July 25th, 2013

Novel Pulmonary Hypertension Drug Shows Modest Promise in Phase 3 Trials

A new drug appears to have promising — but not game-changing — effects in people with two forms of pulmonary hypertension. Riociguat, a soluble guanylate cyclase stimulator under development by Bayer, is thought to have vasodilating, antiproliferative, and antifibrotic effects.

Results of two phase 3, placebo-controlled trials were published today in the New England Journal of Medicine. CHEST-1 studied the clinical impact of riociguat in 261 patients with chronic thromboembolic pulmonary hypertension; PATENT-1 studied the the drug in 443 patients with pulmonary arterial hypertension.

Both forms of pulmonary hypertension are characterized by blockage of the pulmonary vasculature. Patients with pulmonary hypertension are at high risk for right ventricular failure and death. Even though there are now several approved therapies for pulmonary arterial hypertension, the yearly mortality rate remains high, at about 15%. No drugs are approved for chronic thromboembolic pulmonary hypertension, though a surgical procedure, pulmonary endarterectomy, can cure the disease when it is successful. However, pulmonary endarterectomy is a difficult procedure that should only be performed at a very few centers with experience performing the procedure.

In CHEST-1, the primary endpoint of the study, the distance walked in 6 minutes after 16 weeks of treatment, increased by 39 m in the riociguat group, compared with a 6-m decrease in the placebo group (mean difference 46 m, CI 25-67, p<0.001). The investigators also reported that pulmonary vascular resistance decreased in the riociguat group and increased in the placebo group. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and WHO functional class also improved in the riociguat group. Right ventricular failure occurred in 3% of patients in each group; syncope occurred in 2% of the riociguat group and 3% of the placebo group.

In PATENT-1, the primary endpoint of the study, the distance walked in 6 minutes at 12 weeks, increased by 30 m in the highest-dose riociguat group, compared with a 6-m decrease in the placebo group (mean difference 36 m, CI 20-52, p<0.001). Riociguat was equally effective in patients taking no other therapy and in those taking other drugs. Riociguat was also associated with improvements in pulmonary vascular resistance, NT-proBNP levels, WHO functional class, time to clinical worsening, and Borg dyspnea score. Syncope occurred in 4% of the placebo group versus 1% of the riociguat group.

Exploratory analyses of long-term extension studies– CHEST-2 and PATENT-2– suggested that the increase in walking time associated with riociguat may continue to grow after the initial 12 and 16 weeks of the original trials.

In an an accompanying editorial,  Stephen Archer gave a cautious endorsement of riociguat, but noted that the increase in walking distance was modest in both trials. In PATENT-1, the improvement found with riociguat just reached the mark for the smallest beneficial change justifying a change in treatment. The improvement in CHEST-1 was somewhat greater, Archer said, but the expected benefits associated with pulmonary endarterectomy are considerably larger, resulting in a 100-m increase in walking distance instead of the 46-m increase associated with riociguat. He recommended that suitable surgical candidates “should continue to undergo surgery and not be relegated to an inferior treatment.”

Archer concluded:

…the glass may be seen to be half empty because of the modest improvement in 6-minute walk distance with riociguat. However, I view the glass as half full, because riociguat appears to be safe and is a promising addition to the pharmacopeia for Group 1 pulmonary hypertension and potentially the first effective oral therapy for inoperable Group 4 pulmonary hypertension.

Archer discussed another important reason to remain cautious until riociguat undergoes FDA review:

The study was supported by Bayer HealthCare, and although the manuscript was drafted by the first author, editorial assistance was provided by a company supported by the sponsor (Adelphi Communications). In addition, although the authors had access to the complete database, the statistician was employed by Bayer HealthCare.

CardioExchange Associate Editor John Ryan has taken a closer look at the these two trials. Read his analysis and post your comments here.

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