PATENT and CHEST Studies Support Bayer's Riociguat to Treat Pulmonary Hypertension

August 15, 2013—In the New England Journal of Medicine (NEJM), two studies have been published that support the use of the investigational drug riociguat (Bayer AG,  Leverkusen, Germany), a soluble guanylate cyclase stimulator, for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

As reported on August 6 in Cardiac Interventions Today, Bayer announced that the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration has recommended approval for riociguat (proposed trade name: Adempas) to treat PAH and CTEPH.

In the PAH study in NEJM, Hossein-Ardeschir Ghofrani, MD, et al, for the PATENT-1 study group, reported on symptomatic PAH patients who were treated with various doses of riociguat versus a placebo (2013;369:330–340). The background of the study is that riociguat has been shown in a phase 2 trial to be beneficial in treating PAH, the investigators noted.

As summarized in NEJM, the phase 3, double-blind PATENT-1 study randomly assigned 443 patients with symptomatic PAH to receive a placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg maximum), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg maximum). The 1.5-mg group was included for exploratory purposes, and the data from that group were analyzed descriptively. Eligible patients were those receiving no other treatment for PAH and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids.

The primary endpoint was the change in the 6-minute walking distance from baseline to the end of week 12. Secondary endpoints included change in pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety.

The PATENT-1 investigators reported that by week 12, the 6-minute walking distance had increased by a mean of 30 m in the 2.5-mg group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval [CI], 20–52; P < .001).

Prespecified subgroup analyses showed that riociguat improved the 6-minute walking distance in both patients who had not received other treatment for the disease and in those who had been on endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P < .001), NT-proBNP levels (P < .001), WHO functional class (P = .003), time to clinical worsening (P = .005), and Borg dyspnea score (P = .002). The most common serious adverse event in the placebo group and the 2.5-mg group was syncope (4% and 1%, respectively).

The PATENT-1 investigators concluded that riociguat significantly improved exercise capacity and secondary efficacy endpoints in patients with PAH. Patients who have completed the 12 weeks of treatment in the PATENT-1 trial will be asked to participate in PATENT-2, the long-term extension study with riociguat. The PATENT-1 and PATENT-2 studies are funded by Bayer, advised the investigators.

In the CTEPH study in NEJM, Dr. Ghofrani et al for the CHEST-1 study group evaluated riociguat versus placebo in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (2013;369:319–329). Riociguat has been shown in previous clinical studies to be beneficial in the treatment CTEPH, noted the investigators in the background to the study.

As summarized in NEJM, CHEST-1 is a phase 3, multicenter, randomized, double-blind, placebo-controlled study. The CHEST-1 investigators randomly assigned 261 patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary endpoint was the change in the 6-minute walking distance from baseline to the end of week 16. Secondary endpoints included changes from baseline in pulmonary vascular resistance, NT-proBNP level, WHO functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.

The CHEST-1 investigators reported that by week 16, the 6-minute walking distance had increased by a mean of 39 m in the riociguat group compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% CI, 25–67; P < .001). Pulmonary vascular resistance decreased by 226 dyn/s/cm-5 in the riociguat group and increased by 23 dyn/s/cm-5 in the placebo group (least-squares mean difference, -246 dyn/s/cm-5; 95% CI, -303 to -190; P < .001). Riociguat was also associated with significant improvements in the NT-proBNP level (P < .001) and WHO functional class (P = .003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and 3% of the placebo group).

Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with CTEPH, concluded the CHEST-1 investigators in NEJM.

Patients who have completed 16 weeks of treatment in the CHEST-1 trial will be asked to participate in CHEST-2, the long-term extension study with riociguat. CHEST-1 and CHEST-2 are also funded by Bayer.