EU/3/01/019: 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 blood vessel that leads 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 remodel 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 this 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 approximately 0.95 in 10,000 people in the European Union (EU). This was equivalent to a total of around 36,000 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. At the time of designation, this represented a population of 378,800,000 (Eurostat 2001).

One medicinal product was authorised for the treatment of pulmonary arterial hypertension in the Community at the time of submission of the application for orphan-drug designation.

Bosentan might be of potential significant benefit for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension because it may be safer than the existing medicinal product and it might improve the quality of life of the patients. The benefit will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

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

The effects of bosentan have been evaluated in experimental models. At the time of submission of the application for orphan designation, clinical trials in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension had been completed.

Bosentan was not marketed anywhere worldwide for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, at the time of submission. Orphan designation of bosentan had been granted in the United States for the same condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 19 December 2000 recommending the granting of this designation.

Update: Bosentan (Tracleer) was authorised in the EU on 15 May 2002 for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with grade III functional status. Efficacy has been shown in:

• primary (idiopathic and familial) PAH;
• PAH secondary to scleroderma without significant interstitial pulmonary disease and;
• PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology.

In 2008, some improvements were also shown in patients with PAH World Health Organization functional class II and the therapeutic indication was extended accordingly.

• 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 Community) 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.