EU/3/06/403: Orphan designation for the treatment of neonatal brain injury

Neonatal brain injury refers to damage to certain parts of the developing brain. This damage can occur early in pregnancy when the brain is forming, during the birth process or after birth in the first few days to weeks of life. In many cases, the exact cause of the brain damage is not known. The severity of the injury varies widely, from very mild and subtle to very profound. In its severe form, it leads to damage in one or more parts of the brain that control muscle tone and motor activity (movement) and then is called cerebral palsy. These infants are usually slow to reach developmental milestones such as rolling over, sitting, crawling, and walking.

Another possible sign of neonatal brain injury is known as neonatal seizures. These occur within 28 days of birth but often no typical convulsions are detected. Instead, for example their eyes appear to be looking in different directions; or they may have lip smacking or periods of no breathing.

Neonatal brain injury is a life-threatening and chronically debilitating condition.

At the time of designation, neonatal brain injury affected less than 1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 47,000 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 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 468,900,000 (Eurostat 2006).

No satisfactory methods exist that were authorised at the time of application.

5-(2,6-Difluoro-phenoxy)-3(R,S)-{2(S)-[2(S)-(3-methoxycarbonyl-2(S)-{3-methyl-2(S)-[(quinoline-2-carbonyl)-amino]-butyrylamino}-propionylamino)-3-methyl-butyrylamino]-propionylamino}-4-oxo-pentanoic acid methyl ester has been shown to inhibit the function of a cell molecule, called caspase-2. The latter is one of a series of specific enzymes (a type of protein) involved in the “programmed death” of cells. By inhibiting this enzyme, the proposed medicinal product aims to prevent the process of programmed brain cell (neuronal) death, associated with neonatal brain injury. The goal of this treatment is to limit long-term adverse (negative) consequences to proper brain functioning.

The evaluation of the effects of 5-(2,6-Difluoro-phenoxy)-3(R,S)-{2(S)-[2(S)-(3-methoxycarbonyl-2(S)-{3-methyl-2(S)-[(quinoline-2-carbonyl)-amino]-butyrylamino}-propionylamino)-3-methyl-butyrylamino]-propionylamino}-4-oxo-pentanoic acid methyl ester in experimental models is ongoing.

At the time of submission of the application for orphan designation, no clinical trials in patients with neonatal brain injury were initiated.

5-(2,6-Difluoro-phenoxy)-3(R,S)-{2(S)-[2(S)-(3-methoxycarbonyl-2(S)-{3-methyl-2(S)-[(quinoline-2-carbonyl)-amino]-butyrylamino}-propionylamino)-3-methyl-butyrylamino]-propionylamino}-4-oxo-pentanoic acid methyl ester was not authorised anywhere worldwide for neonatal 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 6 September 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 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.