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FDA Accepts New Drug Application for Selexipag (Uptravi) for Treatment of Pulmonary Arterial Hypertension

Approval decision expected in December

The FDA has accepted the new drug application (NDA) for selexipag (Uptravi, Actelion Ltd.) for the treatment of patients with pulmonary arterial hypertension (PAH). The NDA dossier was submitted in December 2014. Results from the review process are expected 12 months from the date of the NDA submission (i.e., in December 2015).

The FDA application for selexipag, the first selective oral prostacyclin receptor agonist, was based on positive findings from the pivotal GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial HypertensiON) trial. In this phase III, randomized, double-blind, placebo-controlled study, 1,156 patients with PAH were randomly assigned to receive twice-daily (BID) selexipag or placebo. The study was designed to demonstrate prolongation of the time to the first morbidity or mortality event for selexipag compared with placebo and to evaluate the safety of selexipag in patients with PAH.

Dosing was initiated at 200 mcg BID and was increased in steps of 200-mcg BID up to a maximum of 1,600 mcg BID. All of the patients had received background treatment with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase-5 (PDE-5) inhibitor for at least 3 months prior to enrollment. At baseline, 80% of the patients were receiving an oral medication specific for PAH: an ERA, a PDE-5 inhibitor, or a combination of the two.

Selexipag decreased the risk of a morbidity or mortality event by 40% compared with placebo (P < 0.0001). The drug’s efficacy was consistent across five key subgroups: age, gender, World Health Organization functional class, PAH etiology, and background PAH therapy. The patients were treated for up to 4.2 years. The tolerability profile of selexipag was consistent with that of prostacyclin therapies. Adverse events occurring more frequently (greater than 5%) with selexipag compared with placebo included headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in an extremity, and flushing.

The new findings will be presented March 15 at the 2015 American College of Cardiology Congress in San Diego, California.

Selexipag selectively targets the prostacyclin receptor (also called the IP receptor). The IP receptor is one of five types of prostanoid receptor. Prostacyclin activates the IP receptor, inducing vasodilation and inhibiting the proliferation of vascular smooth-muscle cells. Unlike prostacyclin analogs, selexipag specifically selects the IP receptor over other prostanoid receptors. In preclinical models, selective IP receptor agonism was shown to maintain efficacy and to reduce the risk of adverse effects mediated by the activation of other prostanoid receptors, such as EP1 and EP3 receptors.

Source: Actelion Ltd.; March 3, 2015.

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