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Orphan designation

On 8 June 2004 orphan designation (EU/3/04/199) was granted by the European Commission to Dr. Gertrud Thormann, France, for tetrahydrobiopterin for the treatment of hyperphenylalaninemia.

The sponsorship was transferred first to BioMarin Europe Ltd, Ireland, in March 2005, then to Serono Europe Limited, United Kingdom, in August 2006, then to Merck KGaA, Germany, in September 2007, then to Merck Serono Europe Limited, United Kingdom, in March 2011 and subsequently to BioMarin International Limited, Ireland, in December 2015.

Tetrahydrobiopterin has been authorised in the EU as Kuvan since 2 December 2008.

What is hyperphenylalaninaemia?

Hyperphenylalaninaemia or phenylketonuria, is an inherited disease caused by a genetic abnormality which results in reduced activity of an enzyme, phenylalanine hydroxylase. This enzyme is responsible for conversion of a certain aminoacid (a building block for a protein) called phenylalanine, into another aminoacid called tyrosine. The result of this enzyme deficiency is an accumulation of high concentrations of phenylalanine in the blood and urine, up to harmful levels. Phenylalanine is toxic at high levels and can lead to severe brain damage. The disease is subdivided into mild, moderate and severe forms, according to the degree of elevation of phenylalanine blood levels.
Hyperphenylalaninaemia is chronically debilitating and is characterised by mental retardation if left untreated.

What is the estimated number of patients affected by the condition?

At the time of designation, hyperphenylalaninaemia affected approximately 1.7 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 64,000 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: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 385,000,000 (Eurostat 2002) and may differ from the true number of patients affected by the condition. This estimate is based on available information and calculations presented by the sponsor at the time of the application.

What treatments are available?

At the time of submission of the application for orphan drug designation, the treatment of hyperphenylalaninaemia consisted of lifelong strict dietary protein restriction aiming to reduce phenylalanine intake.
Satisfactory argumentation has been submitted by the sponsor to justify the assumption that the medicinal product might be of potential significant benefit for the treatment of hyperphenylalaninaemia, particularly in terms of improved tolerance to phenylalanine dietary intake. The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

How is this medicine expected to work?

Tetrahydrobiopterin might help to restore the phenylalanine hydroxylase enzyme activity. As a result more phenylalanine might be converted to tyrosine, so that patients may tolerate more phenyalamine and thus higher protein intake.

What is the stage of development of this medicine?

At the time of the submission of the orphan drug designation application, the evaluation of the effects of tetrahydrobiopterin in experimental models and clinical trials in patients with hyperphenylalaninemia were planned.

Tetrahydrobiopterin was not marketed anywhere worldwide for treatment of hyperphenylaninemia, at the time of submission. Orphan designation of tetrahydrobiopterin was previously granted in the European Union for treatment of hyperphenylalaninemia.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 14 April 2004 recommending the granting of this designation.

Update: Tetrahydrobiopterin (Kuvan) has been authorised in the EU since 2 December 2008 for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients of 4 years of age and over with phenylketonuria (PKU) who have been shown to be responsive to such treatment.

Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment.

More information on Kuvan can be found in the European public assessment report (EPAR) on the Agency’s website.

Opinions on orphan medicinal products designations are based on the following cumulative criteria:
  • 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 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.

Key facts

Product details for <p>Tetrahydrobiopterin</p>
Active substanceTetrahydrobiopterin
Medicine NameKuvan
Disease/conditionTreatment of hyperphenylalaninaemia
Date of decision08/06/2004
Orphan decision numberEU/3/04/199

Review of designation

Sponsor’s contact details

BioMarin International Limited
County Cork
Tel. +353 21 500 8600

Patients’ organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe.
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.