EU/3/00/007: Orphan designation for the treatment of N-acetylglutamate synthetase (NAGS) deficiency

Patients with n-acetylglutamate synthetase (NAGS) deficiency lack a vital enzyme called N-acetylglutamate synthetase. N-acetylglutamate synthetase is a protein that catalyzes (enzyme) a chemical reaction that produces a compound called N-acetylglutamate. This is needed in a process known as urea cycle, which clears harmful ammonia substances from the body by transforming them into urea, which can easily be excreted in urine. Patients affected by NAGS deficiency have a defect in the gene that regulates the production of NAGS leading to a less active or less abundant enzyme in the body. As a result ammonia accumulates in these patients. The disease is chronically debilitating and has acute periods of hyperammonaemia (too much ammonia in the blood). Symptoms usually have an early onset in childhood and include cerebral oedema (swelling around the brain), seizures and coma. N-acetylglutamate deficiency is life-threatening.

At the time of designation, n-acetylglutamate deficiency affected approximately 0.00125 in 10,000 in 10,000 people in the European Union (EU). This was equivalent to a total of around 50 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 no satisfactory treatments authorised in the Community for the treatment of n-acetylglutamate deficiency.

N-carbamyl-l-glutamic acid is structurally similar to n-acetylglutamate, the compound that is produced by NAGS and is missing from patients with the condition. The product is expected to replace the missing compound in patients' body, preventing the accumulation of ammonia and decreasing the symptoms of the disease.

The effects of n-carbamyl-l-glutamic acid were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with n-acetylglutamate synthetase deficiency were ongoing.
N-carbamyl-l-glutamic acid was not authorised anywhere worldwide for the treatment of n-acetylglutamate deficiency, at the time of submission. Orphan designation of n-carbamyl-l-glutamic acid was granted in the United States for this condition.

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: N-carbamyl-l-glutamic acid (Carbaglu) has been authorised in the EU since 28 January 2003 for treatment of hyperammonaemia due to N-acetylglutamate synthase deficiency.

• 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.