Not for distribution to US media

Issued – Thursday 21st February 2008, London, UK

GlaxoSmithKline (GSK) announced today that Volibris^® (ambrisentan) has received a positive opinion from the European Committee for Human Medicinal Products (CHMP) for the treatment of Pulmonary Arterial Hypertension (PAH) in patients classified as World Health Organisation (WHO) Functional Class II and III, to improve exercise capacity¹. Approval by the European Commission and Marketing Authorisation is expected to be granted by the end of April 2008.

Ambrisentan, a non-sulphonamide class endothelin receptor antagonist (ERA), is the first PAH medicine indicated for WHO Functional Class II patients in Europe.

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. As a non-sulphonamide class ERA, the inherent profile of ambrisentan may contribute to a lower risk of both drug-drug interactions^5,6 and liver function test (LFT) abnormalities^2,3,4. Ambrisentan will be available as a once-daily, oral tablet in two doses: 5mg and 10mg.

“Volibris represents a step forward in the treatment of patients with PAH, a progressive and life-threatening disease,” said Professor Nazzareno Galiè, Professor of Cardiology and Head of the Pulmonary Hypertension Centre at the University of Bologna. “Volibris has demonstrated efficacy in Class II and III patients, with a low risk of drug-drug interactions and low incidence of liver function test abnormalities. This is a clear benefit to patients. New treatments like this are important and make incremental improvements to patients’ quality of life.”

“This positive opinion for Volibris is excellent news for patients with PAH across Europe,” said Eddie Gray, President, Pharmaceuticals Europe, GSK. “It demonstrates GSK’s continued commitment to the development of medicines for the treatment of PAH.” GSK also markets Flolan which is indicated for more severe PAH patients.

Ambrisentan data

Positive opinion was reached after the CHMP 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 2.5mg, 5mg and 10mg ambrisentan in patients with PAH.

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 dose². A placebo-adjusted mean change from baseline of 51 metres (p<0.001) was observed for the 10mg dose². In ARIES-2, a placebo-adjusted mean change from baseline of 59 metres (p<0.001) was observed for the 5mg dose³.

Long-term follow-up of these patients is ongoing (ARIES-E) and to date 95 per cent of patients receiving ambrisentan were still alive at one year and 94 per cent of those patients were maintained on ambrisentan monotherapy⁷.

Ambrisentan was well-tolerated in Phase III clinical trials and the most common adverse events during therapy with ambrisentan included peripheral oedema, nasal congestion and headache^4,7. These adverse events are commonly seen with medicines that have a vasodilatory action. Most adverse events were mild to moderate in severity^4,7.

The incidence of LFT abnormalities (aminotransferase elevations greater than three times the upper limit of normal) were similar to placebo. A similarly low incidence was observed in a separate study which evaluated patients treated with ambrisentan who had previously discontinued sulphonamide class ERAs (bosentan, sitaxentan, or both) due to LFT abnormalities (N=36; mean exposure 52 weeks)⁸.

Volibris ^® is a trademark of GlaxoSmithKline. Ambrisentan has been licensed to GlaxoSmithKline by Gilead Sciences Inc. (Nasdaq: GILD) 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^TM.

Notes to the editors

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 worldwide⁹ and can occur at any age. Historically patients with PAH had an estimated median survival of 2.8 years¹⁰, but through improvements in diagnosis and treatment over the last 10 years, recent data suggest that survival rates are improving^11,12. In the late 1990s, GSK’s intravenous treatment for PAH, Flolan ^® (epoprostenol), was the first medicine licensed for the treatment of PAH in many European countries and remains a leading therapy for patients not improving on oral treatments.

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 classes, depending on the severity of symptoms¹³.

WHO Class I patients are asymptomatic, with few patients realising they have the disease at this stage. The most severely ill 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 www.gsk.com.

Enquiries

 

UK Media enquiries:	Philip Thomson	(020) 8047 5502
	Alice Hunt	(020) 8047 5502
	Joss Mathieson	(020) 8047 5502
	Gwenan White	(020) 8047 5502
European Analyst/Investor enquiries:	David Mawdsley	(020) 8047 5564
	Sally Ferguson	(020) 8047 5543

References:

¹ European Medicines Agency. Summary of Opinion. Volibris (ambrisentan). February 2008.

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

⁶ Gerber MJ, Dufton C, Pentikis H, et al. Ambrisentan has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of warfarin. CHEST2006. 256S

⁷ Data on File (Oudiz, ARIES-E, GSK –Amb002).

⁸ 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.

⁹ NICE Health Technology Appraisal. Appendix A. January 2007.

¹⁰ 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.

¹¹ 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.

¹² 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.

¹³ Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S–7S.