EU/3/20/2247: Orphan designation for the treatment of myelofibrosis

Myelofibrosis is a disease in which fibrous tissue forms in the bone marrow (the spongy tissue inside the large bones where blood cells are produced), interfering with normal blood cell production. This causes some immature blood cells to move from the bone marrow to other organs, such as the spleen and liver, which become enlarged. Symptoms of the disease include bone pain, tiredness, weakness, weight loss, fever and bleeding.

Myelofibrosis is a debilitating disease that is long-lasting and life-threatening because it can lead to severe anaemia (low red blood cell counts), infections, and can result in leukaemia (cancer of the white blood cells).

At the time of designation, myelofibrosis affected less than 1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 52,000 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 519,200,000 (Eurostat 2020).

At the time of designation, busulfan, hydroxycarbamide and ruxolitinib were authorised in the EU for myelofibrosis. In addition, medicines were authorised to treat the symptoms, including erythropoietin (a hormone that stimulates the production of red blood cells) to treat anaemia, and surgery was used to remove the enlarged spleen. In some patients, haematopoietic (blood) stem cell transplantation was used to treat the disease. This is a procedure where the patient's bone marrow is cleared of cells and replaced with stem cells from a donor to form new bone marrow that produces healthy blood cells.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with myelofibrosis. This is because early results in patients whose illness did not respond to treatment with ruxolitinib showed improvements when the medicine was added to ruxolitinib treatment or used instead of ruxolitinib. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

The medicine blocks the action of a group of proteins known as BET proteins, which control the production of immature blood cells, inflammation and the development of fibrous tissue in the bone marrow. By blocking the action of these proteins, the medicine is expected to help control the progression of the disease and reduce its symptoms.

The effects of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide monohydrate 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 myelofibrosis were ongoing.

At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of myelofibrosis. Orphan designation of the medicine had been granted in the United States for this condition.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 22 January 2020, 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.