First gene therapy to treat children with rare inherited neurological disease

News 21/05/2021

EMA has recommended granting a marketing authorisation in the European Union for the gene therapy Skysona (elivaldogene autotemcel) for the treatment of children with cerebral adrenoleukodystrophy (CALD), a severe form of a rare inherited neurological disease. This disease, seen almost exclusively in males, affects the brain and leads to an irreversible loss of neurological functions.

CALD is the most common form of adrenoleukodystrophy (ALD), a rare disease affecting approximately 1 in 21,000 newborn males. This condition is caused by abnormalities in a gene called ABCD1 which is responsible for the production of a protein called ALDP (adrenoleukodystrophy protein). Patients with the disease lack ALDP which is needed to break down fatty substances in the body called very long chain fatty acids (VLCFA). As patients with CALD cannot break down these fatty substances, they gradually build up in cells in the brain. The build-up of VLCFA leads to inflammation and destruction of the protective sheath (myelin) that insulates and improves the way the nerves function.

40% of boys diagnosed with ALD develop CALD, typically during childhood. If untreated, nearly half of patients with CALD die within 5 years of symptom onset. Currently, there is no medicine approved for the treatment of this disease. The only therapeutic intervention available to CALD patients is transplantation of stem cells (cells that can develop into different types of blood cells) from a donor. This procedure presents several potential complications and risks which are reduced for those patients who have a matching sibling donor. However, these represent less than 30% of patients with CALD. Therefore, there is an unmet medical need for these patients.

Skysona is made up of immature bone marrow cells that are taken from the patient. The cells are then modified by a virus – a so-called ‘lentivirus’ that has been changed in order not to cause disease in humans - that contains a functional copy of the gene ABCD1 for the ALDP protein, so that this gene is carried into the cells. When these modified cells are given back into the patient by a drip (infusion) into a vein, they are expected to spread through the body and develop into different types of healthy cells, including brain cells, that produce the ALDP protein that patients with CALD lack. As a result, patients should be able to break down the accumulated VLCFA and this will help to reduce the symptoms of the disease.

Skysona is a one-time treatment which can only be given in a specialised hospital by doctors who are experienced in treating patients with CALD, transplanting bone marrow, and using gene therapy medicines.

Skysona was accepted into PRIME, a support scheme EMA developed for promising new medicines that address an unmet medical need.

EMA’s recommendation for a marketing authorisation is based on evidence from a single-arm clinical trial that enrolled 32 male patients with CALD aged 17 years or younger. The results from this study were compared to those from a study in which 59 patients had a stem cell transplantation (either from a matched sibling donor or a matched non-sibling donor). All the patients in the main clinical trial were enrolled in a long-term follow-up study.

An analysis conducted after 24 months from the infusion on 30 subjects enrolled in the study concluded that for 27 of them (90%) treatment with Skysona preserved motor function and communication ability and improved survival when compared to untreated patients at an early stage of cerebral disease.

The most serious adverse reaction in the clinical trials for Skysona was low levels of all types of blood cells (pancytopenia).

Adding a new gene into the stem cells could theoretically cause blood cancers. This was not seen during the clinical trial but after the treatment, patients will be monitored with blood tests to check for any signs of cancer of the blood.

Because Skysona is an advanced-therapy medicinal product (ATMP), it was assessed by the Committee for Advanced Therapies (CAT), EMA's expert committee for cell- and gene-based medicines. Based on the CAT’s assessment and positive opinion, EMA’s human medicines committee (CHMP) recommended approval of this medicine.

Additional long-term efficacy and safety data are being collected through one ongoing study and a long-term registry. All results must be included in post-marketing safety reports, which are continuously reviewed by EMA.

The opinion adopted by the CHMP is an intermediary step on Skysona’s path to patient access. The opinion will now be sent to the European Commission for the adoption of a decision on an 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.


  • The applicant for Skysona is bluebird bio (Netherlands) B.V.
  • Skysona is indicated for the treatment of early cerebral adrenoleukodystrophy in patients less than 18 years of age, with an ABCD1 genetic mutation, and for whom a human leukocyte antigen (HLA) matched sibling haematopoietic stem cell (HSC) donor is not available.
  • Skysona was designated as an orphan medicinal product on 6 June 2012. During the development protocol assistance was received on multiple occasions to obtain guidance on the quality aspects, the non-clinical and the clinical study programme, including the demonstration of significant benefit.
  • Skysona was accepted into the PRIME scheme on 26 July 2018.
  • Following this positive CHMP opinion, the Committee for Orphan Medicinal Products (COMP) will assess whether the orphan designation should be maintained.

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