April 08, 2014

Novel oral therapy for PH

Dr. Michael Scharf is a Clinical Associate Professor of Medicine in Thomas Jefferson University's Division of Pulmonary and Critical Care Medicine where he serves as the Director of the Pulmonary Vascular Disease Program.

Soluble guanylate cyclase stimulator: A novel oral treatment for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Pulmonary vascular obstruction is the common feature in both pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).  Despite currently available therapies, including phosphodiesterase-5 inhibitors, prostanoids, and endothelin-receptor blockers, the annual mortality of patients with PAH approximates 15%.  For patients with CTEPH, thromboendarterectomy may be curative, though requires hard-to-find surgical expertise.  No approved medical therapy for chronic thromboembolic pulmonary hypertension exists.  Recently, a medication which acts on the pulmonary vasculature via a novel pathway has drawn much interest.  Soluble guanylate cyclase stimulators, e.g. Riociguat, stimulate pulmonary vascular dilation by enhancing the nitric oxide–cGMP pathway more so than phosphodiesterase-5 inhibitors or inhaled NO alone.

In the July 25, 2013 issue of The New England Journal of Medicine, Ghofrani et al. assesses riociguat, a soluble guanylate cyclase stimulator, as oral therapy for PAH and CTEPH: Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1) and Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase– Stimulator Trial 1 (CHEST-1).

In PATENT-1, riociguat was assessed in patients with PAH, both treatment-naïve and those who received endothelin- receptor antagonists or non-parenteral prostanoids.  The 6-minute walk distance at 16 weeks increased by 36 meters with riociguat vs. placebo.  Riociguat also decreased pulmonary vascular resistance,  NT-proBNP levels and improved functional class. The benefits of riociguat therapy persisted at 24 weeks and did not result in significantly greater frequencies of serious adverse events or study discontinuations.

In CHEST-1, riociguat was assessed in patients with CTEPH, both treatment-naïve and those who received endothelin- receptor antagonists or non-parenteral prostanoids, considered unsuitable surgical candidates or whom had persistent pulmonary hypertension after pulmonary endarterectomy.  The 6-minute walk distance at 16 weeks increased by46 meters in the riociguat group vs. placebo.  Riociguat also decreased pulmonary vascular resistance, NT-proBNP levels and improved functional class.

At the time of the writing of this blog, The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 11-0 to recommend approval of riociguat to treat patients with PAH and CTEPH.  Riociguat appears to be a safe and promising addition to the medical therapies for PAH and potentially, the first effective oral therapy for inoperable CTEPH.

 

Jefferson