EU/3/09/661

  • Email
  • Help

Orphan designation

On 30 May 2016, orphan designation (EU/3/09/661) was granted by the European Commission to Ipsen Pharma, France, for (S)-ethyl 2-amino-3-(4-(2-amino-6(-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (also known as telotristat etiprate) for the treatment of carcinoid syndrome.

(S)-ethyl 2-amino-3-(4-(2-amino-6(-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate has been authorised in the EU as Xermelo since 18 September 2017.

What is carcinoid syndrome?

Carcinoid syndrome is a condition that may develop in patients with a type of cancer called a neuroendrocrine or carcinoid tumour when the tumour spreads to the liver.

Carcinoid tumours are slow-growing tumours that develop in hormone producing cells usually in the appendix or in the small bowel. The tumour can secrete hormones such as serotonin but these are normally broken down by the liver and do not cause symptoms. However, when the tumour spreads to the liver, the hormones can enter the blood stream and cause symptoms of carcinoid syndrome such as severe diarrhoea, belly cramps and flushing (reddening of the skin). Some patients also develop valvular heart disease (damage to the valves of the heart) or constriction of the airway (bronchoconstriction).

Carcinoid syndrome is a debilitating and life-threatening condition because it can lead to heart failure and difficulty breathing.

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

At the time of designation, carcinoid syndrome affected approximately 0.7 in 10,000 people in the European Union (EU). This was equivalent to a total of around 36,000 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 2016).

What treatments are available?

At the time of designation, somatostatin analogues, such as octreotide and lanreotide, were authorised in the EU to treat the symptoms caused by carcinoid tumours. Other medicines used to treat the condition included everolimus, sunitinib, and interferon alfa. Patients with carcinoid tumours could be cured using surgery to remove the tumours if they are found early.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with carcinoid syndrome because initial studies in patients whose condition has not responded to standard treatments, or who cannot be given them, showed that their symptoms improved. 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?

This medicine is expected to work by blocking an enzyme known as tryptophan hydroxylase (TPH), which is responsible for the production of the hormone serotonin. Serotonin is one of the hormones that are produced in large amounts in patients with carcinoid syndrome. By blocking TPH, the medicine is expected to stop the production of serotonin, reducing the symptoms of the condition.

What is the stage of development of this medicine?

The effects of the medicine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with the medicine in patients with carcinoid syndrome were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for carcinoid syndrome.

This medicine had been designated orphan on 8 October 2009 for the treatment of carcinoid tumours. The original designation was granted to Lexicon Celtic Ltd, United Kingdom; sponsorship was transferred to Ipsen Pharma, France, in April 2015. At the request of the sponsor and having assessed the additional data submitted, the COMP adopted an opinion on 21 April 2016 recommending the change of the orphan condition from carcinoid tumour to carcinoid syndrome.

Orphan designation of the medicine has been granted in the United States for managing symptoms of carcinoid syndrome associated with carcinoid tumour.

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>(S)-ethyl 2-amino-3-(4-(2-amino-6((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate</p>
Active substance(S)-ethyl 2-amino-3-(4-(2-amino-6((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate
Medicine NameXermelo
Disease/conditionTreatment of carcinoid syndrome
Date of decision30/05/2016
OutcomePositive
Orphan decision numberEU/3/09/661

Review of designation

On 25 July 2017, the Committee for Orphan Medicinal Products (COMP) completed a review of the designation EU/3/09/661 for Xermelo (telotristat1) as an orphan medicinal product for the treatment of carcinoid 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 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 carcinoid syndrome. The COMP recommended that the orphan designation of the medicine be maintained2.


1Previously known as (S)-ethyl 2-amino-3-(4-(2-amino-6(-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

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 the same 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 Xermelo for:

‘Xermelo is indicated as an adjunct to somatostatin analogue (SSA) therapy for the treatment of carcinoid syndrome to improve symptom control in adult patients with metastatic neuroendocrine tumours’.

This falls within the scope of the product’s designated orphan indication, which was originally ‘treatment of carcinoid tumours’ and was changed to ‘carcinoid syndrome’ in 2016.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2016. Carcinoid syndrome remains a condition that is debilitating in the long term, particularly due to flushing and diarrhoea, and can be life-threatening due to heart failure and difficulty in breathing.

Prevalence of the condition

The sponsor provided updated information on the prevalence of carcinoid syndrome based on data from national and European cancer registries and articles from the scientific literature.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of carcinoid syndrome 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 1 person in 10,000. This is equivalent to a total of around 52,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, somatostatin analogues, such as octreotide and lanreotide, were authorised in the EU to treat symptomslike diarrhoea caused by carcinoid tumours. Other medicines used to manage aspects of the condition included everolimus, sunitinib, and interferon alfa.

Significant benefit of Xermelo

The COMP concluded that the claim of a significant benefit of Xermelo in carcinoid syndrome is justified on the basis of a clinically relevant decrease in number of bowel movements suffered by patients with carcinoid syndrome not fully controlled with somatostatin analogues.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Xermelo is of significant benefit to patients affected by carcinoid syndrome.

Conclusions

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

Related information

Sponsor’s contact details

Ipsen Pharma
65 Quai Georges Gorse
92100 Boulogne-Billancourt
France
Tel. +33 1 58 33 50 00
E-mail: http://www.ipsen.com/en/contact-us/

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.