EU/3/06/368: Orphan designation for the treatment of Fabry disease

Fabry disease comprises a group of inherited lysosomal storage disorders. Lysosomes are small vesicles within cells containing enzymes that are able to destroy or transform different substances of the cell, such as proteins, fat, nucleic acids (components of the genetic material) and sugars. Any change of the lysosomal enzymes causes abnormal accumulation of the substance (also known as substrate) normally transformed by it. Cells are unable to destroy or eliminate accumulated substrates, and high levels of them can be toxic leading to damage and malfunction of the organ where accumulation occurs. In Fabry disease, the activity of the lysosomal enzyme α-galactosidase A is impaired or absent. Fabry disease is a heterogenous disorder with variable onset of symptoms that affect several organs. Glycosphingolipids (biological molecules composed of a type of sugar and lipid) is the substrate that accumulates in Fabry disease, and severity of the disease depends on the level of accumulation. Fabry disease affects the nervous system, kidneys, heart, skin and gastrointestinal system. Some of the most common pathological symptoms are skin lesions and burning pain of the extremities. This pain can become very intense, especially when one has a fever. Fabry disease is chronically debilitating and life threatening.

At the time of designation, Fabry disease affected approximately 1 in 10,000 people in the European Union (EU). This was equivalent to a total of around 47,000 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 468,900,000 (Eurostat 2006).

Several products were authorised for the condition in the Community at the time of submission of the application for orphan drug designation. In particular, enzymes replacing the missing enzyme were used to treat Fabry disease.
1-deoxygalactonojirimycin hydrochloride might be of potential significant benefit for the treatment of Fabry disease, as it may act in a different way which is hoped to improve the long-term outcome of the patients. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

1-deoxygalactonojirimycin hydrochloride is expected to bind to the abnormal α-galactosidase A enzyme and to correct its transport into the lysosome where its action is needed. This way, it is expected that the α-galactosidase A activity is restored. The abnormally high levels of glycosphingolipids are decreased and the extent of Fabry disease and its clinical consequences are limited.

The effects of 1-deoxygalactonojirimycin hydrochloride were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with Fabry disease were ongoing.

1-deoxygalactonojirimycin hydrochloride was not authorised anywhere worldwide for Fabry disease, at the time of submission. Orphan designation of 1-deoxygalactonojirimycin hydrochloride was granted in the United States for treatment of Fabry disease.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 5 April 2006 recommending the granting of this designation.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• and either the rarity of the condition (affecting not more than five in 10,000 people in the Community) or the 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 the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.