EU/3/08/588: Orphan designation for the treatment of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a disease characterised by the formation of multiple blood clots in the narrow blood vessels and by a low number of platelets in the blood (thrombocytopenia). As platelets are consumed in the blood clotting process, there are fewer platelets in the blood resulting in spontaneous bleeding and bruising of the skin in purple spots (called 'purpura'). Patients with this condition develop neurological symptoms, such as confusion or seizures (fits) . Other signs of the disease are anaemia (low red blood cell counts) and, in some, cases fever.

TTP may be idiopathic, which means that the cause of the disorder is unknown. It may also be secondary to various other conditions such as pregnancy, infections, cancer, and some drugs. A few patients have a familial form of TTP, caused by the deficiency of an enzyme called 'ADAMTS13' due to an inborn mutation (change) in the gene coding for the enzyme. In other patients, the immune system reacts against the enzyme and blocks its function. TTP is a life-threatening disease.

At the time of designation thrombotic thrombocytopenic purpura affected approximately 2.2 in 10,000 people in the European Union (EU) *. This is based on the information provided by the sponsor and knowledge of the Committee for Orphan Medicinal Products (COMP). This is below the threshold for orphan designation which is 5 in 10,000. This is equivalent to a total of around 111,000 people.

*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 Liechtenstein. This represents a population of 502,282,000 (Eurostat 2008).

There are no authorised medicines for TTP in the European Union (EU). At the time of submission for orphan drug designation, the standard therapy of TTP consisted of 'plasma exchange', a procedure in which the patient's blood is taken out of the body and the blood cells are separated from the liquid part (plasma). For TTP, the blood cells are returned to the patient together with plasma from a donor.

However, plasma exchange has been associated with several risks for the patients. The sponsor has provided sufficient information to show that recombinant human ADAMTS13 might be of potential significant benefit for the patients as it could be safer compared to plasma exchange and has a mechanism of action closely related to the pathophysiology of the disease which could result in improved efficacy. These assumptions will need to be confirmed at the time of marketing authorisation, to maintain the orphan status.

ADAMTS13 normally breaks down large aggregations of a substance in the body called 'von Willebrand factor', which is involved in the blood clotting process by linking to platelets. When ADAMTS13 is inactivated, the aggregations of von Willebrand factor are not broken down and more blood clots are formed in the blood vessels. Human recombinant ADAMTS13 is expected to replenish the function of patients' inactivated ADAMTS13. By doing this it is expected that the product will partly restore the normal clotting process.

The effects of human recombinant ADAMTS13 have been evaluated in experimental models.

At the time of submission, human recombinant ADAMTS13 was not authorised anywhere in the world for thrombotic thrombocytopenic purpura. Orphan designation had been granted in the United States for treatment and prevention of thrombotic thrombocytopenic purpura including its congenital, acquired idiopathic, and secondary forms.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 8 October 2008 recommending the granting of this designation.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• and either the rarity of the condition (affecting not more than five in 10,000 people in the Community) or the 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 the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.