EU/3/06/421: Orphan designation for the treatment of acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia is a disease in which cancer cells are found in the blood and the bone marrow. The bone marrow is the spongy tissue inside the large bones in the body. Normally, the bone marrow makes cells called “blasts” that mature into several different types of blood cells that have specific functions in the body. These include red cells, white cells and platelets. Red blood cells carry oxygen and other materials to all tissues of the body. White blood cells fight infection. Platelets make the blood clot. When leukaemia develops, the bone marrow produces large numbers of abnormal blood cells. There are several types of leukaemias. Acute lymphoblastic leukaemia is a cancer of certain white blood cells called lymphocytes. There are two main types of lymphocytes: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). In this disease either B- or T-lymphocytes multiply too quickly and live too long, so there are too many of them circulating in the blood. These leukaemic lymphocytes are not fully developed and do not work properly. Over a period of time these abnormal cells (also called malignant cells) replace the normal white cells, red cells and platelets in the bone marrow, thus leading to a decreased number of these normal cells in the blood. In turn, this facilitates bruising, haemorrhages and infections, and causes anaemia with its symptoms. Acute lymphoblastic leukaemia is the most common type of leukaemia in young children. This disease also affects adults, especially those aged 65 and older. People with acute leukaemia can be cured, particularly children. However, despite the available treatments, acute lymphoblastic leukaemia remains a serious and life threatening condition in a subgroup of patients, who are resistant to treatment or relapse after initial remission.

Treatment for leukaemia is complex and depends on a number of factors including the type of leukaemia, the extent of the disease and whether the leukaemia has been treated before. It also depends on the patient's age, symptoms, and general health. The primary treatment of acute lymphoblastic leukaemia is chemotherapy (using drugs to kill cancer cells) followed by, or combined with, radiotherapy (using high-energy x-rays or other types of high-energy rays to kill cancer cells). Bone marrow transplantation as a curative treatment option is also available.

Satisfactory argumentation has been submitted by the sponsor to justify the assumption that forodesine hydrochloride might be of potential significant benefit for the treatment of acute lymphoblastic leukaemia. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain orphan status.

According to the information provided by the sponsor, acute lymphoblastic leukaemia was considered to affect about 28,000 persons in the European Union.

* 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.

Forodesine hydrochloride is a substance acting specifically on an enzyme called purine nucleoside phosphorylase (PNP). Enzymes are proteins produced by the cells of the body; they speed up the conversion of certain substances into other substances. Forodesine is an inhibitor of PNP. Reducing the activity of this enzyme may cause the accumulation of a substance, called dGTP, which is toxic to these cells if present in high concentrations. Human lymphocytes, particularly malignant T- and B-cells may be susceptible to forodesine, because they have a relatively high activity of another enzyme, dCK, which actually generates dGTP, and a low activity of an opposing enzyme (5' nucleotidase), which instead would prevent dGTP accumulation. Since acute lymphoblastic leukaemia is caused by the uncontrolled growth of the malignant lymphocytes (B- or T- cells), forodesine might help in slowing down or stopping this uncontrolled cell growth.

The effects of the medicinal product were evaluated in experimental models.

At the time of submission of the application for orphan designation, two clinical trials in patients with acute lymphoblastic leukaemia were completed, and another trial was ongoing.

Forodesine hydrochloride was not marketed anywhere in the world for acute lymphoblastic leukaemia; it was designated as orphan medicinal product for this same condition in the United States on 13 August 2004.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 9 November 2006 a positive opinion recommending the grant of the above-mentioned 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.