EU/3/15/1471

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Orphan designation

Please note that this product (marketed as Cuprior) was withdrawn from the Community Register of designated Orphan Medicinal Products by the European Commission in July 2017, at the time of the granting of a marketing authorisation.

On 19 March 2015, orphan designation (EU/3/15/1471) was granted by the European Commission to GMP-Orphan SAS, France, for trientine tetrahydrochloride for the treatment of Wilson's disease.

In July 2015, GMP-Orphan SAS changed name to GMP-Orphan SA.

What is Wilson's disease?

Wilson's disease is a genetic disorder that causes copper absorbed from food to accumulate in the body. In healthy people, liver cells remove most of the excess copper and release it into the bile, which flows into the intestines. In people with Wilson’s disease, due to a genetic defect, the liver cannot remove copper and the copper builds up in the liver and in other organs such as the kidneys, brain and eyes, and damages them.

Wilson's disease is chronically debilitating and can be life threatening if not treated due to the toxicity of copper in the liver and brain.

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

At the time of designation, Wilson's disease affected approximately 0.6 in 10,000 people in the European Union (EU). This was equivalent to a total of around 31,000 people*, and is below the ceiling for orphan designation, which is 5 people in 10,000. This isbased 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 512,900,000 (Eurostat 2015).

What treatments are available?

At the time of designation, several medicines were authorised in the EU for the treatment of Wilson’s disease, including penicillamine and trientine dihydrochloride, which is used in patients who cannot tolerate penicillamine but is only authorised in one EU country. These medicines were used to remove excess copper from the body and to limit the absorption of further copper from food. Zinc acetate was also authorised for Wilson’s disease, although it was not recommended for use at the beginning of treatment.

The sponsor has provided sufficient information to show that trientine tetrahydrochloride might be of significant benefit for patients with Wilson's disease because it is assumed to be similar to trientine dihydrochloride and an orphan designation may encourage it to be made more widely available. 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?

Trientine tetrahydrochloride is expected to work in the same way as trientine dihydrochloride, by attaching to the free copper in the body and forming a compound that can be excreted in the urine by the kidneys.

What is the stage of development of this medicine?

The effects of trientine tetrahydrochloride have been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials with trientine tetrahydrochloride had been started.

At the time of submission, trientine tetrahydrochloride was not authorised anywhere in the EU for Wilson's disease 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 12 February 2015 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>Trientine tetrahydrochloride</p>
Active substanceTrientine tetrahydrochloride
Medicine Name
Disease/conditionTreatment of Wilson's disease
Date of decision19/03/2015
OutcomeWithdrawn
Orphan decision numberEU/3/15/1471

Review of designation

Please note that this product (marketed as Cuprior) was withdrawn from the Community Register of designated Orphan Medicinal Products by the European Commission in July 2017, at the time of the granting of a marketing authorisation.

On 20 July 2017, the Committee for Orphan Medicinal Products (COMP) completed a review of the designation EU/3/15/1471 for Cuprior (trientine tetrahydrochloride) as an orphan medicinal product in the treatment of Wilson's disease. 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 methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with Wilson's disease. As one of the criteria for orphan designation is no longer met, the COMP recommended that the orphan designation of the product should not be maintained1.


1 The 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 the same 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 Cuprior for: ‘treatment of Wilson’s disease in adults, adolescents and children ≥ 5 years intolerant to D-penicillamine therapy’.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of Wilson's disease’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2015. Wilson's disease remains a chronically debilitating disease that can be life threatening if not treated, due to the toxicity of excess copper in the liver and brain.

Prevalence of the condition

The sponsor provided updated information on the prevalence of Wilson's disease based on data from the published literature.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of Wilson's disease 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 still estimated to be approximately 0.6 people in 10,000. This is equivalent to a total of around 31,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, penicillamine, trientine dihydrochloride and zinc acetate were authorised in the EU for the treatment Wilson’s disease.

Significant benefit of Cuprior

The COMP concluded that the claim of a significant benefit of Cuprior over penicillamine is justified because Cuprior is for use in patients who cannot take penicillamine.

Cuprior was also considered of significant benefit over zinc acetate since the latter is for use only when the symptoms have been brought under control and it is not recommended for use at the beginning of treatment. Therefore Cuprior can be used in a wider range of patients with Wilson’s disease.

However, the COMP did not conclude that Cuprior is of significant benefit over trientine dihydrochloride. The company for Cuprior had claimed that Cuprior would significantly improve availability of trientine throughout the EU; however, the company did not provide sufficient evidence to demonstrate lack of availability of trientine in the EU.

Therefore, the COMP concluded that the assumption that Cuprior may be of significant benefit for patients affected by Wilson’s disease is no longer valid.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP concluded that Cuprior no longer meets 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.

More information on the COMP assessment can be found in the September 2017 COMP minutes.

Sponsor's contact details

GMP-Orphan SA
Pépinière Paris Santé Cochin
27-29 rue Faubourg Saint-Jacques
75014 Paris
France
Tel. +33 685833905
E-mail: fred@gmp-o.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.