EU/3/03/133: Orphan designation for the treatment of angioedema

Angioedema is a reaction of the blood vessels. The reaction allows the passage of more fluids across the blood vessels, into the surrounding tissue. The excess fluid builds up in confined areas under the skin producing swelling (oedema). This oedema is painless and does not itch. The oedema often appears in the face, and the neck. Here it may involve the lips, the floor of the mouth, and the tongue. It may also involve the larynx (voice box), leading to airway obstruction. It can also appear in the gut. This may lead to pain in the abdomen, and vomiting. Faeces (stools) may become too liquid, and may be produced too frequently (diarrhoea). Angioedema can occur as a result of various causes. The condition may be inherited via the genes from the parents. It may also develop after birth. In some cases, it is related to the use of certain medications. Angioedema can be a life-threatening condition due to airway obstruction.

At the time of designation, angioedema affected approximately 2-3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 77,000-115,00 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 382,800,000 (Eurostat 2003).

Methods of treatment were authorised in the Community for treatment for angioedema. Certain medicines have been used to treat acute attacks of angioedema. These included agents that prevent the break down of a protein called fibrin. This protein is found in blood clots. Such agents are called antifibrinolytic agents. Other agents include those that inhibit a protein called C1, as abnormal activation of this protein leads to oedema. Such agents are called C1-esterase inhibitors. Other therapies included drugs that prevent new attacks. These include the male sex hormones called androgens.

Icatibant might be of potential significant benefit for the treatment of angioedema, particularly in terms of a selective action. The assumption of benefit is yet to be proven, and will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Angioedema involves fluid leakage from small blood vessels beneath the skin. Certain proteins called proteases control this response. Proteases are a family of proteins that break up other proteins. In this case, the proteases involved cause the release of proteins called kinins. Kinins are small proteins that cause widening of blood vessels. They also alter the passage of fluids across the walls of the vessels.

The activation of kinins requires a series of reactions involving a protein called bradykinin. This is a very potent protein that causes widening of blood vessels, and other effects. Bradykinin is found in human blood. The plasma is the fluid in the blood, in which blood cells are suspended. Icatibant specifically blocks the action of human bradykinin, and hence interrupts the series of reactions that leads to angioedema.

The effects of icatibant have been evaluated in an experimental model.

At the time of submission of the application for orphan designation, no clinical trials in patients with angioedema had been initiated.

The medicinal product was not marketed anywhere worldwide for angioedema or designated as an orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 January 2003 recommending the granting of this designation.

Update: Icatibant acetate (Firazyr) was authorised in the EU on 11 July 2008 for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults (with C1-esterase-inhibitor deficiency).

• 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.