GlaxoSmithKline (GSK) said the European Commission has issued marketing authorisation for Volibris (ambrisentan) for the treatment of Pulmonary Arterial Hypertension (PAH) in patients classified as World Health Organisation (WHO) Functional Class II and III, to improve exercise capacity. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
Ambrisentan is the first non-sulphonamide class endothelin receptor antagonist (ERA) and the first PAH medicine approved for WHO Functional Class II patients in Europe.
"Ambrisentan represents a development in the treatment of patients with PAH," said Professor Nazzareno Galiè, Professor of Cardiology and Head of the Pulmonary Hypertension Centre at the University of Bologna. "It has demonstrated efficacy and safety in both Functional Class II and III patients. New treatments like this are important and make incremental improvements to patients' quality of life."
Combined analysis of two pivotal phase III clinical trials (ARIES-1 and ARIES-2) demonstrated that treatment with ambrisentan resulted in significant improvements in exercise capacity (six minute walk distance (6MWD)), and beneficial changes in other parameters, such as time to clinical worsening, WHO Functional Class, the Borg Dyspnoea Index†, SF-36 Health Survey and B-type natriuretic peptide. Patients in these studies continued ambrisentan treatment in a long-term extension study (ARIES-E). At one year of treatment, 95 per cent of patients who received ambrisentan were still alive and 84 per cent were still alive at two years. Ninety-three per cent of patients were maintained on ambrisentan monotherapy at one year.
Ambrisentan's profile means it is associated with a low potential to affect the metabolism of other medicines. It has no significant drug-drug interactions with sildenafil or warfarin. It also has a low incidence of liver function test (LFT) abnormalities. There was no incidence of LFT abnormalities (>3 times the upper limit of normal) with patients taking ambrisentan in the two 12-week Phase III studies (ARIES-1 and ARIES-2). In patients receiving ambrisentan long-term (mean exposure of 79.5 weeks), the event rate of LFT abnormalities (>3 times the upper limit of normal) was 2.3 events per 100 patient years of exposure to ambrisentan.
In phase III clinical trials the most common adverse events during therapy with ambrisentan included peripheral oedema, nasal congestion and headache. The most common adverse events were dose dependant. These adverse events are commonly seen with medicines that have a vasodilatory action.
"Ambrisentan's low risk of drug-drug interactions and low incidence of liver function test abnormalities offer important additional benefits to patients with PAH whose quality of life is already significantly compromised by this progressive life-threatening condition," said Professor Ardeschir Ghofrani, Head of the Pulmonary Hypertension Division, University Hospital Giessen, Germany.
Ambrisentan offers the convenience of a once-daily oral tablet in two doses, 5mg and 10mg. The first European launches are planned for the summer of 2008 and negotiations are ongoing with individual markets.
Marketing authorisation was granted after the European Commission reviewed data including two pivotal phase III randomised, double-blind, placebo-controlled, 12-week clinical trials (ARIES-1 and ARIES-2) involving a total of 393 patients. The trials evaluated the efficacy and safety of a once daily dose of either 5mg (N=130) and 10mg (N=67) doses (and in addition a 2.5mg dose which is not licensed in Europe).
An increase in the 6MWD was observed after four weeks of treatment with each dose regimen of ambrisentan, with a dose-response observed after 12 weeks of treatment. In ARIES-1, a placebo-adjusted mean change from baseline of 31 metres (p=0.008) was observed for the 5mg dose. A placebo-adjusted mean change from baseline of 51 metres (p<0.001) was observed for the 10mg dose.2 In ARIES-2, a placebo-adjusted mean change from baseline of 59 metres (p<0.001) was observed for the 5mg dose.
The incidence of LFT abnormalities (aminotransferase elevations >3 times the upper limit of normal) seen with ambrisentan over 12 weeks was similar to that seen in the placebo arm. In patients receiving ambrisentan long term (mean exposure of 79.5 weeks) the event rate of LFT abnormalities (>3 times the upper limit of normal) was 2.3 events per 100 patient years of exposure to ambrisentan. A low incidence of transaminase abnormalities (>3 times the upper limit of normal) was observed in a separate study which evaluated patients treated with ambrisentan who had previously discontinued sulphonamide class ERAs due to LFT abnormalities (N=36; mean exposure 52 weeks).
Volibris is a trademark of Gilead Sciences, Inc., used under license by the GlaxoSmithKline group of companies. Ambrisentan has been licensed to GlaxoSmithKline by Gilead for all countries of the world, except the United States (US). Ambrisentan was approved by the US Food and Drug Administration and launched in the US by Gilead in June 2007 under the trade name Letairis.