EU/3/09/636: Orphan designation for the treatment of corneal graft rejection

Corneal graft rejection is a problem that can occur after a cornea transplant, when the recipient's body rejects the transplanted cornea (the 'graft'). The cornea is the transparent surface at the front of the eye that covers the iris and the pupil. Corneal graft rejection is caused by the patient's immune system (the body's natural defences) recognising the transplanted cornea as 'foreign' and producing antibodies against it. This results in inflammation and damage to the graft.

Corneal graft rejection is a long-term debilitating disease because it can lead to loss of vision in the affected eye.

At the time of designation, corneal graft rejection affected less than 1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 50,000 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 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 504,800,000 (Eurostat 2009).

At the time of submission of the application for orphan-drug designation, corticosteroids (substances that reduce the activity of the immune system) were authorised in the EU to prevent or treat graft rejection after cornea transplants. These medicines are available in various forms, such as eye drops, tablets and solutions for injection.

The sponsor has provided sufficient information to show that dexamethasone phosphate (iontophoretic solution, ocular use) might be of significant benefit for patients with corneal graft rejection because the medicine is given to patients directly into the eye using a particular device rather than as eye drops, as medicine taken by mouth or given by intravenous (into the vein) injection. This system may deliver higher amounts of the medicine into the eye and may lead to better outcomes for patients. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Dexamethasone phosphate is a corticosteroid that is already available in the EU as eye drops for the treatment of corneal graft rejection. It works by attaching to receptors on various types of immune cells in the eye fluid. This leads to a reduction in inflammation and damage caused to the transplanted cornea.

This medicine is a new formulation of dexamethasone phosphate that is given directly into the eye using an 'iontophoretic' device. The device is placed around the cornea and uses a small electrical current to move a dose of dexamethasone phosphate from a reservoir into the eye. In this way, a higher amount of corticosteroid is expected to penetrate into the anterior chamber (the fluid-filled space behind the cornea where the medicine works) than can be achieved with eye drops, oral or intravenous medicines.

The effects of dexamethasone phosphate (iontophoretic solution, ocular use) have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with corneal graft rejection were being designed.

At the time of submission, dexamethasone phosphate (iontophoretic solution, ocular use) was not authorised anywhere in the EU for the treatment of corneal graft rejection. Orphan designation of this medicine had been granted in the United States for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 2 April 2009 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 Community) 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.