EU/3/05/273: Orphan designation for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Pulmonary arterial hypertension is a rare blood vessel disorder of the lung in which the pressure in the pulmonary artery (the vessel that leads blood from the heart to the lungs) rises above normal levels. An increase of the number of smooth muscle cells in the walls of small lung arteries (a phenomenon called proliferation) that are remoddeling the vessels, may lead to obstructions in the microcirculation, which will then lead to an increase in the blood pressure.

Chronic thromboembolic pulmonary hypertension is a complication representing less than 1% of all cases of acute pulmonary embolism (the sudden blocking of a lung artery by a clot or foreign material which has been brought to its site by the blood current), which directly leads to pulmonary hypertension. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension are chronically debilitating and life-threatening.

At the time of designation, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension affected less than 2 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 93,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 466,600,000 (Eurostat 2005).

Several medicinal products were authorised for the treatment of pulmonary arterial hypertension in the Community at the time of submission of the application for orphan drug designation.

Ambrisentan might be of potential significant benefit for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension because it might act in a different way and thereby improve the long-term outcome of the patients. This benefit will have to be confirmed at the time of marketing authorisation and will be necessary to maintain the orphan status.

Ambrisentan opposes the effect of a substance called endothelin-1. Endothelin-1 belongs to a group of naturally produced substances, called hormones, released by the cells which are lining the inside surface of the blood vessels. Endothelin-1 is known to be the most powerful substance that can cause narrowing of blood vessels. By blocking the effect of endothelin-1, the diameter of the blood vessels can normalise and this might induce a decrease of the blood pressure.

At the time of submission of the application for orphan designation, preliminary clinical trials in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension had been performed and more studies were planned.

Ambrisentan was not marketed anywhere worldwide for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 3 March 2005 a positive opinion recommending the grant of the above-mentioned designation.

Update: ambrisentan (Volibris) has been authorised in the EU since 21 April 2008 for the treatment of pulmonary arterial hypertension (PAH).

More information on Volibris can be found in the European public assessment report (EPAR) on the Agency's website.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.