EU/3/18/2025: Orphan designation for the treatment of methylmalonic acidaemia

Methylmalonic acidaemia is an inherited condition in which the body does not process proteins and fats properly. It is caused by mutations (changes) in certain genes responsible for producing a protein called methylmalonyl-CoA mutase.

The condition usually appears in early infancy, with the patient having high levels of acid and ammonia in the blood. Symptoms include poor feeding, vomiting, weak muscle tone causing floppiness, lethargy (lack of energy) and problems with the brain.

Methylmalonic acidaemia is a long-term debilitating condition and is life threatening due to complications affecting the nervous system, gut and blood.

At the time of designation, methylmalonic acidaemia affected less than 0.4 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 21,000 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 28), Norway, Iceland and Liechtenstein. This represents a population of 517,400,000 (Eurostat 2018).

At the time of the orphan designation, Carbaglu was authorised in the EU for treating high levels of ammonia that occur in patients with methylmalonic acidaemia. Other medicines were used to reduce production of acid in the gut. Patients could also avoid further build-up of ammonia in the blood by eating a low-protein diet.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with methylmalonic acidaemia, with laboratory data indicating that it could reduce the build-up of acid and improve survival.

This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

In patients with methylmalonic acidaemia, the methylmalonyl-CoA mutase protein, which is involved in reactions to break down proteins and fats, does not work properly.

This medicine is made of genetic material contained in fatty particles. When injected into the patient, it is expected that the fatty particles deliver the genetic material to liver cells, making them able to produce functional methylmalonyl-CoA mutase. This is expected to reduce patients' symptoms.

The effects of the medicine have been evaluated in experimental models.

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

At the time of submission, the medicine was not authorised anywhere in the EU for methylmalonic acidaemia or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 19 April 2018 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 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.