EU/3/18/2099: Orphan designation for the treatment of primary mediastinal large B-cell lymphoma

Primary mediastinal large B-cell lymphoma is an aggressive cancer of a type of white blood cell called B lymphocytes, or B cells. In patients with this cancer, the B cells multiply quickly and live for too long. Patients usually present with a tumour mass in the chest cavity, which may cause breathlessness, coughing and swelling in the face and arms.

The disease is more common in women and typically affects people younger than 40 years. Although some people with primary mediastinal large B-cell lymphoma can be cured, it remains a serious and life-threatening disease, particularly when the disease is diagnosed late or has come back after initial treatment.

At the time of designation, primary mediastinal large B-cell lymphoma affected approximately 0.5 in 10,000 people in the European Union (EU). This was equivalent to a total of around 26,000 people¹, 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).

¹Disclaimer: 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 517,400,000 (Eurostat 2018).

At the time of designation, the medicine Yescarta (axicabtagene ciloleucel) was authorised for the treatment of primary mediastinal large B-cell lymphoma. Chemotherapy (medicines to treat cancer) was also used, usually in combination with other medicines called monoclonal antibodies and sometimes in combination with radiotherapy (treatment with radiation). Autologous haematopoietic (blood) stem-cell transplantation was used in patients at risk of the disease coming back after treatment. This is a complex procedure where patients receive their own stem cells to help restore the bone marrow so that it can produce healthy blood cells.

The sponsor has provided sufficient information to show that lisocabtagene maraleucel might be of significant benefit for patients with primary mediastinal large B-cell lymphoma. Preliminary studies showed that patients whose cancer came back despite several previous treatments responded to the medicine. Also, in patients treated with the medicine there were fewer reports of a serious side effect called ‘cytokine release syndrome’ than with the authorised treatment Yescarta.

These assumptions will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

The abnormal B cells in patients with primary mediastinal large B-cell lymphoma produce a protein on their surface called CD19.

This medicine is made up of immune cells (called T cells) which are taken from the patient. The T cells are modified in the laboratory with a virus that carries a gene into the T cells so that they can recognise and attach to CD19. The modified T cells are then given back to the patient, and they are expected to attach to CD19 on the cancer cells and kill them. These T cells are also expected to activate other T cells from the patient to act against the cancer cells.

The type of virus used in this medicine ('lentivirus') is modified in order not to cause disease in humans.

The effects of lisocabtagene maraleucel 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 primary mediastinal large B-cell lymphoma were ongoing.

At the time of submission, lisocabtagene maraleucel was not authorised anywhere in the EU for primary mediastinal large B-cell lymphoma. Orphan designation of the medicine had been granted in the United States for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 18 October 2018 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.