Actelion has announced that Health Canada has granted a Notice of Compliance (NOC) approving the orally active, selective IP prostacyclin receptor agonist Uptravi (selexipag),originally discovered and synthesized by Nippon Shinyaku, for the treatment of pulmonary arterial hypertension.
Uptravi® is indicated for the long-term treatment of idiopathic pulmonary arterial hypertension (iPAH), heritable pulmonary arterial hypertension (HPAH), PAH associated with connective tissue disorders and PAH associated with congenital heart disease, in adult patients with WHO functional class (FC) II-III to delay disease progression. Disease progression included hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance [6MWD] associated with either worsened PAH symptoms or need for additional PAH-specific treatment). Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.
Jean-Paul Clozel, MD and Chief Executive Officer of Actelion commented: "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."
The safety of selexipag has been evaluated in a long-term, Phase III placebo-controlled study enrolling 1,156 patients with symptomatic PAH. The mean treatment duration was 76.4 weeks (median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median 63.7 weeks) for patients on placebo. The exposure to selexipag was up to 4.2 years.
The most commonly reported adverse drug reactions related to the pharmacological effects of Uptravi are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in the extremity, flushing, and arthralgia. These reactions are more frequent during the dose titration phase. The majority of these reactions are of mild to moderate intensity.
About The GRIPHON Study Data
GRIPHON was a long-term, global Phase III study in 1,156 patients treated for up to 4.2 years. The GRIPHON study, in which more than 80% of patients were already receiving PAH-specific therapies, showed that the risk of the primary composite endpoint was reduced by 40% (p<0.0001) with selexipag compared to placebo.
The benefit of selexipag was consistent across pre-specified patient subgroups such as disease etiology, functional class and baseline PAH therapy, including patients already receiving combination therapy with an ERA and a PDE-5 inhibitor.
Titrating selexipag to an individualized maintenance dose based on tolerability was effective in achieving long-term outcome benefits across the tested dose range. The dosing in GRIPHON was initiated at 200 micrograms (mcg) twice daily (b.i.d.) and increased weekly in steps of 200 mcg up to a maximum of 1600 mcg b.i.d. or to the patient's individual highest tolerated dose. The benefit was consistent across the pre-specified low (200, 400 mcg b.i.d.), medium (600, 800, 1'000 mcg b.i.d.) and high maintenance (1'200, 1'400, 1'600 mcg b.i.d.) dose groups.