EU/3/07/523

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Orphan designation

This medicine is now known as lutetium (177Lu) oxodotreotide.

On 31 January 2008, orphan designation (EU/3/07/523) was granted by the European Commission to BioSynthema Global Operations B.V, the Netherlands, for lutetium (177Lu)-N-[(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide for the treatment of gastro-entero-pancreatic neuroendocrine tumours.

The sponsorship was transferred to Advanced Accelerator Applications, France, in September 2011.

Lutetium (177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide has been authorised in the EU as Lutathera since 26 September 2017.

What are gastro-entero-pancreatic neuroendocrine tumours?

Gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) are a group of tumours that share a number of common characteristics, for example content of specific chemical substances called “neuroendocrine markers”. There are two main types of GEP-NET: carcinoid tumours, and “pancreatic-type” endocrine tumours (these often occur in the pancreas, but also in other sites). GEP-NET are chronically debilitating as they often produce and secrete hormonal substances that may cause severe symptoms, and are life-threatening if they spread to other organs in the body.

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

At the time of designation, GEP-NET affected approximately 1.6 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 80,000 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 based on data from the European Union (EU 27), Norway, Iceland and Lichtenstein. This represents a population of 498,000,000 (Eurostat 2006). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

What treatments are available?

At the time of the application for orphan designation, several products were authorised in the Community for the treatment of one or more of GEP-NET. In most cases, these products are active against the symptoms caused by the secretion of hormones, but are not active against the growth of the tumours. Commonly, surgery and treatment with so called somatostatin analogues were used. Somatostatin analogues are similar to a naturally occurring hormone in the body called somatostatin that prevents the release of many hormones.

Lutetium(177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide may be of potential significant benefit, as it is expected to kill tumour cells, and thus reduce tumour size and eventually improve the long term outcome of the patients. These assumptions 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?

Lutetium(177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide contains a somatostatin analogue together with a radioactive form of a chemical called Lutetium (177Lu). The product is expected to bind to the tumour cells thanks to the somatostatin analogue and to kill them with the radiation from the lutetium component.

What is the stage of development of this medicine?

The effects of lutetium (177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical studies in patients with GEP-NET were ongoing.

Lutetium(177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide was not authorised anywhere worldwide for GEP-NET or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 5 December 2007 recommending the granting of this designation.

Opinions on orphan medicinal products designations are based on the following cumulative 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>Lutetium (177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide&#160;<span style="font-size: 9pt; font-family: 'Verdana','sans-serif'; mso-fareast-font-family: Verdana; mso-bidi-font-family: Verdana; mso-ansi-language: EN-GB; mso-fareast-language: EN-GB; mso-bidi-language: AR-SA;">(lutetium (<sup>177</sup>Lu) oxodotreotide)</span></p>
Active substanceLutetium (177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide (lutetium (177Lu) oxodotreotide)
Medicine Name
Disease/conditionTreatment of gastro-entero-pancreatic neuroendocrine tumours
Date of decision30/01/2008
OutcomePositive
Orphan decision numberEU/3/07/523

Review of designation

On 25 July 2017, the Committee for Orphan Medicinal Products (COMP) completed a review of the designation EU/3/07/523 for Lutathera (lutetium (177Lu) oxodotreotide) as an orphan medicinal product for the treatment of gastro-entero-pancreatic neuroendocrine tumours. 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 gastro-entero-pancreatic neuroendocrine tumours. The COMP recommended that the orphan designation of the medicine be maintained1.


1The 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 Lutathera for:

‘treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP‑NETs) in adults’.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of gastro-entero-pancreatic neuroendocrine tumours’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2008. Gastro-entero-pancreatic neuroendocrine tumours remain chronically debilitating as they may cause severe symptoms, and are life-threatening if they spread to other organs in the body.

Prevalence of the condition

The sponsor provided updated information on the prevalence of gastro-entero-pancreatic neuroendocrine tumours based on data from the published literature and from the RARECARE database.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of gastro-entero-pancreatic neuroendocrine tumours 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 3.8 people in 10,000. This is equivalent to a total of around 196,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, several products were authorised in the EU for the treatment of gastro-entero-pancreatic neuroendocrine tumours. Commonly, surgery and treatment with so called somatostatin analogues were used. These products are active against the symptoms, but are not active against the growth of the tumours. The cancer medicines Afinitor (everolimus) and Sutent (sunitinib), which target the growth of the tumours, were used for the treatment of pancreatic neuroendocrine tumours.

Significant benefit of Lutathera

The COMP concluded that the claim of a significant benefit of Lutathera in the treatment of gastro-entero-pancreatic neuroendocrine tumours is justified on the basis of the longer time patients lived without their disease getting worse when treated with Lutathera compared with other existing treatments. These included somatostatin analogues, everolimus and sunitinib.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Lutathera is of significant benefit to patients affected by gastro-entero-pancreatic neuroendocrine tumours.

Conclusions

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

Further information on Lutathera can be found in the European public assessment report (EPAR) on the Agency’s website. 

Related information

Sponsor’s contact details:

Advanced Accelerator Applications
20, rue Diesel
01630 Saint-Genis-Pouilly
France
Tel.: +33 4 50 99 30 76
E-mail: Regulatory_Affairs@adacap.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.