EU/3/19/2209: Orphan designation for the prevention of haemolytic disease of the foetus and newborn

Haemolytic disease of the foetus and newborn (HDFN) is a condition in which red blood cells in the foetus or a newborn baby break down rapidly. This can cause anaemia in the baby and a build-up of bilirubin, a breakdown product of blood. The condition may cause the baby to have a large liver, spleen or heart. The excess bilirubin may cause jaundice and it can enter the brain to cause kernicterus, which affects brain development.

HDFN commonly occurs because the baby's red blood cells have a protein (antigen) that is absent from the mother's red blood cells. A common antigen associated with HDFN is called Rhesus antigen D protein (RhD). The baby is said to have RhD positive blood. The mother's immune system (the body's defence) makes antibodies against RhD if the mother's and baby's blood have come into direct contact. The antibodies enter the baby's circulation and attack the baby's red blood cells. Other types of antigens present on red blood cells can trigger HDFN.

HDFN is a life-threatening and chronically debilitating condition due to the development of haemolytic anaemia, which often requires red blood cells transfusion. It can damage the baby's vital organs including the brain and, in the most severe form, can cause the baby's death inside the womb.

At the time of designation, the number of patients at risk of HDFN was estimated to be approximately 3.6 people in 10,000 in the European Union (EU). This was equivalent to a total of around 190,000 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 at risk of developing 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 518,400,000 (Eurostat 2019).

At the time of submission, pregnant women who were RhD negative typically received prophylaxis with Rh immunoglobulins if their foetus was confirmed to be RhD positive. This prevented certain types of disease (those associated with D-type antigens of Rh group). However, no prophylactic therapy was available to prevent HDFN associated with other types of antigens or if a pregnant woman had already developed HDFN-associated antibodies. For pregnancies at risk of HDFN, specialised prenatal care by maternal–foetal medicine doctors was recommended. Intrauterine transfusion was used when the pregnancy was more advanced and the foetus had anaemia.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients at risk of developing HDFN. Early laboratory data showed that the medicine can reduce transfer across the placenta of maternal antibodies and therefore prevent HDFN associated with different types of antigens. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

The medicine is a monoclonal antibody (a type of protein) designed to block a receptor (target) called FcRn, which is involved in the circulation of antibodies. When given to the mother during pregnancy it is expected to reduce the level of antibodies in the mother’s blood circulation and thereby the transfer of maternal antibodies across the placenta. This should lower the amount of antibodies transferred to the foetus, and therefore prevent or reduce the destruction of the baby’s red blood cells.

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

At the time of submission of the application for orphan designation, clinical trials with the medicine in patients with HDFN were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for the prevention of HDFN or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 12 September 2019, 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.