EU/3/00/006

Gaucher disease is characterised by the accumulation of specific chemical substances (glucocerebrosides) in several types of cells of the immune system (the body's natural defence system) that are localised throughout the body, but particularly in the spleen, liver and bone marrow, and cells of the nervous system (neurons). The disorder results from decreased activity of an enzyme (a protein that can trigger a chemical reaction in the body), called glucocerebrosidase or acid β–glucosidase; this enzyme normally degrades the glucocerebrosides. Since glucocerebrosides are not cleared, they progressively accumulate in the cells. The disorder has a genetic origin, so it is caused by damage in a gene that carries the information necessary for the production of the enzyme. The severity of Gaucher disease is extremely variable; some patients present in childhood with virtually all the complications of Gaucher disease, while others remain asymptomatic for more than 70 years.

Gaucher disease has traditionally been divided into the following three clinical subtypes, according to the absence or presence of damage to the nerves and its progression:

• type 1 - non-neuronopathic form (the most common and least severe form);
• type 2 - acute neuronopathic form (the most severe form, usually diagnosed shortly after birth);
• type 3 - chronic neuronopathic form (a form of intermediate severity between type 1 and type 2).

However, some cases do not fit precisely into one of these categories. Gaucher disease can be life-threatening (type 2 and 3) or chronically debilitating (type 1).

At the time of designation, Gaucher disease affected less than 0.6 in 10,000 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 23,000 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. At the time of designation, this represented a population of 375,500,000 (Eurostat 2000).

At the time of submission of application for orphan-drug designation, there were only medicinal products authorised for the treatment of type-1 Gaucher disease. These products aimed to replace the missing or defective enzyme. Some patients were treated symptomatically with splenectomy (surgical removal of the spleen) or bone marrow transplantation.

Satisfactory argumentation has been submitted by the sponsor to justify the assumption that 1,5-(butylimino)-1,5-dideoxy, D-glucitol might be of potential significant benefit for the treatment of Gaucher disease, mainly because it may be of major contribution to patient care. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

1,5-(Butylimino)-1,5-dideoxy, D-glucitol is structurally similar to glucose, a sugar that is used by the body to make glucocerebrosides. According to the sponsor, 1,5-(butylimino)-1,5-dideoxy, D-glucitol will bind to the enzyme that produces the harmful accumulating glucocerebrosides and thus reduces them in the body.

The effects of 1,5-(butylimino)-1,5-dideoxy, D-glucitol have been evaluated in experimental models.

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

1,5-(Butylimino)-1,5-dideoxy, D-glucitol was not authorised anywhere worldwide for the treatment of Gaucher disease, at the time of submission. Orphan designation of 1,5-(butylimino)-1,5-dideoxy, D-glucitol had been granted in the United States for the treatment of Gaucher disease, among other indications.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 13 September 2000 recommending the granting of this designation.

Update: 1,5-(butylimino)-1,5-dideoxy, D-glucitol (Zavesca) was authorised in the EU on 20 November 2002 for the oral treatment of mild to moderate type-1 Gaucher disease. Zavesca may be used only in the treatment of patients for whom enzyme replacement therapy is unsuitable.

• 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.