EU/3/07/514: Orphan designation for the treatment of Gaucher disease

Gaucher disease is characterized by the accumulation of specific chemical substances (glucocerebrosides) in several cells (macrophages and monocytes) that are localized throughout the body, but particularly in the spleen, liver and bone marrow. The disorder results from the decreased activity of an enzyme (a protein that stimulates a chemical reaction in the body), called glucocerebrosidase; this enzyme destroys the glucocerebrosides. Since glucocerebrosides are not destroyed, 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. Usually both parents are healthy carriers of a single copy of the damaged gene. To develop the disease, two damaged copies must be present in the same individual (this is called autosomal recessive inheritance). The severity of Gaucher disease is extremely variable; some patients show with virtually all the complications of Gaucher disease during childhood, while others remain asymptomatic for more than 70 years.

Gaucher disease has traditionally been divided into the following 3 clinical subtypes, according to the absence or presence of damage to the nerves and its progression:

• Type 1 - Nonneuronopathic form (the most common and less 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 precisely fit 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 approximately 0.3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 15,000 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 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 500,300,000 (Eurostat 2007).

At the time of the application for orphan designation, two medicinal products were authorized in the European Union for the treatment of Gaucher syndrome, miglustat (Zavesca, given orally) and imiglucerase (Cerezyme, given intravenously). Given its different mechanism of action, (1R,2R)-octanoic acid[2-(2',3'-dihydro-benzo[1,4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt may be of potential significant benefit over the currently authorised medicinal products. This assumption will have to be confirmed at the time of marketing authorisation, and this will be necessary to maintain the orphan status.

(1R,2R)-Octanoic acid[2-(2',3'-dihydro-benzo [1,4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt blocks the function of an enzyme called glucosylceramide synthase. This enzyme helps to build the substance that accumulates in Gaucher disease (the glucocerebrosides, which then cannot be eliminated because of the genetic defect in the enzyme that destroys them). Thus, by blocking the action of glucosylceramide synthase, the levels of glucocerebrosides in the body are reduced and its accumulation should also be reduced.

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

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

The medicinal product was not authorised anywhere in the world for Gaucher disease, or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 October 2007 recommending the granting of this designation.

Update: (1R,2R)-octanoic acid[2-(2',3'-dihydro-benzo[1,4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt, eliglustat (Cerdelga) has been authorised in the EU since 19 January 2015 for the long-term treatment of adult patients with Gaucher disease type 1 (GD1), who are CYP2D6 poor metabolisers (PMs), intermediate metabolisers (IMs) or extensive metabolisers (EMs).

• 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 5 in 10,000 people in the EU) 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.