Please note that this product was withdrawn from the Community register of designated orphan medicinal products in July 2013 on request of the sponsor.
On 9 February 2012, orphan designation (EU/3/12/951) was granted by the European Commission to Lucane Pharma SA, France, for sodium phenylbutyrate for the treatment of carbamoyl-phosphate-synthase-1 deficiency.
For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.
- What is carbamoyl-phosphate-synthase-1 deficiency?
Carbamoyl-phosphate-synthase-1 deficiency is one of the inherited disorders known as ‘urea-cycle disorders’, which cause ammonia to accumulate in the blood. Patients with carbamoyl-phosphate-synthase-1 deficiency lack ‘carbamoyl-phosphate synthase’, one of the liver enzymes that are needed to get rid of excess nitrogen. In the absence of this enzyme, excess nitrogen accumulates in the body in the form of ammonia, which can be toxic at high levels, especially to the brain. Symptoms of the disease usually appear in the first few days of life and include lethargy (lack of energy), vomiting, loss of appetite, seizures (fits) and coma.
Carbamoyl-phosphate-synthase-1 deficiency is a long-term debilitating and life-threatening disease that leads to mental retardation and is associated with a high mortality rate.
- What is the estimated number of patients affected by the condition?
At the time of designation, carbamoyl-phosphate synthase-1 deficiency affected less than 0.02 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 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. At the time of designation, this represented a population of 509,000,000 (Eurostat 2012).
- What treatments are available?
At the time of designation, sodium phenylbutyrate was already authorised in the EU for the treatment of some urea-cycle disorders, including carbamoyl-phosphate-synthase-1 deficiency. This medicine is known to have a bitter taste, which may decrease compliance with treatment. In addition, patients were advised to control their dietary intake of proteins, which are rich in nitrogen, to reduce the amount of ammonia formed in the body.
The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with carbamoyl-phosphate-synthase-1 deficiency because it is a new tasteless granule formulation of sodium phenylbutyrate developed to mask its bitter taste, which is expected to help patients to follow their treatment. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.
- How is this medicine expected to work?
After it is ingested, sodium phenylbutyrate is converted into a substance called phenylacetate in the body. Phenylacetate attaches to the amino acid glutamine, which contains nitrogen, forming a substance that is eliminated in the urine. This allows the levels of nitrogen in the body to decrease, reducing the amount of ammonia produced.
This medicine is a new formulation of sodium phenylbutyrate in which the granules are coated in a way that masks the bitter taste of the medicine, making it more palatable.
- What is the stage of development of this medicine?
The effects of sodium phenylbutyrate 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 carbamoyl-phosphate-synthase-1 deficiency had been started.
At the time of submission, this medicine was not authorised anywhere in the EU for carbamoyl-phosphate-synthase-1 deficiency 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 7 December 2011 recommending the granting of this designation.
- 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 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.
|Name||Language||First published||Last updated|
|EU/3/12/951: Public summary of opinion on orphan designation: Sodium phenylbutyrate for the treatment of carbamoyl-phosphate-synthase-1||(English only)||2012-03-01||2013-07-31|
|Active substance||Sodium phenylbutyrate|
|Disease/condition||Treatment of carbamoyl-phosphate-synthase-1 deficiency|
|Date of decision||09/02/2012|
|Orphan decision number||EU/3/12/951|
Review of designation
Please note that this product (Pheburane) was withdrawn from the Community register of designated orphan medicinal products in July 2013 on request of the sponsor, at the time of the granting of a marketing authorisation.
During its meeting of 12-13 April 2013, the Committee for Orphan Medicinal Products (COMP) reviewed the designations EU/3/12/951, EU/3/12/950 and EU/3/12/949 for Pheburane (sodium phenylbutyrate) as an orphan medicinal product for the treatment of the following urea-cycle disorders: carbamoyl-phosphate-synthase-1 deficiency, ornithine-transcarbamylase deficiency and citrullinaemia type 1. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other satisfactory methods of treatment.
As other satisfactory methods of treatment for patients with this condition are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. As one of the criteria for orphan designation is no longer met (i.e. the significant benefit), the COMP recommended that the orphan designation of the product should not be maintained1.
The sponsor requested a re-examination of the COMP opinion. After considering the grounds for this request, the COMP re-examined the initial opinion, and confirmed the removal of the orphan designation on 1 July 2013.
1The removal of the orphan designation at time of marketing authorisation means that the product cannot benefit from 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with a comparable therapeutic indication can be placed on the market.
- Life-threatening or chronically debilitating nature of the condition
The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Pheburane for adjunctive therapy in the chronic (long-term) management of urea-cycle disorders, involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase.
This falls within the scope of the product’s designated orphan indications, which are treatment of carbamoyl-phosphate-synthase-1 deficiency, ornithine-transcarbamylase deficiency and citrullinaemia type 1 (also known as argininosuccinate-synthetase deficiency).
The COMP concluded that there had been no change in the seriousness of these conditions since the orphan designation in February 2012. The three urea-cycle disorders remained conditions that were debilitating in the long term and life-threatening because they lead to mental retardation and are associated with poor overall survival.
- Prevalence of the condition
The sponsor performed a literature search and concluded that the prevalence of urea-cycle disorders had not changed since the orphan designation in February 2012.
On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of the three urea-cycle disorders remained 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 was still estimated to be:
- less than 0.02 people in 10,000 for carbamoyl-phosphate-synthase-1 deficiency. This is equivalent to a total of fewer than 1,000 people in the EU;
- less than 0.1 people in 10,000 for ornithine-transcarbamylase deficiency. This is equivalent to a total of fewer than 5,000 people in the EU;
- less than 0.24 people in 10,000 for citrullinaemia type 1. This is equivalent to a total of fewer than 12,000 people in the EU.
- Existence of other satisfactory methods of treatment
At the time of the review of the orphan designation, sodium phenylbutyrate was already authorised as Ammonaps in the EU for the treatment of some urea-cycle disorders, including carbamoyl-phosphate-synthase-1 deficiency, ornithine-transcarbamylase deficiency and citrullinaemia type 1. This medicine is known to have a bitter taste.
- Significant benefit over existing treatments
The COMP noted that Pheburane is a new, tasteless granule formulation of sodium phenylbutyrate that contains excipients (inactive ingredients) to mask the unpleasant taste of the active substance.
Data have been provided that show that Pheburane has improved palatability over Ammonaps and that there are difficulties in administering the latter because of its bitter taste. However, the sponsor had not provided sufficient data to confirm that the improved palatability of Pheburane results in a better outcome for patients with urea-cycle disorders, such as improved treatment compliance or enhanced quality of life. As these data are needed to demonstrate that Pheburane is of significant benefit over current treatment, the COMP concluded that the criteria to show a significant benefit of Pheburane in the treatment of urea cycle disorders had not been met.
Based on the data submitted and the scientific discussion within the COMP, the COMP concluded that Pheburane does not meet one of the criteria for designation as an orphan medicinal product. Therefore, the COMP recommended that the product should be removed from the Community register of orphan medicinal products.
|Name||Language||First published||Last updated|
|Recommendation for removal of orphan designation at the time of marketing authorisation: Pheburane (sodium phenylbutyrate) for the treatment of urea-cycle disorders (carbamoyl-phosphate-synthase-1 deficiency, ornithine-transcarbamylase deficiency and citrullinaemia type 1)||(English only)||2013-08-08|
Sponsor’s contact details:
Lucane Pharma SA
9 rue Nicolas Charlet
Tel. +33 153 868 753
Fax +33 147 345 672
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.