GlaxoSmithKline (GSK) announced that 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.1 Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.1

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‡.2,3,4 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 percent were still alive at two years. Ninety-three percent of patients were maintained on ambrisentan monotherapy at one year.5

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.6,7 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).2,3,4 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.8

In Phase III clinical trials the most common adverse events during therapy with ambrisentan included peripheral oedema, nasal congestion and headache.4,5 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.

Ambrisentan data

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.2 A placebo-adjusted mean change from baseline of 51 metres (p3 times the upper limit of normal) was 2.3 events per 100 patient years of exposure to ambrisentan.8 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).9

VOLIBRIS is a trademark of Gilead Sciences, Inc. (Nasdaq: GILD), 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 (U.S.). Ambrisentan was approved by the U.S. Food and Drug Administration and launched in the U.S. by Gilead in June 2007 under the trade name Letairis®.

About Pulmonary Arterial Hypertension (PAH)

PAH is a rare and fatal disorder of the arteries in the lungs which also affects the heart. It afflicts approximately 200,000 patients worldwide10 and can occur at any age. Historically patients with PAH had an estimated median survival of 2.8 years,11 but, through improvements in diagnosis and treatment over the last 10 years, recent data suggest that survival rates are improving.12,13 The effect of ambrisentan on this outcome is unknown.8

PAH is a debilitating disease characterised by constriction of the blood vessels in the lungs which leads to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs. As the heart struggles to pump against these high pressures, patients become increasingly short of breath. Ultimately, heart failure is the cause of death for many patients. PAH can occur with no known underlying cause, or it can occur in association with other conditions such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection.

PAH has been classified by the WHO into four functional classes, depending on the severity of symptoms.14 WHO Class I patients are asymptomatic, with few patients realising they have the disease at this stage. The most severely ill Functional Class IV patients have debilitating symptoms even at rest.

About GlaxoSmithKline

GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies and is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For more information, visit GlaxoSmithKline at gsk.

References

Clinical worsening of PAH was pre-defined as death, hospitalisation for PAH, lung transplantation, atrial septostomy, or study withdrawal due to initiation of other PAH therapies or two or more early escape criteria.

The Borg Dyspnoea Index is a numerical scale for assessing perceived breathing discomfort.

B-type natriuretic peptide is a hormone secreted primarily from the cardiac ventricles and which has been proposed as a prognostic indicator of mortality in patients with PAH.

1. EMEA Press Office.

2. Oudiz R, Torres F, Frost A, et al. ARIES-1: A placebo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension. CHEST 2006;130:121S.

3. Oudiz RJ, Olschewski H, Galie N, et al. Ambrisentan improves exercise capacity and time to clinical worsening in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2006 A728.

4. Galie N. Ambrisentan therapy for pulmonary arterial hypertension: An integrated analysis of the ARIES-1 and ARIES-2 studies; ATS 2007, Poster 3192.

5. Data on File (Oudiz, ARIES-E, GSK Amb002).

6. Dufton C, Gerber MJ, Yin O, et al. No clinically relevant pharmacokinetic interactions between ambrisentan and sildenafil [abstract]. CHEST 2006;130(suppl 4):254S.

7. Gerber MJ, Dufton C, Pentikis H, et al. Ambrisentan has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of warfarin. CHEST 2006;130:256S.

8. Volibris Summary of Product Characteristics 21 April 2008

9. McGoon M, Frost A, Oudiz R, et al. Ambrisentan rescue therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxentan due to liver function abnormalities. CHEST 2006;130:254S.

10. NICE Health Technology Appraisal. Appendix A. January 2007.

11. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343-349.

12. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40(4):780-788.

13. Provencher S, Sitbon O, Humbert M, et al. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J 2006;27(5):589-595.

14. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S - 7S.

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