EU/3/11/857: Orphan designation for the treatment of transthyretin-mediated amyloidosis

Transthyretin-mediated amyloidosis (ATTR amyloidosis) belongs to a group of diseases called systemic amyloidosis in which deposits of proteins (called amyloids) accumulate and cause damage in body organs. In ATTR amyloidosis, the amyloids are made up of transthyretin, a protein produced in the liver that transports various substances in the blood.

In patients with ATTR amyloidosis, transthyretin deposits accumulate mainly in the heart and the nervous system. Patient with this condition usually have heart problems and symptoms such as muscle weakness in the limbs and, at later stages, inability to walk, problems affecting the stomach and the gut (leading to malnutrition), and bladder dysfunction.

ATTR amyloidosis is a long-term debilitating disease due to the progressive worsening of nervous system symptoms. It is also life threatening because amyloid deposits in the heart can cause fatal heart conditions.

At the time of designation, ATTR amyloidosis affected less than 0.2 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 10,000 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 on the basis of data from the European Union (EU 28), Norway, Iceland and Liechtenstein. This represents a population of 515,700,000 (Eurostat 2017).

At the time of designation, the only medicine authorised in the EU to treat ATTR amyloidosis was Vyndaqel (tafamidis). Vyndaqel was authorised to delay nerve damage caused by ATTR amyloidosis in patients with the early stage of nerve disease. The only other treatment option was liver transplantation.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with all forms of ATTR amyloidosis because early studies in patients showed that the medicine may stabilise the heart symptoms of the condition. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

The medicine is made of a small strand of synthetic genetic material, called 'small interfering RNA' (siRNA), that stops the gene for transthyretin from working and thereby blocks the production of transthyretin in the liver. This reduces the accumulation of transthyretin deposits in the tissues and slows down the progression of the disease.

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

At the time of orphan designation, clinical trials with the medicine in patients with ATTR amyloidosis were ongoing.

At the time of orphan designation, this medicine was not authorised anywhere in the EU for ATTR amyloidosis.

This medicine had been designated orphan on 15 April 2011 for the treatment of familial amyloid polyneuropathy (FAP). At the request of the sponsor and having assessed the additional data submitted, the COMP adopted a positive opinion on 19 January 2017 recommending the designation be changed to treatment of transthyretin-mediated amyloidosis, a class of diseases to which FAP belongs.

Orphan designation of the medicine has been granted in the United States for familial amyloidotic polyneuropathy.

• 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.