EU/3/04/209: Orphan designation for the prevention of graft rejection after lung transplantation

Lung transplantation is performed when, because of underlying conditions, the lungs are so damaged that one or both need to be replaced. It is most commonly performed in pulmonary emphysema, idiopathic pulmonary fibrosis, pulmonary hypertension and cystic fibrosis.

Rejection is the process by which the organ recipient's defence (immune) system recognises, becomes sensitised against, and attempts to eliminate the foreign donor organ.

It has been observed that at least one episode of rejection is common within the first year after a transplant. More than 80% of people who receive a lung transplant develop some symptoms of rejection within a month of transplantation. Symptoms include fever, shortness of breath, and weakness due to the non-optimal functioning of the transplanted lungs. Scar tissue may form in the small airways and gradually block them, possibly indicating gradual rejection.

The condition can be chronically debilitating and life threatening due to the high incidence of severe infections and graft rejection.

At the time of designation, the number of patients at risk of graft rejection after lung transplantation was estimated to be approximately 0.01 people in 10,000 in the European Union (EU)*. This is equivalent to a total of around 460 people, which 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 based on data from the European Union (EU 25), Norway, Iceland and Lichtenstein. This represents a population of 459,700,000 (Eurostat 2004). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

In order to preserve the new lung(s) in the recipient's body a suppression of the patient's defence potential (immunosuppression) is induced after lung transplantation. The immunosuppressive agents already authorized for the use in the prevention of graft rejection are represented by ciclosporin (oral and intravenous administration) and corticosteroids. Other therapies that can be used are medicinal products called antibodies that are aimed at targeting and blocking the cells that produce the immune response: antithymocyte globulins or monoclonal CD3 antibodies.

Inhaled ciclosporin might be of potential significant benefit for the prevention of graft rejection after lung transplantation due to its new route of administration. The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Ciclosporin for inhalation use is an immunosuppressive drug used to prevent the body from rejecting transplanted organs, as it suppresses the body's natural reaction to the transplanted organ and is a component of most of the post transplant regimens. Ciclosporin acts by inhibiting some special defence cells called lymphocyte T cells. It inhibits also the production of some special substances called lymphokines, which play a role in the defence reactions of the body. Ciclosporin for inhalation is meant to be used in patients to prevent development of a rejection against lung transplants by delivering the medicinal product directly to the lungs.

The effects of ciclosporin for inhalation use were evaluated in experimental models. At the time of submission of the application for orphan designation, no clinical trials in patients with lung transplantation were initiated.

Ciclosporin for inhalation use was not marketed anywhere worldwide for graft rejection in lung transplantation 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 16 of June 2004 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.