On 7 November 2008, orphan designation (EU/3/08/575) was granted by the European Commission to Orphan Europe SARL, France, for carglumic acid for the treatment of isovaleric acidaemia.
For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.
- What is isovaleric acidaemia?
Isovaleric 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 isovaleric acidaemia produce defective versions of an enzyme called isovaleryl-coenzyme A dehydrogenase, which is normally involved in the breakdown of parts of proteins in the body. When this breakdown process does not happen normally, it results in a build-up of isovaleric 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 isovaleric acidaemia are disabling and can be life-threatening.
- What is the estimated number of patients affected by the condition?
At the time of designation, isovaleric acidaemia affected approximately 0.01 in 10,000 people in the European Union (EU). This was equivalent to a total of 500 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 502,800,000 (Eurostat 2008).
- What treatments are available?
Current treatments for isovaleric 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 up ammonia in the blood). Patients can also avoid further build-up of ammonia in the blood by reducing their intake of nitrogen by eating a low-protein diet.
Carglumic acid could be of significant benefit for the treatment of isovaleric 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.
- How is this medicine expected to work?
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 isovaleric acidaemia that are caused by high blood ammonia levels.
- What is the stage of development of this medicine?
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 isovaleric acidaemia had been initiated.
At the time of submission carglumic acid was not authorised anywhere in the world for isovaleric 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 isovaleric acidaemia.
- Opinions on orphan medicinal product designations are based on the following three criteria:
- 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.
|Name||Language||First published||Last updated|
|EU/3/08/575: Public summary of positive opinion for orphan designation of carglumic acid for the treatment of isovaleric acidaemia||(English only)||02/04/2009||17/09/2013|
|Active substance||Carglumic acid|
|Disease/condition||Treatment of isovaleric acidaemia|
|Date of decision||06/11/2008|
|Orphan decision number||EU/3/08/575|
Review of designation
During its meeting of 4-5 May 2011, the Committee for Orphan Medicinal Products (COMP) reviewed the designations for Carbaglu (carglumic acid) as an orphan medicinal product for the treatment of isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia.
The COMP assessed whether, at the time of addition of these new indications to the marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the conditions, and the existence of other satisfactory methods of treatment.
As other satisfactory methods of treatment for patients with these conditions are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designations of the medicine be maintained.
- Life-threatening or long-term debilitating nature of the conditions
In April 2011, the Committee for Medicinal Products for Human Use (CHMP) recommended extending the approved therapeutic indication for Carbaglu to include the following indications:
- treatment of hyperammonaemia due to isovaleric acidaemia;
- treatment of hyperammonaemia due to methymalonic acidaemia;
- treatment of hyperammonaemia due to propionic acidaemia.
This falls within the scope of the product’s designated orphan conditions, which are ‘treatment of isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia’.
The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designations in 2008. Isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia remain conditions that are debilitating in the long term and life-threatening, particularly due to neurological complications caused by hyperammonaemia.
- Prevalence of the conditions
On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia remain below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence of these conditions were still estimated to be approximately 0.01, 0.02 and 0.02 in 10,000 people, respectively. This is equivalent to a total of around 3,000 people in the EU affected by these conditions.
- Existence of other satisfactory methods of treatment
At the time of the review of the orphan designations, other methods were authorised in the EU for the treatment of isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia. Treatments aimed to remove the ammonia that builds up in the blood, and included sodium benzoate (an ammonia scavenger). Patients were also advised to avoid further build-up of ammonia in the blood by reducing their intake of nitrogen by eating a low-protein diet.
- Significant benefit over existing treatments
The COMP concluded that the claim of a significant benefit of Carbaglu in the treatment of isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia is justified on the basis of its new mechanism of action for reducing ammonia, which involves restoring the physiological pathway of ureagenesis. This is supported by data from an observational study including patients with isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia. The study showed that treatment with Carbaglu on its own or in combination with sodium benzoate induced a rapid decrease in ammonia levels in all age groups, reducing the risk of neurological complications.
Therefore, although other satisfactory methods for the treatment of these conditions have been authorised in the EU, the COMP concluded that Carbaglu is of significant benefit for patients affected by these conditions.
Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Carbaglu still meets the criteria for designation as an orphan medicinal product and that it should remain in the Community register of orphan medicinal products.
|Name||Language||First published||Last updated|
|Recommendation for maintenance of orphan designation at the time of addition of new indications to the marketing authorisation: Carbaglu (carglumic acid) for the treatment of isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia||(English only)||10/10/2011|
Sponsor’s contact details
Orphan Europe SARL
Immeuble "Le Wilson"
70 Avenue du Général de Gaulle
Tel. +33 1 47 73 64 58
Fax +33 1 49 00 18 00
For contact details of patients’ organisations whose activities are targeted at rare diseases, see:
- Orphanet, a database containing information on rare diseases, which includes a directory of patients’ organisations registered in Europe;
- European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.