EU/3/06/390: Orphan designation for the treatment of moderate and severe traumatic brain injury

Traumatic brain injury is brain damage caused by a head injury (in a traffic accident or a fall). The initial injury to the head and brain usually goes on to cause 'secondary' problems, most frequently due to bleeding or swelling of the brain tissue (oedema) increasing the pressure within the skull. Traumatic brain injury is classified as minor, moderate or severe according to the patient's symptoms: patients with moderate injury are lethargic (lacking in energy) or stuporous (unaware of their surroundings), and those with severe injury are comatose (unconscious). People with moderate or severe traumatic brain injury need to be admitted to hospital for observation and examination, in case the condition gets worse.

Moderate and severe traumatic brain injury is chronically debilitating and life threatening.

At the time of designation, moderate and severe traumatic brain injury affected less than 4 in 10,000 people in the European Union (EU)*. This is equivalent to a total of fewer than 184,000 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 based on data from the European Union (EU 25), Norway, Iceland and Liechtenstein. This represents a population of 459,700,000 (Eurostat 2004).

Various treatments to reduce pressure within the skull in patients with moderate or severe closed traumatic brain injury, including medicines and surgery were available at the time of submission of the application for orphan drug designation.

4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride, as a new medicine in the treatment of moderate and severe traumatic brain injury, might help to achieve better overall control of the condition in particular by decreasing oedema formation. These benefits will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride is an inhibitor of the nitric oxide synthase enzyme (a type of protein). An inhibitor is a substance that tends to nullify the action of another. Nitric oxide is generated in the brain (due to action by nitric oxide synthase) following a brain injury and causes dilatation (widening) of blood vessels and swelling of the brain tissue (oedema). 4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride is expected to act by inhibiting nitric oxide synthase and thus reducing the swelling of the brain following brain injury. This might improve the long-term outcome of the patients.

The effects of 4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride were evaluated in experimental models.
At the time of submission of the application for orphan designation, no clinical trials in patients with moderate and severe traumatic brain injury were initiated.
4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride was not authorised anywhere worldwide for moderate and severe traumatic brain injury 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.

• 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