EU/3/07/455: Orphan designation for the prevention of corneal graft rejection

After transplantation of the cornea (the central transparent part of the eye, external to the iris), there is a risk that the transplant (graft) will not be accepted by the patient's immune system, which would lead to a phenomenon called “rejection”.
The cornea does not have blood vessels, so it is usually difficult for white blood cells and antibodies (both agents of the immune system and involved in rejection) to reach it and activate rejection mechanisms. For this reason, rejection tends to occur less frequently in corneal transplants compared to other organs that do have blood vessels, such as the kidney. However, it is still a feared complication as it can lead to loss of vision in the affected eye.

At the time of designation, the number of patients at risk of corneal graft rejection was estimated to be approximately 1.1 people in 10,000 in the European Union (EU). This was equivalent to a total of around 55,000 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 27), Norway, Iceland and Liechtenstein.
At the time of designation, this represented a population of 500,300,000 (Eurostat 2007).

Currently, no satisfactory methods exist in the European Union that were authorised at the time of application, for the prevention of corneal graft rejection. However, eye drops containing corticosteroids (that reduce inflammation and suppress the immune system) are commonly prescribed after corneal transplantation to prevent rejection; other drugs that have been employed (although they are not authorized in the European Union) are ciclosporin and tacrolimus, both for the treatment and the prevention of corneal graft rejection.

Ciclosporin is an immunosuppressor, in other words it acts by reducing the activity of the immune system. Ciclosporin given by mouth or as an injection is authorized for the prevention and treatment of the rejection of many other organs, including the kidney, the heart and the liver. Local administration (as eye drops) of ciclosporin is expected to reduce the chance of corneal graft rejection.

The effects of ciclosporin were evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials in patients with corneal transplants were initiated.

Ciclosporin was not authorised anywhere in the world for the prevention of corneal graft rejection, or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 12 September 2007 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.