Actelion receives US FDA approval of Uptravi (selexipag) for the treatment of pulmonary arterial hypertension

Actelion has announced that the United States Food and Drug Administration (FDA) has approved the use of the orally active, selective IP prostacyclin receptor agonist Uptravi (selexipag),originally discovered and synthesized by Nippon Shinyaku, for the treatment of pulmonary arterial hypertension (PAH).

Uptravi is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%).

Vallerie McLaughlin MD, Director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan, United States, commented: "The prostacyclin pathway has long been recognized as a key target in PAH treatment. However, until now, it has been underutilized. This is in part due to the significant burden existing prostanoid treatments have placed on the patients and on those supporting them. The approval of Uptravi with its convincing long-term outcome results means that many more patients can benefit from this pathway and be treated much earlier in the course of their disease."

Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, commented: "Today's FDA approval of Uptravi is another major landmark for Actelion. Together with our partners at Nippon Shinyaku we are proud to be able to offer an outstanding oral therapy targeting the prostacyclin pathway. The label for Uptravi recognizes the improvement in long-term outcomes, including reducing the risk of hospitalization for PAH regardless of whether patients received background therapy including an ERA, a PDE-5 inhibitor, or - for the first time ever in PAH - on top of a combination of both, an ERA and a PDE-5 inhibitor."

Jean-Paul Clozel concluded: "Uptravi will significantly expand the options to delay disease progression after initiation of therapy with a baseline treatment like Opsumit and well ahead of Veletri for the late disease stage. Actelion now has an unparalleled portfolio of treatments across the continuum of care in PAH that offer a combination of long term-efficacy, safety and convenience."

The safety of Uptravi has been evaluated in a long-term, placebo-controlled study enrolling 1,156 patients with symptomatic PAH (GRIPHON study). The exposure to Uptravi in this trial was up to 4.2 years with median duration of exposure of 1.4 years.

Adverse reactions occurring more frequently on Uptravi compared to placebo - greater than or equal to 3% - over the course of the study, were headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, arthralgia, anemia, decreased appetite and rash. These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on Uptravi and in none of the patients on placebo.

Actelion expects Uptravi to become available to patients in the United States in early January 2016. Outside of the United States, Actelion continues to work with health authorities to obtain regulatory approval for Uptravi.

About the GRIPHON Study Data

The Uptravi approval was based in part on data from the long-term, global, Phase III GRIPHON 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. After titrating to the 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.