EU/3/04/244: Orphan designation for the treatment of emphysema secondary to congenital alpha-1 antitrypsin deficiency

Congenital alpha-1-antitrypsin deficiency is an inherited disease characterised by reduced levels in the blood of the substance alpha-1 antitrypsin (AAT). This substance is a protein that is normally made by the liver and reaches other organs (such as the lungs) after being released into the blood circulation. AAT has the role of inactivating some substances such as elastase normally produced by the body. The action of elastase is to destroy certain molecules that form the lung tissue. AAT controls this action of elastase. If AAT is missing then the action of elastase is no longer opposed. In the long term, this may damage the lungs and cause a lung disease where air is abnormally accumulated in the tissue around the alveoli (the small cells containing the air in the lungs). Lung disease due to this deficiency is also called 'hereditary emphysema' or emphysema secondary to congenital AAT deficiency. The condition is chronically debilitating and life-threatening.

At the time of designation, emphysema secondary to congenital AAT deficiency affected not more than 2 in 10,000 people in the European Union (EU). This was equivalent to a total of not more than 93,000 people*, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and 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 464,200,000 (Eurostat 2004).

Therapy for lung disease due to AAT deficiency includes the use of medicines to help breathing, or to help to clear mucus. Lung infections require treatment with antibiotics. Human AAT to be administered intravenously is authorised for replacement therapy of this condition. Oxygen may also be given in the more advanced stages and lung transplantation is used as a last resource.

Alpha-1 antitrypsin (inhalation use) might be of potential significant benefit for the treatment of emphysema secondary to congenital AAT deficiency because of the different route of administration. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Alpha-1 antitrypsin (inhalation use) is made into an aerosol, which the patient can inhale. In this way, the inhaled protein can reach the lungs where it is expected to provide the lacking AAT and thereby reduce the accumulated elastase. This action is expected to slow down the worsening of the lung disease.

The effects of alpha-1 antitrypsin (inhalation use) have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with emphysema secondary to congenital alpha-1 antitrypsin deficiency were ongoing.

Alpha-1 antitrypsin (inhalation use) was not marketed anywhere worldwide for the treatment of emphysema secondary to congenital alpha-1 antitrypsin deficiency or designated as 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 7 October 2004 recommending the granting of this designation.

• 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.