in the 6-minute walk test in these two groups of pulmonary hypertension patients.

At a meeting on August 6, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 11-0 that riociguat, the first in a new class of drugs, should be approved for these two groups of patients. The manufacturer, Bayer HealthCare Pharmaceuticals, has proposed that the drug be approved to improve exercise capacity, improve WHO functional class, delay clinical worsening in patients with PAH (WHO Group 1), and to improve exercise capacity and WHO functional class in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or with persistent or recurrent CTEPH after surgical treatment.

Riociguat is a soluble guanylate cyclase (sGC) stimulator and, if approved, it will be first treatment approved for CTEPH. The drug affects both pulmonary and systemic vascular resistance in pulmonary hypertension, which is associated with impaired synthesis of nitric oxide and insufficient stimulation of the nitric-oxide-sGC-cGMP pathway. Riociguat stimulates sGc, independent of nitric oxide, increasing the sensitivity of sGC to nitric oxide, according to Bayer.

The company presented the results of two double-blind, international studies, which randomized patients to riociguat or placebo, titrated from 0.5 mg to 2.5 mg three times a day, using the same endpoints and dosing titration strategy.

PATENT-1 (Pulmonary Arterial Hypertension sGC-stimulator Trial) compared riociguat with placebo in 380 mostly female patients (mean age, 51 years) with PAH. At 12 weeks, the change in the 6-minute walk test from baseline improved by a mean of 30 m among those treated with riociguat but dropped by a mean of 6 m in the placebo group. WHO functional class improved in 21% of those on riociguat, compared with 14% of those on placebo, and deteriorated in 4% of those on riociguat and 14% of those on placebo.

CHEST (Chronic Thomboembolic Pulmonary Hypertension sGC-Stimulator Trial) enrolled 261 patients with inoperable (WHO group 4) or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy; their mean age was 59 years, and about 61%-68% were female. At 16 weeks, the change in the 6-minute walk test from baseline improved by a mean of 39 m among those treated with riociguat but dropped by a mean of 6 m among those on placebo. WHO functional class improved in 33% of those on riociguat, compared with 15% of those on placebo, and deteriorated in 5% of those on riociguat and in 7% of those on placebo.

In both studies, there were statistically significant improvements in secondary clinically relevant endpoints.

In a pooled safety analysis of the two studies, the rates of adverse outcomes and serious adverse outcomes were similar in patients on the drug and those on placebo. The most common adverse events associated with treatment were headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting, according to Bayer.

Hypotension was higher among those on riociguat (10% vs 3.7%), with most cases mild to moderate. There were a few cases of hemoptysis in riociguat-treated patients (five cases in the two studies), which is included in the warning in the company’s proposed label.

The panel agreed that the effectiveness of the drug in the two studies was an adequate basis for approval of the two indications. Dr. Stuart Rich, professor of medicine at the University of Chicago, cautioned about the possible misuse of the drug in patients with CTEPH who could benefit from surgery and said that there should be measures in place to ensure that the drug is used to treat only those patients with CTEPH who are truly inoperable.

The panel members were not overly concerned about the effects of systemic vasodilation of the drug, although, once used in the general population outside of a controlled clinical trial, risks could increase in some patients, they pointed out.

Dr. Rich, an attending physician in the center for pulmonary hypertension at the University of Chicago Hospitals, said that there should be a strong warning pointing out that riociguat should never be used with inhaled nitric oxide, sublingual nitroglycerin, or a phosphodiesterase-5 (PDE- 5) inhibitor. His biggest concern is that it will be marketed as a new drug. "Physicians may not think that the mechanism [of riociguat] has similarities to the nitric oxide pathway, which in fact it really does," he said. Therefore, it is important that prescribers understand that, if those drugs were combined, they would be giving patients "a whopping dose of nitric oxide."

The FDA agreed with the company’s conclusions regarding the clinical trial results and supported the approval of the drug. The FDA review, however, raised the issue of hypotension associated with the higher dose and recommended capping the dose at 1.5 mg three times a day since the higher dose did not appear to add an incremental benefit, Dr. Preston Dunmon, a medical officer in the FDA’s division of cardiovascular and renal drug products, told the panel. But panelists said that there should be a broad range of doses to choose from and that the 2.5 mg t.i.d. dose should be available.

Currently, there is no drug approved for treating CTEPH. Bosentan (Tracleer), an endothelin receptor antagonist, and sildenafil (Revatio), a PDE-5 inhbitor, are approved for PAH (WHO Group 1). The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts before the meeting.

If approved, Bayer plans to market the drug as Adempas.

The results of the two studies were published in the July 25 issue of the New England Journal of Medicine (PATENT-1 [369:330-40]; CHEST-1 [369:319-29]).

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended that riociguat, an orally administered potent vasodilator, should be approved for treating patients with pulmonary arterial hypertension (World Health Organization Group 1) and with chronic thromboembolic pulmonary hypertension (WHO Group 4), based on two phase-III international studies that found the drug was associated with significant improvements in the 6-minute walk test in these two groups of pulmonary hypertension patients.

At a meeting on August 6, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 11-0 that riociguat, the first in a new class of drugs, should be approved for these two groups of patients. The manufacturer, Bayer HealthCare Pharmaceuticals, has proposed that the drug be approved to improve exercise capacity, improve WHO functional class, delay clinical worsening in patients with PAH (WHO Group 1), and to improve exercise capacity and WHO functional class in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or with persistent or recurrent CTEPH after surgical treatment.

Riociguat is a soluble guanylate cyclase (sGC) stimulator and, if approved, it will be first treatment approved for CTEPH. The drug affects both pulmonary and systemic vascular resistance in pulmonary hypertension, which is associated with impaired synthesis of nitric oxide and insufficient stimulation of the nitric-oxide-sGC-cGMP pathway. Riociguat stimulates sGc, independent of nitric oxide, increasing the sensitivity of sGC to nitric oxide, according to Bayer.

The company presented the results of two double-blind, international studies, which randomized patients to riociguat or placebo, titrated from 0.5 mg to 2.5 mg three times a day, using the same endpoints and dosing titration strategy.

PATENT-1 (Pulmonary Arterial Hypertension sGC-stimulator Trial) compared riociguat with placebo in 380 mostly female patients (mean age, 51 years) with PAH. At 12 weeks, the change in the 6-minute walk test from baseline improved by a mean of 30 m among those treated with riociguat but dropped by a mean of 6 m in the placebo group. WHO functional class improved in 21% of those on riociguat, compared with 14% of those on placebo, and deteriorated in 4% of those on riociguat and 14% of those on placebo.

CHEST (Chronic Thomboembolic Pulmonary Hypertension sGC-Stimulator Trial) enrolled 261 patients with inoperable (WHO group 4) or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy; their mean age was 59 years, and about 61%-68% were female. At 16 weeks, the change in the 6-minute walk test from baseline improved by a mean of 39 m among those treated with riociguat but dropped by a mean of 6 m among those on placebo. WHO functional class improved in 33% of those on riociguat, compared with 15% of those on placebo, and deteriorated in 5% of those on riociguat and in 7% of those on placebo.

In both studies, there were statistically significant improvements in secondary clinically relevant endpoints.

In a pooled safety analysis of the two studies, the rates of adverse outcomes and serious adverse outcomes were similar in patients on the drug and those on placebo. The most common adverse events associated with treatment were headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting, according to Bayer.

Hypotension was higher among those on riociguat (10% vs 3.7%), with most cases mild to moderate. There were a few cases of hemoptysis in riociguat-treated patients (five cases in the two studies), which is included in the warning in the company’s proposed label.

The panel agreed that the effectiveness of the drug in the two studies was an adequate basis for approval of the two indications. Dr. Stuart Rich, professor of medicine at the University of Chicago, cautioned about the possible misuse of the drug in patients with CTEPH who could benefit from surgery and said that there should be measures in place to ensure that the drug is used to treat only those patients with CTEPH who are truly inoperable.

The panel members were not overly concerned about the effects of systemic vasodilation of the drug, although, once used in the general population outside of a controlled clinical trial, risks could increase in some patients, they pointed out.

Dr. Rich, an attending physician in the center for pulmonary hypertension at the University of Chicago Hospitals, said that there should be a strong warning pointing out that riociguat should never be used with inhaled nitric oxide, sublingual nitroglycerin, or a phosphodiesterase-5 (PDE- 5) inhibitor. His biggest concern is that it will be marketed as a new drug. "Physicians may not think that the mechanism [of riociguat] has similarities to the nitric oxide pathway, which in fact it really does," he said. Therefore, it is important that prescribers understand that, if those drugs were combined, they would be giving patients "a whopping dose of nitric oxide."

The FDA agreed with the company’s conclusions regarding the clinical trial results and supported the approval of the drug. The FDA review, however, raised the issue of hypotension associated with the higher dose and recommended capping the dose at 1.5 mg three times a day since the higher dose did not appear to add an incremental benefit, Dr. Preston Dunmon, a medical officer in the FDA’s division of cardiovascular and renal drug products, told the panel. But panelists said that there should be a broad range of doses to choose from and that the 2.5 mg t.i.d. dose should be available.

Currently, there is no drug approved for treating CTEPH. Bosentan (Tracleer), an endothelin receptor antagonist, and sildenafil (Revatio), a PDE-5 inhbitor, are approved for PAH (WHO Group 1). The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts before the meeting.

If approved, Bayer plans to market the drug as Adempas.

The results of the two studies were published in the July 25 issue of the New England Journal of Medicine (PATENT-1 [369:330-40]; CHEST-1 [369:319-29]).

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended that riociguat, an orally administered potent vasodilator, should be approved for treating patients with pulmonary arterial hypertension (World Health Organization Group 1) and with chronic thromboembolic pulmonary hypertension (WHO Group 4), based on two phase-III international studies that found the drug was associated with significant improvements in the 6-minute walk test in these two groups of pulmonary hypertension patients.

At a meeting on August 6, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 11-0 that riociguat, the first in a new class of drugs, should be approved for these two groups of patients. The manufacturer, Bayer HealthCare Pharmaceuticals, has proposed that the drug be approved to improve exercise capacity, improve WHO functional class, delay clinical worsening in patients with PAH (WHO Group 1), and to improve exercise capacity and WHO functional class in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or with persistent or recurrent CTEPH after surgical treatment.

Riociguat is a soluble guanylate cyclase (sGC) stimulator and, if approved, it will be first treatment approved for CTEPH. The drug affects both pulmonary and systemic vascular resistance in pulmonary hypertension, which is associated with impaired synthesis of nitric oxide and insufficient stimulation of the nitric-oxide-sGC-cGMP pathway. Riociguat stimulates sGc, independent of nitric oxide, increasing the sensitivity of sGC to nitric oxide, according to Bayer.

The company presented the results of two double-blind, international studies, which randomized patients to riociguat or placebo, titrated from 0.5 mg to 2.5 mg three times a day, using the same endpoints and dosing titration strategy.

PATENT-1 (Pulmonary Arterial Hypertension sGC-stimulator Trial) compared riociguat with placebo in 380 mostly female patients (mean age, 51 years) with PAH. At 12 weeks, the change in the 6-minute walk test from baseline improved by a mean of 30 m among those treated with riociguat but dropped by a mean of 6 m in the placebo group. WHO functional class improved in 21% of those on riociguat, compared with 14% of those on placebo, and deteriorated in 4% of those on riociguat and 14% of those on placebo.

CHEST (Chronic Thomboembolic Pulmonary Hypertension sGC-Stimulator Trial) enrolled 261 patients with inoperable (WHO group 4) or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy; their mean age was 59 years, and about 61%-68% were female. At 16 weeks, the change in the 6-minute walk test from baseline improved by a mean of 39 m among those treated with riociguat but dropped by a mean of 6 m among those on placebo. WHO functional class improved in 33% of those on riociguat, compared with 15% of those on placebo, and deteriorated in 5% of those on riociguat and in 7% of those on placebo.

In both studies, there were statistically significant improvements in secondary clinically relevant endpoints.

In a pooled safety analysis of the two studies, the rates of adverse outcomes and serious adverse outcomes were similar in patients on the drug and those on placebo. The most common adverse events associated with treatment were headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting, according to Bayer.

Hypotension was higher among those on riociguat (10% vs 3.7%), with most cases mild to moderate. There were a few cases of hemoptysis in riociguat-treated patients (five cases in the two studies), which is included in the warning in the company’s proposed label.

The panel agreed that the effectiveness of the drug in the two studies was an adequate basis for approval of the two indications. Dr. Stuart Rich, professor of medicine at the University of Chicago, cautioned about the possible misuse of the drug in patients with CTEPH who could benefit from surgery and said that there should be measures in place to ensure that the drug is used to treat only those patients with CTEPH who are truly inoperable.

The panel members were not overly concerned about the effects of systemic vasodilation of the drug, although, once used in the general population outside of a controlled clinical trial, risks could increase in some patients, they pointed out.

Dr. Rich, an attending physician in the center for pulmonary hypertension at the University of Chicago Hospitals, said that there should be a strong warning pointing out that riociguat should never be used with inhaled nitric oxide, sublingual nitroglycerin, or a phosphodiesterase-5 (PDE- 5) inhibitor. His biggest concern is that it will be marketed as a new drug. "Physicians may not think that the mechanism [of riociguat] has similarities to the nitric oxide pathway, which in fact it really does," he said. Therefore, it is important that prescribers understand that, if those drugs were combined, they would be giving patients "a whopping dose of nitric oxide."

The FDA agreed with the company’s conclusions regarding the clinical trial results and supported the approval of the drug. The FDA review, however, raised the issue of hypotension associated with the higher dose and recommended capping the dose at 1.5 mg three times a day since the higher dose did not appear to add an incremental benefit, Dr. Preston Dunmon, a medical officer in the FDA’s division of cardiovascular and renal drug products, told the panel. But panelists said that there should be a broad range of doses to choose from and that the 2.5 mg t.i.d. dose should be available.

Currently, there is no drug approved for treating CTEPH. Bosentan (Tracleer), an endothelin receptor antagonist, and sildenafil (Revatio), a PDE-5 inhbitor, are approved for PAH (WHO Group 1). The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts before the meeting.

If approved, Bayer plans to market the drug as Adempas.

The results of the two studies were published in the July 25 issue of the New England Journal of Medicine (PATENT-1 [369:330-40]; CHEST-1 [369:319-29]).

[email protected]