Riociguat showed benefit in patients with two forms of pulmonary hypertension

Riociguat, a novel soluble guanylate cyclase stimulator, improved exercise capacity and was associated with other benefits for patients with two forms of pulmonary hypertension in the CHEST-1 and PATENT-1 trials.

The investigational drug is being developed by Bayer HealthCare. Riociguat was formulated to counteract “impairment of nitric oxide synthesis and signaling through the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway,” according to background information in the study.

Riociguat was tested in two phase 3, international, multicenter, randomized, double blind, placebo-controlled trials. CHEST-1 tested the efficacy and adverse event profile of riociguat in patients with chronic thromboembolic pulmonary hypertension who were ineligible for pulmonary endarterectomy or for whom the procedure was ineffective (n=261). PATENT-1 evaluated the efficacy and adverse event profile of riociguat in symptomatic patients with pulmonary arterial hypertension (n=443). Some participants were receiving no other treatment, while some were also taking endothelin-receptor antagonists or nonintravenous prostanoids.

The primary endpoint in CHEST-1 was change in 6-minute walk distance over 16 weeks. The primary endpoint in PATENT-1 was change in 6-minute walk distance over 12 weeks. Secondary endpoints of both trials included changes in pulmonary vascular resistance and safety.

CHEST-1 participants were assigned riociguat — starting with a dose of 1 mg three times daily and then adjusted accordingly for each patient — or placebo. PATENT-1 participants were assigned riociguat in up to 2.5-mg doses three times daily, riociguat in up to 1.5-mg doses three times daily (this group was excluded from efficacy analysis) or placebo.

Improved walk distance

In the CHEST-1 trial, participants assigned riociguat improved their 6-minute walk distance by a mean of 39 m over 16 weeks, whereas those assigned placebo experienced a decrease in their 6-minute walk distance by a mean of 6 m (least-squares mean difference, 46 m; 95% CI, 25-67). The riociguat group showed a decrease in pulmonary vascular resistance of 226 dyne/s/cm^–5, whereas the placebo group showed an increase of 23 dyne/s/cm^–5 (least-squares mean difference, –246 dyne/s/cm^–5; 95% CI, –303 to –190). The drug was also associated with improvement in N-terminal pro–brain natriuretic peptide (NT-proBNP) level (P<.001) and WHO functional class (P=.003). The most common serious adverse events were right ventricular failure (3% in each group) and syncope (2% in the riociguat group, 3% in the placebo group), according to study results.

Hossein-Ardeschir Ghofrani

In the PATENT-1 trial, participants assigned a 2.5-mg maximum dose of riociguat improved their 6-minute walk distance by a mean of 30 m over 12 weeks, whereas those assigned placebo experienced a decrease in their 6-minute walk distance by a mean of 6 m (least-squares mean difference, 36 m; 95% CI, 20-52). Those assigned a 2.5-mg maximum dose of riociguat showed a decrease in pulmonary vascular resistance of 223 dyne/s/cm^–5, whereas the placebo group showed a decrease of 9 dyne/s/cm^–5 (least-squares mean difference, –226 dyne/s/cm^–5; 95% CI, –281 to –170). Riociguat also was associated with improvement in NT-proBNP level (P<.001) and WHO functional class (P=.003), as well as pulmonary vascular resistance (P<.001), time to clinical worsening (P=.005) and Borg dyspnea score (P=.002). The most common serious adverse events included syncope (1% in the 2.5-mg-maximum-dose group, 4% in the placebo group), worsening pulmonary hypertension (<1% in the 2.5-mg-maximum-dose group, 2% in the placebo group), chest pain (1% in both the 2.5-mg-maximum-dose group and the placebo group), and right ventricular failure (1% in both the 2.5-mg-maximum-dose group and the placebo group), according to the study results.

The next step could be studies in different patient populations, Hossein-Ardeschir Ghofrani, MD, of the University Hospital Giessen in Germany, and colleagues wrote. “Future studies with riociguat could address its usefulness in reducing preoperative hemodynamics and improving physical condition in patients who are eligible for pulmonary endarterectomy.”

Surgery vs. drug treatment

In a related editorial, Stephen L. Archer, MD, of the department of medicine, Queen’s University, Kingston, Ontario, Canada, said a limitation of the CHEST-1 and PATENT-1 trials is no demonstration of the effects of riociguat on the right ventricle. In addition, the CHEST-1 trial showed that the benefits of riociguat are not as good as the benefits of pulmonary endarterectomy.

Stephen L. Archer

“Patients who are suitable candidates for surgery should continue to undergo surgery and not be relegated to an inferior treatment,” he wrote. Furthermore, in PATENT-1, the riociguat group only modestly passed the minimal clinically important difference in 6-minute-walk distance, defined as 33 m in a previous study.

However, Archer said, the results have value despite the “modest improvement” in walk distance. “I view the glass as half full, because riociguat appears to be safe and is a promising addition to the pharmacopeia for … pulmonary [arterial] hypertension and potentially the first effective oral therapy for inoperable … [chronic thromboembolic] pulmonary hypertension,” he wrote.

For more information:

Archer SL. N Engl J Med. 2013;369:386-388.

Ghofrani HA. N Engl J Med. 2013;369:319-329.

Ghofrani HA. N Engl J Med. 2013;369:330-340.

Disclosure: The studies were funded by Bayer HealthCare. See the full studies for lists of the researchers’ relevant financial disclosures. Archer reports no relevant financial disclosures.