EU/3/03/178: 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 are remodelling 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.

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.

Sildenafil citrate might be of potential significant benefit for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in particular with regards to improved efficacy based on the new mechanism of action and preliminary preclinical and clinical results. This benefit will have to be confirmed at the time of marketing authorisation and will be necessary to maintain the orphan status.

According to the information provided by the sponsor, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension was considered to affect not more than 38,500 persons in the European Union.

*Disclaimer: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 385,000,000 (Eurostat 2002) and may differ from the true number of patients affected by the condition. This estimate is based on available information and calculations presented by the sponsor at the time of the application.

Sildenafil citrate has vasodilating (enlargement of the vessel) properties, including an effect on pulmonary arteries. Furthermore, information deriving from some preclinical tests suggests that sildenafil citrate inhibits the proliferation of smooth muscle cells in the vessels, which might have a beneficial effect on the changes in the pulmonary microcirculation.

At the time of submission of the application for orphan designation, clinical trials in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension were ongoing.

Sildenafil citrate 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 10 October 2003 a positive opinion recommending the grant of the above-mentioned designation.

Update: Sildenafil citrate (Revatio) is authorised in the European Union as of 28 October 2005 for the treatment of patients with pulmonary arterial hypertension classified as WHO functional class III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

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