EU/3/06/401

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Orphan designation

On 28 August 2006, orphan designation (EU/3/06/401) was granted by the European Commission to ICON Clinical Research Limited, United Kingdom for N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl) ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate for the treatment of familial amyloid polyneuropathy.

The sponsorship was transferred to FoldRx Pharmaceuticals Limited, United Kingdom, in September 2009 and to Pfizer Limited, United Kingdom, in May 2012.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

What is familial amyloid polyneuropathy?

Familial amyloid polyneuropathy is a hereditary (familial) disease caused by a defective gene that regulates the production of a protein called transthyretin, which is involved in the transport of various substances in the blood. Transthyretin is primarily produced in the liver. The normal form of transthyretin is a homotetramer (it is made up of four identical parts attached to each other). In affected patients, the protein is modified in a way that makes it break up and lose its function. The broken up parts of the initial protein then start accumulating and depositing in so-called amyloid structures in various tissues (including the nervous system) and eventually interfere with organ function. The primary symptom of the condition is progressive loss of neurological functions (polyneuropathy). Additionally, the eyes and kidneys can become affected. Familial amyloid polyneuropathy is chronically debilitating and life-threatening.

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

At the time of designation familial amyloid neuropathy affected less than 0.1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 4,600 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 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 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 464,200,000 (Eurostat 2004).

What treatments are available?

The only available treatment of the condition is liver transplantation; surgically removing the liver and replacing it with a liver from a donor that produces the healthy unmodified transthyretin. Satisfactory argumentation has been submitted by the sponsor to justify the assumption that N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl) ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate might be of potential significant benefit for the treatment of familial amyloid polyneuropathy, mainly because it has a new mechanism of action and may be used in patients for whom liver transplantation is unavailable. This assumption 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?

N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl) ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate is a molecule designed to bind to and stabilise the transthyretin homotetramer. According to the sponsor, it will thus prevent the protein from breaking up and decrease the amount of harmful amyloid deposits in the organs of the affected patients.

What is the stage of development of this medicine?

The effects of N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl) ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate have been evaluated in experimental models. At the time of submission of the application for orphan designation, clinical trials in patients with familial amyloid polyneuropathy were ongoing.

N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl) ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate was not authorised anywhere worldwide for the treatment of familial amyloid polyneuropathy 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 12 July 2006 recommending the granting of this designation.

Update: N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl) ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate (Vyndaqel) was authorised in the EU on 16 November 2011 for the treatment of transthyretin amyloidosis in adult patients with stage-1 symptomatic polyneuropathy to delay peripheral neurologic impairment.

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 Community) 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>N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl)-ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate</p>
Active substanceN-methyl D-(2,3,4,5,6-pentahydroxy-hexyl)-ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate
Medicine NameVyndaqel
Disease/conditionTreatment of familial amyloid polyneuropathy
Date of decision28/08/2006
OutcomePositive
Orphan decision numberEU/3/06/401

Review of designation

During its meeting of 6–8 September 2011, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/06/401 for Vyndaqel (N-methyl D-(2,3,4,5,6-pentahydroxy-hexyl)-ammonium; 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylate) as an orphan medicinal product for the treatment of familial amyloid polyneuropathy. 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 exist in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. 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 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 Vyndaqel for 'the treatment of transthyretin amyloidosis in adult patients with stage-1 symptomatic polyneuropathy to delay peripheral neurologic impairment'.

This falls within the scope of the product’s designated orphan indications, which is ‘treatment of familial amyloid polyneuropathy’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2006. Familial amyloid polyneuropathy remains a condition that is debilitating in the long term and life-threatening, particularly due to the progressive loss of the functions of nervous system causing symptoms such as loss of sensation and muscle weakness.

Prevalence of the condition

The sponsor provided updated prevalence data for familial amyloid polyneuropathy. On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of familial amyloid polyneuropathy 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 less than 0.1 people in 10,000. This is equivalent to a total of less than 5,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, the only available treatment in the EU for the condition was liver transplantation.

Significant benefit over existing treatments

The COMP concluded that the claim of a significant benefit of Vyndaqel in familial amyloid polyneuropathy is justified by the fact that it is the first medicine for this condition authorised in the EU which targets the disease thereby providing an additional treatment option.

Therefore, although other satisfactory methods for the treatment of this condition exist in the EU, the COMP concluded that Vyndaqel is of significant benefit for patients affected by familial amyloid polyneuropathy.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Vyndaqel still meets the criteria for designation as an orphan medicinal product and that Vyndaqel should remain in the Community register of orphan medicinal products.

Related information

Sponsor’s contact details:

Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
United Kingdom
Tel. +44 (0)1304 616161
Fax +44 (0)1304 652144
E-mail: orphan_enquiries@pfizer.com

Patients’ associations contact points:

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.