Actelion Pharmaceuticals, Ltd., recently announced that the selective IP receptor agonist Uptravi (selexipag) has been granted Notice of Compliance (NOC) approval by Health Canada for the treatment of pulmonary arterial hypertension (PAH).
Uptravi (selexipag) was originally discovered and synthesized by Nippon Shinyaku as an oral, prostacyclin receptor agonist formulated as a tablet. Uptravi selectively targets the prostacyclin receptor (also known as the IP receptor), one of five major types of prostanoid receptors (FP, TP, DP, EP and IP). Prostacyclin activates the IP receptor to induce vasodilation and inhibit proliferation of vascular smooth muscle cells.
Uptravi proved its efficacy in combination with an endothelin receptor antagonist (ERA), a phosphodiesterase-5 (PDE-5) inhibitor, in triple combination with an ERA and a PDE-5 inhibitor, and also as a monotherapy. Uptravi is indicated for the long-term treatment of PAH associated with congenital heart disease or with connective tissue disorders, heritable pulmonary arterial hypertension (HPAH), idiopathic pulmonary arterial hypertension (iPAH), and in adult patients with WHO functional class 2-3 to delay disease progression, including the initiation of prostanoids, decreases in the six-minute walk distance (6MWD; a test of exercise capacity), and PAH-related hospitalizations.
The Phase III GRIPHON study assessed the safety of selexipag in a placebo-controlled trial with 1,156 participants with symptomatic PAH. The study dosing began at 200 mcg twice-a-day and increased weekly in steps of 200 mcg, up to a maximum of 1600 mcg or to the individual’s highest tolerated dose. The benefit was consistent across the pre-specified low (200 to 400 mcg), medium (600, 800 and 1,000 mcg), and high (1,200, 1,400 and 1,600 mcg) dose groups.
Treatment continued up to 4.2 years, with an average of 76.4 weeks for patients receiving selexipag versus 71.2 weeks for patients on placebo. The study, in which over 80 percent of participants already had received PAH-specific therapies, showed that the risk of mortality or morbidity events was reduced by 40 percent with selexipag when compared to placebo. The most common adverse reactions reported were arthralgia, extremity pain, myalgia, jaw pain, nausea and vomiting, diarrhea and headaches — reactions that were more frequent during the dose titration phase, with mild to moderate intensities. Titrating selexipag to an individualized maintenance dose based on tolerability was effective in achieving long-term outcome benefits across the dose range.
“This approval represents a major milestone: the approval of a new oral medication that effectively targets the prostacyclin pathway. Uptravi is supported by robust long-term outcome results in combination with an ERA, or a PDE-5 inhibitor, and, for the first time in PAH, in triple combination with both an ERA and a PDE-5 inhibitor. We are now working diligently to make Uptravi available to patients in Canada as soon as possible, since we know how eagerly anticipated it is,” Dr. Jean-Paul Clozel, Actelion’s CEO, said in a company press release.