Actelion submits US FDA New Drug Application for selexipag (Uptravi) in patients with pulmonary arterial hypertension - Seite 2

In PAH, survival rates are unacceptably low and PAH remains incurable.

THE ROLE OF THE PROSTACYCLIN PATHWAY

The prostacyclin pathway is one of the 3 essential pathways involved in the pathophysiology and treatment of PAH. Prostacyclin is a prostanoid and serves as a signaling molecule in the human body. It is produced, like other vasoactive substances, by endothelial cells. Prostacyclin induces vasodilation, is anti-proliferative, has anti-inflammatory effects and inhibits platelet aggregation. In certain disease conditions, the production of prostacyclin by the endothelium is impaired, allowing for example, the deleterious effects of excessive levels of endothelin to predominate.

ABOUT SELEXIPAG

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective IP prostacyclin receptor agonist.

Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP₁ and EP₃ receptors. [1,2,3]

Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [4]

REGULATORY STATUS OF SELEXIPAG

Submission of a centralized Marketing Authorisation Application (MAA) was made to the European Medicines Agency (EMA) for selexipag (Uptravi®) in the treatment of pulmonary arterial hypertension in December 2014. The application is now pending validation. Regulatory review is also ongoing in New Zealand.

ABOUT GRIPHON

GRIPHON, (Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial HypertensiON) was a randomized, multicenter, double-blind, placebo-controlled trial evaluating the long term efficacy and safety of oral selexipag in patients with pulmonary arterial hypertension.

The GRIPHON study was the largest outcome trial ever conducted in PAH, enrolling patients in 181 centers from 39 countries in North and Latin America, Europe, Asia-Pacific and Africa.

GRIPHON enrollment was completed in May 2013 with 1,156 patients and represents the largest randomized, controlled study in PAH patients. Patients received twice daily administration of selexipag or placebo and were also permitted to receive background therapy of endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor when on a stable dose for at least 3 months prior to enrollment. At baseline, 80% of patients were receiving oral medication specific for PAH: either an ERA, a PDE-5 inhibitor, or a combination of the two.