EC grants marketing authorization for Actelion’s Uptravi to treat pulmonary arterial hypertension

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II-III, either as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients who are not candidates for these therapies.

Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease.

The EU label for Uptravi (originally discovered and synthesized by Nippon Shinyaku) was based in part on the Phase III GRIPHON study, whose main findings were published in the New England Journal of Medicine in December 2015. This placebo-controlled study, the largest ever in PAH, established the effectiveness, safety and tolerability of Uptravi in PAH patients with WHO Functional Class II-III.

In GRIPHON, the risk of a primary composite endpoint event, of complication related to PAH or death from any cause, up to the end of the treatment period, was reduced by 40% (p<0.001) with selexipag compared to placebo. The treatment effect was driven by hospitalization and disease progression, which accounted for 81.9% of the primary endpoint events.

The benefit of selexipag was consistent across pre-specified patient subgroups such as PAH classification, WHO functional class and use of medication for PAH, which included patients receiving an ERA and a PDE-5 inhibitor at baseline (n = 376; 32.5%).

Professor Sean Gaine, Consultant Respiratory Physician at Mater Misericordiae Hospital Dublin, commented: "For many years we have known that the prostacyclin pathway can be key in treating PAH – yet due to the route of administration of the existing therapies being so burdensome, the pathway has been largely underused, with only about 20% of patients ever receiving a prostacyclin at some point during their PAH treatment. Uptravi, as an innovative oral treatment that is supported by long-term outcome results, now allows us to offer combination therapy regimens that target all three established treatment pathways."

Professor Nazzareno Galiè, Head of the Pulmonary Hypertension Center at the Institute of Cardiology, University of Bologna, added: "The approval of Uptravi is very positive news for the PAH community in Europe. With Uptravi, for the first time ever, we see a significant clinical benefit in combination with one and even two drugs targeting other treatment pathways. Together with its favorable tolerability profile, this makes Uptravi a treatment option that could truly change PAH care, for many patients."

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion, commented: "Actelion has a comprehensive portfolio of treatments across the continuum of care in PAH that provide long-term outcome benefits. We are very pleased with today’s approval of Uptravi by the European Commission as it enables us to offer this outstanding oral medication, which provides long-term outcome benefits even for patients receiving background therapy, to PAH patients in Europe. We will now do our best to make Uptravi available to patients in the European Union as soon as possible."

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 reactions related to the pharmacological effects of Uptravi are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during the up-titration phase. The majority of these reactions are of mild to moderate intensity.

The company will now work diligently to make Uptravi available throughout the European Union as soon as possible and start with the market introduction in Germany in the near future. In France, a cohort ATU for Uptravi has been approved, which has commenced for patients insufficiently controlled on an ERA/PDE-5 inhibitor combination therapy.