EU/3/19/2235: Orphan designation for the treatment of congenital alpha-1 antitrypsin deficiency

Congenital alpha-1 antitrypsin deficiency is an inherited disease characterised by a lack of normal forms of a protein called ‘alpha-1 proteinase inhibitor’ or ‘alpha-1 antitrypsin’ (AAT).

The liver makes AAT. One of the functions of AAT is to protect the lungs from an enzyme called neutrophil elastase. Neutrophil elastase attacks bacteria and other pathogens, and is also involved in breaking down damaged lung tissue. In patients lacking AAT, excessive neutrophil elastase activity can damage lung tissue and results in emphysema, which causes shortness of breath, coughing and wheezing. Sometimes, AAT deficiency can lead to a build-up of defective forms of AAT in liver cells, which can cause severe liver cirrhosis (scarring) often requiring liver transplantation.

Congenital AAT deficiency is a debilitating disease that is long lasting and can be life threatening due to worsening lung function and lung infections as well as liver injury.

At the time of designation, congenital alpha-1 antitrypsin deficiency affected approximately 2.4 in 10,000 people in the European Union (EU). This was equivalent to a total of around 124,000 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 28), Norway, Iceland and Liechtenstein. This represents a population of 518,400,000 (Eurostat 2019).

At the time of orphan drug designation, the medicine Respreeza (human alpha1-proteinase inhibitor) was authorised in the EU for slowing down the worsening of emphysema caused by congenital AAT deficiency and worked by replacing the missing enzyme. Patients were also given other medicines to manage the symptoms of obstructive lung disease and help prevent infections of the lungs and the airways. Some patients who developed liver disease were given liver transplantation.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with congenital alpha-1 antitrypsin deficiency because laboratory studies suggest that unlike current medicines, this medicine could treat patients with AAT disease affecting the liver.

This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Patients with congenital AAT deficiency have a mutation (change) in the SERPINA1 gene which causes the production of a defective AAT protein that builds up in the liver.

The medicine is made of a small strand of synthetic genetic material, called ‘small interfering RNA’ (siRNA), that interferes with the function of the gene SERPINA1 and blocks the production of the defective protein. The medicine has been designed to allow it to enter the liver cells in order to reach the areas where the defective protein is assembled. This is expected to reduce the build-up of defective proteins and the damage to the liver.

The effects of the medicine have been evaluated in experimental models.

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

At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of congenital alpha-1 antitrypsin deficiency or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 7 November 2019, 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 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.