EU/3/14/1330: Orphan designation for the treatment of pyruvate kinase deficiency

Pyruvate kinase deficiency is an inherited disease that affects red blood cells, which carry oxygen to all tissues in the body. It is caused by mutations (defect) in the gene that makes an enzyme called pyruvate kinase, which is essential for the normal function of red blood cells. This results in a lack of the enzyme and reduced lifespan and early breakdown of these cells in the blood (haemolytic anaemia). Symptoms can include very pale skin, yellowing of the eyes and skin (jaundice), tiredness, shortness of breath (dyspnoea), enlarged spleen (splenomegaly) and heart problems. Anaemia and associated complications may be severe enough to require periodic blood transfusions.

Pyruvate kinase deficiency is a long-term debilitating disease because of its symptoms and the periodic blood transfusions. The condition can also be life threatening because the anaemia can worsen during pregnancy or during a viral infection.

At the time of designation, pyruvate kinase deficiency affected approximately 0.5 in 10,000 people in the European Union (EU). This was equivalent to a total of around 26,000 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 on the basis of data from the European Union (EU 28), Norway, Iceland and Liechtenstein. This represents a population of 511,100,000 (Eurostat 2014).

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of pyruvate kinase deficiency. Patients were given treatments to help alleviate their symptoms such as periodic red blood cell transfusions. In some patients, allogeneic stem-cell transplantation was used. This is a complex procedure where the patient receives stem cells from a matched donor to help restore the bone marrow.

This medicine is made up of a virus that contains a working copy of the PKLR gene which is responsible for making the pyruvate kinase enzyme that is missing in patients with pyruvate kinase deficiency. Immature bone marrow cells (called CD34+) with the ability to develop into red blood cells are taken from the patient and the virus is used to deliver the gene into these cells. When these modified cells are transplanted back into the patient, they are expected to produce red blood cells that can produce the missing enzyme and have a more normal lifespan, thus improving the symptoms of the disease.

The type of virus used in this medicine (lentivirus) is modified so that it does not cause disease in humans.

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

At the time of submission of the application for orphan designation, no clinical trials with the medicine in patients with pyruvate kinase deficiency had been started.

At the time of submission, the medicine was not authorised anywhere in the EU for pyruvate kinase deficiency or designated as an 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 10 July 2014 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.