EU/3/10/737

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Orphan designation

On 10 June 2010, orphan designation (EU/3/10/737) was granted by the European Commission to Hyperion Therapeutics Limited, United Kingdom, for glyceryl tri-(4-phenylbutyrate) for the treatment of hyperargininaemia.

In June 2015, Hyperion Therapeutics Limited changed name to Horizon Therapeutics Limited.

The sponsorship was transferred to Horizon Pharma Ireland Limited, Ireland, in January 2016.

Update: Glyceryl tri-(4-phenylbutyrate) (Ravicti) has been authorised in the EU since 27 November 2015. Ravicti is indicated for use as adjunctive therapy  for chronic management of adult and paediatric patients ≥2 months of age with urea cycle disorders (UCDs) including deficiencies of carbamoyl phosphate-synthase-I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.

Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

What is hyperargininaemia?

Hyperargininaemia is one of the inherited disorders known as ‘urea cycle disorders’, which cause ammonia to accumulate in the blood. Patients with hyperargininaemia lack ‘arginase’, 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.

Hyperargininaemia is a long-term debilitating and life-threatening disease that leads to mental retardation and is associated with poor overall survival.

What is the estimated number of patients affected by the condition?

At the time of designation, hyperargininaemia affected approximately 0.03 in 10,000 people in the European Union (EU). This was equivalent to a total of around 2,000 people*, and is below the threshold 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 506,300,000 (Eurostat 2010).

What treatments are available?

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of hyperargininaemia. 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.

How is this medicine expected to work?

Glyceryl tri-(4-phenylbutyrate) is a ‘prodrug’ of phenylbutyrate. It consists of three molecules of phenylbutyrate linked together. After it is swallowed, the medicine is expected to be broken down into phenylbutyrate in the gut. Phenylbutyrate works by being converted into phenylacetate in the body and combining with the amino acid glutamine, which contains nitrogen, to form a substance that can be removed from the body by the kidneys. This allows the levels of nitrogen in the body to decrease, reducing the amount of ammonia produced.

What is the stage of development of this medicine?

The effects of glyceryl tri-(4-phenylbutyrate) have been evaluated in experimental models.

At the time of submission of the application for orphan designation, a study with glyceryl tri-(4-phenylbutyrate) in patients with urea cycle disorders had been completed.

At the time of submission, glyceryl tri-(4-phenylbutyrate) was not authorised anywhere in the EU for hyperargininaemia. Orphan designation of glyceryl tri-(4-phenylbutyrate) had been granted in the United States of America for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 3 February 2010 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.

Key facts

Product details for <p>Glyceryl tri-(4-phenylbutyrate)</p>
Active substanceGlyceryl tri-(4-phenylbutyrate)
Medicine Name
Disease/conditionTreatment of hyperargininaemia
Date of decision10/06/2010
OutcomePositive
Orphan decision numberEU/3/10/737

Review of designation

During its meeting of 6 to 8 October 2015, the Committee for Orphan Medicinal Products (COMP) reviewed the designations EU/3/10/733, EU/3/10/734, EU/3/10/735, EU/3/10/736, EU/3/10/737 and EU/3/10/738 for Ravicti (glycerol phenybutyrate1) as an orphan medicinal product for the treatment of the following urea cycle disorders: carbamoyl phosphate-synthase-1 deficiency, ornithine carbamoyltransferase deficiency, citrullinaemia type 1, argininosuccinic aciduria, hyperargininaemia and ornithine translocase deficiency (hyperornithinaemia-hyperammonaemia homocitrullinuria (HHH) syndrome). 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 conditions, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU) for three of the above conditions (carbamoyl phosphate-synthase-1 deficiency, ornithine carbamoyltransferase deficiency, and citrullinaemia type 1), the COMP also considered whether the medicine is of significant benefit to patients with these conditions. The COMP recommended that the orphan designations of the medicine be maintained2.


1Previously known as glyceryl tri-(4-phenybutyrate).

2The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 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 cannot be placed on the market.

Life-threatening or long-term debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Ravicti for:

‘use as adjunctive therapy for chronic management of adult and paediatric patients ≥2 months of age with urea cycle disorders (UCDs) including deficiencies of carbamoyl phosphate-synthase-I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency (hyperornithinaemia-hyperammonaemia homocitrullinuria (HHH) syndrome) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone’.

This falls within the scope of the product’s designated orphan indications, which are: carbamoyl phosphate-synthase-1 deficiency, ornithine carbamoyltransferase deficiency, citrullinaemia type 1 (also known as argininosuccinate synthetase deficiency), argininosuccinic aciduria (also known as argininosuccinate lyase deficiency), hyperargininaemia (also known as arginase deficiency) and ornithine translocase deficiency (hyperornithinaemia-hyperammonaemia homocitrullinuria (HHH) syndrome).

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designations in 2010. Urea cycle disorders remain long-term debilitating and life-threatening conditions that lead to learning disability and are associated with poor overall survival.

Prevalence of the condition

The sponsor performed a literature search and concluded that there were no major changes in the prevalence of the six urea cycle disorders since the orphan designations in June 2010.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of the six urea cycle disorders remains 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 estimated to be:

  • approximately 0.14 people in 10,000 for carbamoyl phosphate-synthase-1 deficiency. This is equivalent to a total of around 7,000 people in the EU;
  • approximately 0.14 people in 10,000 for ornithine carbamoyltransferase deficiency. This is equivalent to a total of around 7,000 people in the EU;
  • approximately 0.2 people in 10,000 for citrullinaemia type 1. This is equivalent to a total of around 10,000 people in the EU;
  • approximately 0.06 people in 10,000 for argininosuccinic aciduria. This is equivalent to a total of around 3,000 people in the EU;
  • approximately 0.03 people in 10,000 for hyperargininaemia. This is equivalent to a total of around 1,500 people in the EU;

approximately 1.2 people in 10,000 for ornithine translocase deficiency (hyperornithinaemia-hyperammonaemia homocitrullinuria (HHH) syndrome). This is equivalent to a total of around 61,500 people in the EU.

Existence of other methods of treatment

The COMP noted that, at the time of the review of the orphan designations, no treatments were authorised in the EU for patients affected by argininosuccinic aciduria, hyperargininaemia and ornithine translocase deficiency.

Treatments were authorised in the EU for the treatment of carbamoyl phosphate-synthase-1 deficiency, ornithine carbamoyltransferase deficiency and citrullinaemia type 1 and included Ammonaps (sodium phenylbutyrate) and Pheburane (sodium phenylbutyrate).

Significant benefit of Ravicti

The COMP concluded that the claim of a significant benefit of Ravicti in the treatment of carbamoyl phosphate-synthase-1 deficiency, ornithine carbamoyltransferase deficiency and citrullinaemia type 1 is justified on the basis of data showing that the frequency of hyperammonaemia crises (high blood levels of ammonia) was much lower in patients treated with Ravicti compared with patients treated with other treatments. Furthermore, Ravicti is available as an oral liquid and this is considered to be beneficial especially for children, because it can improve adherence to treatment.

Therefore, although other methods for the treatment of these three urea cycle disorders have been authorised in the EU, the COMP concluded that Ravicti is of significant benefit to patients affected by these conditions.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Ravicti still meets the criteria for designation as an orphan medicinal product and that it should remain in the Community Register of Orphan Medicinal Products.

Sponsor’s contact details

Horizon Pharma Ireland Limited
Connaught House, 1st Floor
1 Burlington Road
Dublin 4
D04 C5Y6
Ireland
Tel. +353 1 772 2137
Fax: +353 1 772 2101
E-mail: customerservice@horizonpharma.com

Patients' organisations

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.