Bayer’s riociguat meets primary endpoint in phase III study in patients with pulmonary arterial hypertension


Bayer HealthCare announced positive data for riociguat from the pivotal phase III study PATENT-1. The study met its primary endpoint by demonstrating a statistically significant improvement in the six-minute walk test (6MWT), a predictor of improved outcome in patients suffering from pulmonary arterial hypertension (PAH).  

In the PATENT-1 study, 443 patients with symptomatic PAH were randomised and treated with either placebo or two different doses of riociguat orally over a period of 12 weeks. Riociguat was titrated, over a period of eight weeks, in 0.5mg increments from 1.0mg up to 2.5mg three times daily, or up to 1.5mg in an exploratory arm. After the titration phase, patients were followed up for an additional four weeks to the completion of the study. Patients treated with riociguat showed an improvement of 36 meters (95%-CI [20-52 meters] p<0.0001) from baseline after 12 weeks compared with placebo.The data was presented on 23 October 2012, in the late-breaking abstracts session at CHEST 2012, the annual meeting of the American College of Chest Physicians (ACCP) in Atlanta, USA.

Additionally, statistically significant improvements were observed across secondary endpoints, including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-pro BNP), WHO functional class (FC), time to clinical worsening (TTCW) and Borg dyspnea score. A positive trend was observed in European quality of life 5-dimensions questionnaire (EQ-5D) and living with pulmonary hypertension questionnaire (LPH).

The study also showed that riociguat was well tolerated with a good safety profile as monotherapy or in combination with ERAs or non-iv prostanoid monotherapy in patients with PAH. The most frequent treatment emergent adverse events with riociguat were headache, dizziness, peripheral edema, and gastrointestinal symptoms such as dyspepsia and nausea.

“The six-minute walk test is a key indicator for improved outcomes in patients with PAH and, therefore, the positive results of the PATENT-1 trial are encouraging,” said Ardeschir Ghofrani, University Hospital Giessen and Marburg, Germany, and principal investigator of the PATENT study. “The improvements were not limited to treatment naive patients receiving riociguat monotherapy, but were also statistically significant for those who received combination treatment with an endothelin receptor antagonist or a non-iv prostanoid.”

“We are optimistic about the potential of riociguat to add a much needed treatment option for PAH,” said Kemal Malik, member of the Bayer HealthCare Executive Committee and Head of Global Development. “We look forward to working closely with regulatory authorities and healthcare professionals and plan to submit this novel treatment for marketing authorisation during the first half of 2013.”

Riociguat is the first of a novel class of compounds, the stimulators of soluble guanylate cyclase (sGC). Riociguat restores  the NO-sGC-cGMP (nitric oxide–sGC-cyclic guanosine monophosphate) pathway and leads to increased generation of cGMP, which plays an important role in regulating vascular tone, proliferation, fibrosis, and inflammation. The ability of riociguat to directly stimulate sGC independent of NO while also increasing the sensitivity of sGC to NO is potentially important in PH. Endothelial dysfunction associated with PH can be related to low levels of NO.

“As PAH is associated with endothelial dysfunction, decreased NO levels and impaired sGC activity, this result with riociguat is a real step forward and gives us hope for a much-needed new treatment option for this serious and deadly disease,” said Ghofrani.