EU/3/08/594: Orphan designation for the treatment of hypophosphatasia

Hypophosphatasia is a rare inherited metabolic disorder. It is caused by defects in the gene for tissue non-specific alkaline phosphatase (TNSALP), an enzyme that is involved in the development of bone, particularly the hardening of the bones. Patients with hypophosphatasia have symptoms such as early loss of teeth, malformed (unusually shaped) bones and frequent bone fractures (breaks).

There are five forms of the disease. Perinatal and infantile hypophosphatasia affect unborn babies and children, and are life-threatening either in the womb or in early infancy because of the incomplete development of the bones and lungs. The other three forms (childhood and adult hypophosphatasia, and odontohypophosphatasia) are generally not lethal but are debilitating and long-lasting.

At the time of designation, hypophosphatasia affected less than 0.01 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 500 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 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 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 502,800,000 (Eurostat 2008).

At the time of submission of the application for orphan drug designation, there were no satisfactory methods authorised for the treatment of hypophosphatasia. Treatment has been aimed at relieving the symptoms of the disease such as setting fractures in plaster casts, controlling pain and controlling the levels of calcium in the blood. Patients are sometimes treated with surgery, and dental hygiene is carefully monitored.

Recombinant human tissue non-specific alkaline phosphatase - Fc - deca-aspartate fusion protein contains TNSALP, the enzyme that is missing in patients with hypophosphatasia. The enzyme is produced by a method known as 'recombinant DNA technology': it is made by a cell that has received a gene (DNA), which makes it able to produce TNSALP. In this medicine, the TNSALP is attached to a protein called deca-aspartate, which guides the TNSALP to the bones. Providing TNSALP is expected to replace the missing enzyme in the bones, improving their development and making them harder.

The evaluation of the effects of recombinant human tissue non-specific alkaline phosphatase - Fc - deca-aspartate fusion protein in experimental models is ongoing.

At the time of submission of the application for orphan designation, no clinical trials in patients with hypophosphatasia had been started.

At the time of submission, recombinant human tissue non-specific alkaline phosphatase - Fc - deca-aspartate fusion protein was not authorised anywhere in the world for hypophosphatasia. Orphan designation of the product had been granted in the United States for hypophosphatasia.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 8 October 2008 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 five in 10,000 people in the Community) 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.