EU/3/14/1254: Orphan designation for the prevention of graft rejection following solid organ transplantation

Graft rejection following solid organ transplantation is a problem that can occur when the recipient's body rejects the transplanted organ. Graft rejection is caused by the patient's immune system (the body's natural defences) recognising the transplanted graft as 'foreign' and attacking it. This results in inflammation and damage to the organs.

Graft rejection following solid organ transplantation is a life-threatening condition because the transplanted organ may fail and because medication is required to suppress the patient's immune system, which can result in infections and malignancies.

At the time of designation, the number of patients at risk of graft rejection following solid organ transplantation was estimated to be not more than 0.9 people in 10,000 in the European Union (EU). This was equivalent to a total of not more than 46,000 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.
At the time of designation, this represented a population of 512,900,000 (Eurostat 2014).

At the time of designation, several medicines to suppress the immune system in order to prevent rejection after transplantation were authorised in the EU. These include the antibodies basiliximab and antithymocyte immunoglobulin, calcineurin inhibitors such as ciclosporin or tacrolimus, azathioprine, mycophenolate mofetil and corticosteroids such as prednisolone or methylprednisolone.

The sponsor has provided sufficient information to show that eculizumab might be of significant benefit for patients at risk of graft rejection following solid organ transplantation because early results suggest that use in combination with existing treatments improves the survival of transplanted organs compared with existing treatments alone. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Eculizumab has been authorised in the EU as Soliris for the treatment of two rare genetic diseases, paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. It is a monoclonal antibody, a type of protein that has been designed to recognise and attach to a specific structure (called an antigen) that is found in the body. Eculizumab has been designed to attach to and block a protein called C5 that plays an important role in the complement system, part of the immune system. The complement system is involved in producing the inflammation and damage seen in graft rejection.

By attaching to the C5 complement protein, eculizumab is expected to block the activation of the complement system in patients who have undergone solid organ transplantation, thus limiting the development of inflammation and damage, and helping to prevent rejection of the graft.

The effects of eculizumab have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with eculizumab in patients at risk of graft rejection were ongoing.

At the time of submission, eculizumab was not authorised anywhere in the EU for prevention of graft rejection following solid organ transplantation or designated as an orphan medicine in this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 6 February 2014 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.