On 17 October 2019, orphan designation EU/3/19/2210 was granted by the European Commission to Vertex Pharmaceuticals (Ireland) Limited, Ireland, for autologous CD34+ hematopoietic stem cells with a CRISPR-edited erythroid enhancer region of the bcl11a gene (also known as CTX001) for the treatment of beta-thalassaemia intermedia and major.
The sponsor’s address was updated in January 2022.
Beta-thalassaemia is an inherited disease in which patients are unable to make enough haemoglobin, the protein found in red blood cells that carry oxygen around the body. Beta thalassaemia major is a severe form of the disease in which patients need frequent blood transfusions, while beta thalassaemia intermedia is a less severe form, which may worsen with age. Both types of beta thalassaemia are caused by defects in the gene responsible for producing beta-globin, one of the components of haemoglobin, which result in low levels of haemoglobin in the blood.
Beta thalassaemia intermedia and major are life-long debilitating diseases. They may be life threatening because of severe anaemia (low red blood-cell count due to lack of haemoglobin), the need for repeated blood transfusions and the risk of complications associated with them.
At the time of designation, beta-thalassaemia intermedia and major affected approximately 0.80 in 10,000 people in the European Union (EU). This was equivalent to a total of around 41,000 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 518,400,000 (Eurostat 2019).
At the time of designation, the main treatments for beta thalassaemia intermedia and major were blood transfusions and the use of iron chelators (medicines for reducing ‘iron overload’ - the high iron levels in the body caused by repeated blood transfusions). The gene therapy medicine Zynteglo was authorised to treat beta thalassaemia in patients 12 years and older who require regular blood transfusions. In some cases, allogeneic haematopoietic stem cell transplantation was used to cure the disease. This is a complex procedure where the bone marrow of the patient is cleared of cells and replaced with healthy bone marrow cells from a matched donor, allowing the patient to produce red blood cells with normal haemoglobin.
The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with beta-thalassaemia intermedia and major because early results from a clinical study suggest that this medicine could restore a normal level of haemoglobin; in addition, it has a different mechanism of action compared to existing treatments. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.
The medicine is made up of immature bone marrow (haematopoietic) cells that are taken from the patient. These cells are modified to make them produce gamma-globin, one of the components of foetal haemoglobin, which is normally not produced beyond one year after birth. When they are given back to the patient, the modified cells are expected to produce gamma-globin which will in turn lead to the production of foetal haemoglobin. This is expected to increase the formation of new red blood cells and reduce anaemia.
The modification of the cells is made using CRISPR-cas9, an enzyme combined with a small piece of genetic material (RNA) that is able to edit a specific gene. In this medicine, CRISPR-cas9 creates defects in a gene for a protein called BCL11A which normally stops the production of gamma-globin. These defects prevent the production of BCL11A and allow gamma-globin to be produced.
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 beta-thalassaemia intermedia and major were ongoing.
At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of beta-thalassaemia intermedia and major 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.
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.
Vertex Pharmaceuticals (Ireland) Limited
EMA publishes information on orphan medicinal product designation adopted by the Committee for Orphan Medicinal Products (COMP) on the IRIS online platform:
For contact details of patients’ organisations whose activities are targeted at rare diseases, see:
European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.
Orphanet, a database containing information on rare diseases, which includes a directory of patients’ organisations registered in Europe.
The list of medicines that have received an orphan designation in the EU is available on the European Commission's website: