EU/3/14/1338 - orphan designation for treatment of Crigler-Najjar syndrome

adeno-associated viral vector serotype 8 containing the human UGT1A1 gene (volrubigene ralaparvovec)

Overview

On 15 October 2014, orphan designation (EU/3/14/1338) was granted by the European Commission to Genethon, France, for adeno-associated viral vector serotype 8 containing the human UGT1A1 gene for the treatment of Crigler-Najjar syndrome.

What is Crigler-Najjar syndrome?

Crigler-Najjar syndrome is a genetic disorder in which there is an accumulation of high amounts of toxic bilirubin in the body.

Bilirubin is a waste product that results from the breakdown of haemoglobin from old or damaged red blood cells. Normally bilirubin is converted in the liver to a less toxic, soluble form called 'conjugated' bilirubin that can be excreted into the bile and so removed from the body via the gut. However, patients with this condition lack the enzyme required to convert the bilirubin and as a result it accumulates in the liver and then in the blood stream and body tissues, where it can lead to damage.

Because of the yellow colour of bilirubin, jaundice, which is the yellowing of the skin and eyes, is usually seen within a few days of birth. The most severe complication is kernicterus, where bilirubin causes damage to the brain tissue that can lead to serious problems with muscle tone, movement, hearing and intellectual ability.

The condition is long-term debilitating and life threatening due to the development of kernicterus.

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

At the time of designation, Crigler-Najjar syndrome affected less than 0.1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 5,000 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).

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*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 511,100,000 (Eurostat 2014).

What treatments are available?

At the time of designation, there was no satisfactory method of treatment authorised in the EU for patients with Crigler-Najjar syndrome. Some patients were given treatments such as phototherapy (using light of certain wavelengths to break down some of the bilirubin), blood transfusions and liver transplantation.

How is this medicine expected to work?

Crigler-Najjar syndrome is caused by mutations (defects) in a gene called UGT1A1, which is needed for the body to produce the enzyme that converts unconjugated bilirubin into the conjugated form that can be easily removed from the body. This medicine is made of a virus that contains a normal copy of the UGT1A1 gene. When given to the patient the virus is expected to carry the gene into the cells of the liver, enabling the cells to produce the required enzyme, thus reducing levels of bilirubin in the body and preventing development of symptoms.

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

What is the stage of development of this medicine?

At the time of submission of the application for orphan designation, the evaluation of the effects of the medicine in experimental models was ongoing.

At the time of submission, no clinical trials with the medicine in patients with Crigler-Najjar syndrome had been started.

At the time of submission, the medicine was not authorised anywhere in the EU for Crigler-Najjar syndrome or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 4 September 2014 recommending the granting of this designation.

Opinions on orphan medicinal product designations are based on the following three 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 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.

EU/3/14/1338: Public summary of opinion on orphan designation: Adeno-associated viral vector serotype 8 containing the human UGT1A1 gene for the treatment of Crigler-Najjar syndrome

Adopted Reference Number: EMA/COMP/558518/2014

Key facts

• Active substance:
  adeno-associated viral vector serotype 8 containing the human UGT1A1 gene (volrubigene ralaparvovec)
• Intended use:
  Treatment of Crigler-Najjar syndrome
• Orphan designation status:
  Positive
• EU designation number:
  EU/3/14/1338
• Date of designation:
  15/10/2014
• Sponsor:

  Généthon; 1 bis rue de l'Internationale; 91000 Evry; France; Tel. [phone]; Fax [phone]; E-mail: [e-mail]

Review of designation

The Committee for Orphan Medicinal Products reviews the orphan designation of a product if it is approved for marketing authorisation.