EU/3/05/265: Orphan designation for the treatment 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, graft rejection after lung transplantation affected approximately 0.05 in 10,000 people in the European Union (EU). This was equivalent to a total of around 2,300 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 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 466,600,000 (Eurostat 2005).

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 treatment of graft rejection are ciclosporin (intravenous administration) and corticosteroids. Other therapies that can be used are other immunosuppressive drugs such as methotrexate, or other methods that decrease the number of immune cells of the recipient, such as photopheresis and antilymphocyte antibodies.

Inhaled ciclosporin might be of potential significant benefit for the treatment 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 to treat patients who develop a rejection against their lung transplants by delivering the medicinal product directly to the lungs.

The effects of ciclosporin for inhalation use was evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with graft rejection in lung transplantation were completed.

Ciclosporin for inhalation use was not marketed anywhere worldwide for graft rejection in lung transplantation at the time of submission.

Orphan designation of ciclosporin for inhalation use was granted in the United States for prophylaxis of acute rejection in patients requiring allogenic lung transplant and for treatment of refractory acute graft rejection in patients requiring allogenic lung transplant.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 3 February 2005 recommending the granting of this designation.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

Designated orphan medicinal products are still investigational products which were considered for designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy will be necessary before this product can be granted a marketing authorisation.