EU/3/07/440: Orphan designation for the treatment of 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 inactivates some substances, such as elastase, normally produced by the body. The action of elastase is to destroy certain molecules that form the lung tissue. 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 lungs. Lung disease due to AAT deficiency is often called "hereditary emphysema" or emphysema secondary to congenital AAT deficiency. The condition is chronically debilitating and life-threatening.

At the time of designation, congenital AAT deficiency affected approximately 2.5 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 115,000 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. This represents a population of 459,700,000 (Eurostat 2004).

Therapy for lung disease due to AAT deficiency includes the use of medicines to help breathing, or to help to clear mucus (phlegm) from the lungs. The frequent lung infections seen in this disorder require treatment with antibiotics. Oxygen may also be given in the more advanced stages; lung transplantation may be used in the most severe cases. Human alpha-1 antitrypsin, to be administered intravenously, is authorised for replacement therapy of this condition.
Satisfactory argumentation has been submitted by the sponsor to justify the assumption that “recombinant adeno-associated viral vector containing human alpha-1 antitripsin gene” might be of potential significant benefit for the treatment of emphysema secondary to congenital AAT deficiency, because it might represent a significant contribution to patient care. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

“Recombinant adeno-associated viral vector containing human alpha-1 antitripsin gene” is a medicinal product which uses a virus to carry the gene necessary for the production of the AAT protein. A virus is a small organism capable of introducing genetic material in cells. The type of virus (adeno-associated virus) used in this medicinal product is modified in order to avoid causing any disease in humans. The administration of the virus containing the human AAT gene is expected to increase the concentration of AAT. In this way AAT would be able to oppose the effects of elastase. This action is expected to slow down or stop the worsening of the lung disease.

The effects of recombinant adeno-associated viral vector containing human alpha-1 antitripsin gene were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with in patients with congenital AAT deficiency were ongoing.

Recombinant adeno-associated viral vector containing human alpha-1 antitripsin gene was not authorised anywhere in the world for emphysema secondary to congenital AAT 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 February 2007 recommending the granting of this designation.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• 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 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.