EU/3/18/2109: Orphan designation for the treatment of phenylalanine hydroxylase deficiency

Phenylalanine hydroxylase deficiency is a condition in which the body cannot process phenylalanine, an amino acid found in dietary proteins, because an enzyme called phenylalanine hydroxylase is lacking. This causes phenylalanine to build up in the blood to harmful levels and can lead to brain damage and impair normal development.

Phenylalanine hydroxylase deficiency is debilitating in the long-term because of its effects on the brain in patients who are not treated.

At the time of designation, phenylalanine hydroxylase deficiency affected less than 2 in 10,000 people in the European Union (EU). This was equivalent to fewer than 103,000 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 517,400,000 (Eurostat 2018).

At the time designation, Kuvan (sapropterin) was authorised in the EU to treat high blood levels of phenylalanine. In addition, because phenylalanine can only come from the diet, dietary restriction has been an important part of treatment.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with phenylalanine hydroxylase deficiency. Early laboratory studies have shown that a single injection could normalise phenylalanine levels in the blood and reduce the need to use the currently authorised treatment.

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

Patients with phenylalanine hydroxylase deficiency cannot process phenylalanine usually because of mutations (changes) in the gene for phenylalanine hydroxylase. This medicine is made of a virus that contains normal copies of the gene for phenylalanine hydroxylase. When given to the patient, it is expected that the virus will be carried into the patient’s cells enabling them to start producing the enzyme and thereby reduce levels of the amino acid in the blood.

The type of virus used in this medicine ('adeno-associated virus') does not cause disease in humans.

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

At the time of submission of the application for orphan designation, no clinical trials with the medicine in patients with phenylalanine hydroxylase deficiency had been started.

At the time of submission, the medicine was not authorised anywhere in the EU for phenylalanine hydroxylase deficiency. Orphan designation of the medicine had been granted in the United States for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 8 November 2018 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.