The European Medicines Agency (EMA) has recommended a marketing authorisation in the European Union (EU) for Ebvallo (Tabelecleucel) for the treatment of adult and paediatric patients who experience a serious complication following solid organ transplantation (SOT) or bone marrow transplantation (hematopoietic cell transplant – HCT) called Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD).
Ebvallo will be available as a dispersion for injection containing 2.8 × 107 – 7.3 × 107 viable T cells/mL. The active substance of Ebvallo is tabelecleucel, an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates EBV-infected cells in a human leukocyte antigen (HLA)-restricted manner.
This medicine was designated an “orphan medicine”. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. About 30 million people living in the European Union (EU) suffer from a rare disease. The European Medicines Agency (EMA) plays a central role in facilitating the development and authorisation of medicines for rare diseases, which are termed ‘orphan medicines’ in the medical world.
EBV+ PTLD is one of the most important malignancies after transplantation. It is a result of the immunosuppression caused by the medication required to reduce the possibility of rejection of the transplanted organ or cells and the most common form of this condition is associated with the Epstein-Barr virus. Ebvallo is indicated in patients after a transplant and who have received at least one prior therapy when the symptoms of the disease come back after treatment (relapsed) or when the treatment does not work (refractory).
A significant unmet need exists for patients who fail first-line therapies as they have only weeks to a few months’ survival after treatment failure, and other treatment options are limited. The aim of new treatments is to achieve the disappearance of all signs of cancer after treatment (complete remission) and prolong overall-survival, thereby reducing transplantation-related mortality of patients with EBV+ PTLD.
Tabelecleucel, the active substance of Ebvallo, targets and eliminates infected cells. It is an advanced therapy medicinal product made of cells of the immune system called T-cells that have been taken from a donor (allogeneic). The T-cells are first mixed with another type of white blood cells in the immune system (B-cells) from the same donor that have been infected with the Epstein-Barr virus so that the T-cells learn to recognise infected B-cells. The T-cells are then grown to increase their numbers. When the medicine is given to the patient, the T-cells are expected to attack and kill the patient’s own infected B-cells, thereby helping to control cancers associated with the virus.
At the time of designation, post-transplant lymphoproliferative disorder affected approximately 1.6 in 10,000 people in the European Union (EU). This was equivalent to a total of around 82,000 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). Before this approval no satisfactory method was authorised in the European Union for the treatment of post-transplant lymphoproliferative disorder. Patients with the condition were treated with medicines authorised for non-Hodgkin’s lymphoma.
EMA’s recommendation is based on the results of an ongoing multicentre, phase 3, single-arm, open-label clinical trial. The study investigated the efficacy and safety of tabelecleucel in 43 patients with relapsed/refractory EBV+ PTLD who had received at least one prior therapy. Approximately half of the treated subjects achieved partial or complete remission. A significant number of patients enrolled in the study responded to the treatment with a durable response of six months or more without disease signs or symptoms after treatment.
The most common side effects are fever, diarrhoea, tiredness, feeling sick, low levels of red blood cells, decreased appetite and low blood sodium levels.
In its overall assessment of the available data, the Committee for Advanced Therapies (CAT), EMA’s expert committee for cell and gene-based medicines, found that the benefits of Ebvallo outweighed the risks in patients with EBV+ PTLD. The CHMP, EMA’s human medicines committee, agreed with the CAT’s assessment and positive opinion, and recommended approval of this medicine under exceptional circumstances.
A marketing authorisation under exceptional circumstances allows patients’ access to medicines that cannot be approved using a standard authorisation route as comprehensive data cannot be obtained under normal conditions of use. Sometimes this is due to the small number of patients with the disease. In other cases, the collection of complete information on the efficacy and safety of the medicine is not possible or would be unethical. The medicines concerned are subject to specific post-authorisation obligations and monitoring.
The CHMP requested the applicant to submit data to further characterise the long-term efficacy and safety of patients enrolled in the clinical trials, and to conduct a post-authorisation observational safety study in patients treated with the medicine in Europe.
The opinion adopted by the CHMP is an intermediary step on Ebvallo’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on the EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.
Sources:
https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation-overview