EU/3/19/2225: Orphan designation for the treatment of autosomal recessive congenital ichthyosis

Autosomal recessive congenital ichthyosis is an inherited skin disorder caused by changes (mutations) in genes responsible for producing proteins which are important for the formation of the outer layer of the skin. The main feature of the disorder is dry, thick, scaly or flaky skin. In its most severe form, children are born prematurely and have problems such as dehydration and difficulties in maintaining a normal body temperature.

Autosomal recessive congenital ichthyosis is a long-term debilitating disease due to the appearance of symptoms at birth or in early childhood. It can cause life-threatening complications in newborn babies including breathing and feeding problems and infections.

At the time of designation, autosomal recessive congenital ichthyosis affected less than 0.17 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 9,000 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 designation, acitretin was authorised in some countries of the EU to treat congenital ichthyosis. In addition, basic measures to manage this condition included mechanical scale removal and moisturising the skin. 

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with autosomal recessive congenital ichthyosis because early data showed improvement in the skin tissue following use of the medicine in a patient who had previously been treated with existing treatments.

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

Some forms of autosomal recessive congenital ichthyosis are caused by changes (mutations) in a gene called TGM1. As a result, patients cannot produce a form of the enzyme transglutaminase-1 that works properly. This enzyme is important for normal formation of the outer layer of the skin. The medicine is made of a virus that contains the normal TGM1 gene. When applied on the patient’s skin, the virus is expected to carry the normal TGM1 gene into the patient’s skin cells. The skin cells are then expected to produce the enzyme transglutaminase-1, reducing symptoms of the disease. 

The virus used in this medicine (herpes simplex) has been modified so that it 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, clinical trials with the medicine in patients with autosomal recessive congenital ichthyosis were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of autosomal recessive congenital ichthyosis. Orphan designation had been granted in the United States for TGM-1 deficient autosomal recessive congenital ichthyosis.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 10 October 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.