EU/3/04/227: Orphan designation for the treatment to mobilize progenitor cells prior to stem cell transplantation

The term “progenitor cell” or “stem cell” is used to indicate those cells which are still immature and do not express all the characteristics of the future mature cells which will derive from them. Haematopoietic progenitor cells are able to produce the cells of the immune system and bone marrow. For diseases where the bone marrow or the immune system are absent, or working abnormally, or invaded by cancer cells, it is sometimes appropriate to use a treatment called haematopoietic progenitor cell transplantation. This consists of replacing the abnormal cells of the immune system and bone marrow, and introducing new progenitor cells. Two types of stem cell transplants can be used: autologous blood stem cell transplants using the patient's own blood stem cells, or allogeneic blood stem cell transplants using the blood stem cells from another person (“donor”). Diseases requiring such transplantation are life-threatening.

At the time of designation, treatment to mobilize progenitor cells prior to stem cell transplantation affected less than 1 in 10,000 people in the European Union (EU)*. This is equivalent to a total of fewer than 46,000 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 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).

Mobilisation therapies aim at bringing the progenitor cells into peripheral blood to improve the yield of cells which can be collected for subsequent transplantation. Several medicines can be used in order to mobilise the stem cells such as chemotherapy (using drugs to destroy cells) or haematopoietic growth factors (drugs that stimulate the proliferation of the blood cells).

1, 1'-[1,4-Phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane might be of potential significant benefit for the mobilisation therapy. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

1, 1'-[1,4-Phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane might stimulate the mobilization of the stem cells into peripheral blood by inhibiting a substance called chemokine that normally prevents the progenitor cells from migrating out of the bone marrow.

The effects of 1, 1'-[1,4-phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients undergoing stem cell transplantation were ongoing.

The medicinal product was not marketed anywhere worldwide for treatment to mobilize progenitor cells prior to stem cell transplantation, at the time of submission. Orphan designation of 1, 1'-[1,4-phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane was granted in the United States for the indication “to improve the yield of progenitor cells in the apheresis product for subsequent stem cells transplantation following myelosupressive or myeloablative chemotherapy”.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted a positive opinion on 9 September 2004 recommending the granting of the above-mentioned designation.

Update: 1, 1'-[1,4-phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane (Mozobil) has been authorised in the EU since 31 July 2009. Mozobil is indicated in combination with G-CSF to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma whose cells mobilise poorly.

• the seriousness of the condition;
• the existence or not 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 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.