EU/3/06/401: Orphan designation for the treatment of 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.

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).

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.

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.

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.

• 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.