EU/3/11/909: Orphan designation for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension is a condition where there is high blood pressure in the arteries that supply the lungs. In patients with pulmonary arterial hypertension, there is a thickening of the muscles in the walls of the arteries and a narrowing of the arteries in the lungs, making it harder for blood to flow to the lungs. Pulmonary arterial hypertension is a long-term debilitating and life-threatening condition that shortens patients' life expectancy because it may lead to heart failure and difficulty breathing.

At the time of designation, pulmonary arterial hypertension affected less than 1.8 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 91,000 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 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 507,700,000 (Eurostat 2011).

Several medicines were authorised for the treatment of pulmonary arterial hypertension in the EU at the time of designation. They included bosentan, ambrisentan, tadalafil, sildenafil, iloprost, epoprostenol, and treprostinil sodium. Surgery was also used in some patients to carry out a lung transplant or atrial septostomy (where a small hole is created between the upper two chambers of the heart, the atria).

The sponsor has provided sufficient information to show that macitentan might be of significant benefit for patients with pulmonary arterial hypertension because it may penetrate the diseased tissue more effectively than current treatments with a similar mechanism of action, which may improve the outcome of patients with pulmonary arterial hypertension, particularly when used in combination with existing treatments. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Macitentan is expected to work as an 'endothelin receptor antagonist'. This means that it is expected to block the receptors (type A and B) which the substance called 'endothelin-1' normally attaches to and activates. Endothelin is a naturally occurring substance that is released from lining of the blood vessels. It is present at raised levels in patients with pulmonary arterial hypertension, causing the blood vessels to constrict and the blood vessel walls to thicken. By blocking endothelin receptors , macitentan is expected to stop endothelin from constricting the blood vessels, thereby leading to a decrease in the blood pressure and a reduction of the symptoms of pulmonary arterial hypertension.

The effects of macitentan have been evaluated in experimental models.

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

At the time of submission, macitentan was not authorised anywhere in the EU for pulmonary arterial hypertension. Orphan designation of macitentan had been granted in the United States for the treatment of pulmonary arterial hypertension.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 8 July 2011 recommending the granting of this designation.

Update: Macitentan (Opsumit) has been authorised in the EU since 20 December 2013. Opsumit, as monotherapy or in combination, is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III.

Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease

More information on Opsumit can be found in the European public assessment report (EPAR).

• 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.