EU/3/09/629: Orphan designation for the treatment of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a disease of the blood clotting system. It is characterised by the formation of multiple blood clots in the narrow blood vessels and by low levels of platelets (components that help the blood to clot) in the blood (thrombocytopenia). Because 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 TTP develop symptoms affecting the nervous system, such as seizures (fits), altered behaviour, confusion, stroke and headache. Symptoms of the disease may also include anaemia (low red blood cell counts) and fever. The patients may develop problems with their heart or kidneys if blood clots form in the blood vessels supplying them.
TTP is often caused by the inactivation of an enzyme called 'ADAMTS13', which breaks down large aggregations of a substance in the body called 'von Willebrand factor'. These aggregations are involved in the blood clotting process by linking platelets together. When ADAMTS13 is inactivated, the aggregations of von Willebrand factor are not broken down, so more blood clots are formed in the blood vessels. ADAMTS13 is inactivated either because of an inborn genetic mutation, or by the immune system (the body's natural defences) attacking the enzyme. TTP can also develop after pregnancy or some medical conditions, such as infections and cancer. TTP has also been associated with the use of certain medicines.
TTP is a life-threatening disease because it can severely damage the brain, the heart and the kidneys.

At the time of designation, TTP affected between 2.2 and 2.9 in 10,000 people in the European Union (EU)*. This is equivalent to a total of between 111,000 and 150,000 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 27), Norway, Iceland and Liechtenstein. This represents a population of 504,800,000 (Eurostat 2009).

At the time of designation, there were no authorised medicines for TTP in the EU. The standard therapy of TTP consisted of 'plasma exchange', a procedure that helps restore the inactivated enzyme from the blood by replacing the patient's plasma (the liquid part of the blood) with plasma from a donor.
The sponsor has provided sufficient information to show that this medicine might be of significant benefit for the patients because of the way the medicine is expected to work. This could reduce the need for plasma exchange. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Nanobody directed towards the human A1 domain of von Willebrand factor is a very small antibody (a type of protein) that has been made to recognise and attach to a specific part of von Willebrand factor. By attaching to von Willebrand factor, this medicine is expected to prevent the factor from linking to platelets and inducing the formation of blood clots, reducing the symptoms of the disease.

The effects of nanobody directed towards the human A1 domain of von Willebrand factor have been evaluated in experimental models.
At the time of submission of the application for orphan designation, a clinical trial in healthy volunteers had finished, and further trials were ongoing or were planned.
At the time of submission, this medicine was not authorised anywhere in the EU for TTP or designated as orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 4 March 2009 recommending the granting of this designation.

• 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.