EU/3/08/576: Orphan designation for the treatment of methylmalonic acidaemia

Methylmalonic acidaemia is an inherited disease that usually appears in early infancy. It is caused by an abnormal gene. For a patient to develop this disease, he or she needs to have inherited one copy of the abnormal gene from each parent. This is called 'autosomal recessive' transmission. Patients with methylmalonic acidaemia produce defective versions of an enzyme called methylmalonyl-coenzyme A mutase, which is involved in breaking down proteins and fats in the body. When this breakdown process does not happen normally, it results in a build-up of methylmalonic acid and the toxic substance ammonia in the blood. This causes symptoms such as poor feeding, vomiting, hypotonia (weak muscle tone causing floppiness), lethargy (lack of energy) and encephalopathy (problems with the brain).

The effects of methylmalonic acidaemia can be life-threatening.

At the time of designation, propionic acidaemia affected approximately 0.02 in 10,000 people in the European Union (EU). This was equivalent to a total of around 1,000 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. This represents a population of 509,000,000 (Eurostat 2013).

Current treatments for methylmalonic acidaemia aim to remove the ammonia that builds up in the blood. They include sodium benzoate, which is an ammonium scavenger (a substance that mops us ammonia in the blood). Patients can also avoid further build-up of ammonia in the blood by reducing their intake of nitrogen intake by eating a low-protein diet.

Carglumic acid could be of significant benefit for the treatment of methylmalonic acidaemia, because it acts differently from other medicinal products. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Carglumic acid is very similar in structure to N-acetylglutamate, which activates an enzyme that breaks down ammonia. Carglumic acid therefore helps break down ammonia, reducing ammonia blood levels and its toxic effects. This is expected to relieve the symptoms of methylmalonic acidaemia that are caused by high blood ammonia levels.

The effects of carglumic acid have not been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials in patients with methylmalonic acidaemia had been initiated.

At the time of submission carglumic acid was not authorised anywhere in the world for methylmalonic acidaemia or designated as orphan medicinal product elsewhere for this condition.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted a positive opinion on 10 September 2008 recommending the granting of this designation.

Update: Carglumic acid (Carbaglu) was authorised in the EU on 27 May 2011 for treatment of hyperammonaemia due to methylmalonic acidaemia.

• 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 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.