EU/3/16/1684: Orphan designation for the treatment of Crigler-Najjar syndrome

Crigler-Najjar syndrome is an inherited disorder in which harmful levels of bilirubin build up in the body. Bilirubin is a waste product of the breakdown of haemoglobin from old or damaged red blood cells.

Normally bilirubin is converted in the liver to a less toxic form called 'conjugated' bilirubin that is removed from the body via the gut. However, patients with Crigler-Najjar syndrome lack the enzyme that converts bilirubin into the less toxic form and as a result it builds up in the liver and then in the blood stream and body tissues where it can cause 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 damages brain tissue and leads 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.

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).

* 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 513,700,000 (Eurostat 2016).

At the time of designation, no satisfactory methods of treatment were authorised in the EU for patients with Crigler-Najjar syndrome. Some patients were given treatments such as phototherapy (using light to help break down the bilirubin) and liver transplantation.

Patients with Crigler-Najjar syndrome lack UGT1A1, the enzyme that converts bilirubin to conjugated bilirubin. The medicine consists of genetic material (mRNA) that cells need to produce the missing enzyme. In this medicine, the mRNA is enclosed in microscopic fat particles, which help it to be taken up by liver cells. The mRNA is then released inside the liver cells where it can act as a template for producing UGT1A1. This is expected to increase the conversion of bilirubin to conjugated bilirubin and improve the symptoms of Crigler-Najjar syndrome.

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 of the application for orphan designation, 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 19 May 2016 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.