Clinical Overview: Skysona for Early Cerebral Adrenoleukodystrophy


Cerebral adrenoleukodystrophy is a progressive neurodegenerative disease causes irreversible neurologic decline and can result in functional disabilities, such hearing loss and cortical blindness.

On September 19, bluebird bio received FDA approval for Skysona (elivaldogene autotemcel [eli-cel]) to slow the progression of neurologic dysfunction in boys 4 to 17 years of age with early, active cerebral adrenoleukodystrophy (CALD). CALD, the most common form of adrenoleukodystrophy, is a rare X-chromosome linked disease affecting approximately 1 in 21,000 newborn males.1

CALD affects the white matter of the nervous system and the adrenal cortex. This progressive neurodegenerative disease causes irreversible neurologic decline and can result in functional disabilities, such hearing loss and cortical blindness.2

Skysona is a single-use treatment that utilizes the patient's blood stem cells in ex vivo transduction with the Lenti-D lentiviral vector (LVV) to add functional ABCD1 genes into the patient's hematopoietic stem cell. During development, Skysona was granted orphan drug, breakthrough therapy, and rare pediatric disease designation by the FDA.

Following priority review, bluebird bio received a pediatric priority review voucher along with accelerated approval.2 Prior to Skysona’s approval, the only treatment option available to patients with CALD was an allogeneic hematopoietic stem cell transplant (allo-HSCT).

Although this procedure is effective in stabilizing neurologic function, it is associated with serious potential complications and mortality that increases in patients without a matched sibling donor. It is estimated that more than 70% of patients diagnosed with CALD do not have a matched sibling donor.3

In August 2021, the FDA had placed a clinical hold on 1 of the phase 3 trials after a patient who was treated with Skysona developed myelodysplastic syndrome (MDS).4 At the time of the event, available evidence showed that the mechanism of the lentiviral vector used in the drug likely contributed to the event.4

Since then, bluebird bio participated in the FDA Cellular, Tissue and Gene Therapy Advisory Committee (CTGTAC) discussion in which the committee unanimously voted that the benefits outweigh the risks for the intended indication.3 With Skysona receiving FDA approval, the company also confirmed that the clinical hold mentioned earlier has been lifted.1


The efficacy of Skysona was assessed in a pair of 24-month, open-label, single-arm studies in patients with gadolinium enhancement (GdE+) on MRI, a Loes score between 0.5 and 9, as well as a neurologic function score (NFS) of ≤ 1. The patients enrolled in either of those studies (Study 1 and Study 2) all had confirmed mutations in the ABCD1 gene and elevated levels of very long chain fatty acids (VLCFAs).

After completion of either of those studies (Study 1 and Study 2), the patients were enrolled in a subsequent and long-term follow-up study. The efficacy of Skysona was compared to an external untreated natural history control. At the time of product approval, Study 1 is complete and Study 2 is ongoing.

Patients treated with Skysona and natural history patients were compared in a post-hoc enrichment analysis for onset of symptoms (NFS ≥1) to time to first Major Functional Disability (MFD) or death. The MFDs observed for CALD progression include cortical blindness, tube feeding requirements, total incontinence, wheelchair dependence, loss of communication, or complete loss of voluntary movement.

Skysona (n = 11) demonstrated a slower progression to MFD or death from time to symptom onset in patients with early, active CALD compared to patients with a similar natural history of the disease (n = 7). The estimated MFD-free survival at month 24 from time of first NFS ≥1 was 72% (95% CI: 35%, 90%) for the Skysona group and 43% (95% CI: 10%, 73%) for the natural history group.

There were limited data beyond 24 months to assess the long-term MFD-free survival between the 2 groups and there was limited time for follow-up to assess efficacy in asymptomatic patients treated with Skysona.


Skysona has a black box warning for hematologic malignancies as some patients developed MDS during clinical trials. Other warnings and precautions with using Skysona include risk of serious infections, prolonged cytopenia, delayed platelet engraftment, risk of neutrophil engraftment failure, hypersensitivity reactions, antiretroviral use, and laboratory test interferences.

The most common non-laboratory serious adverse events that have occurred with Skysona include vomiting, mucositis, pancytopenia, pseudomonal bacteremia, seizure, fever, vascular device infection and febrile neutropenia. The most common grade 3 or 4 laboratory abnormalities include hypokalemia, anemia, thrombocytopenia, neutropenia, leukopenia, and lymphopenia.

The wholesale acquisition cost of Skysona has been set at $3 million in the United States.1 This price makes Skysona the most expensive therapy ever launched on a single-use basis, exceeding the cost of bluebird bio’s other $2.8 million gene therapy.6

Additional information will be available through the company’s patient support program to support children and caregivers through all stages of the gene therapy journey, connect them with treatment centers, and assist with benefits verification and financial services.1

As part of the accelerated approval, bluebird bio has agreed to provide confirmatory long-term clinical data to the FDA. Its long-term follow-up study (LTF-304) is tracking patients treated in clinical trials for 15 years, as well as tracking commercially treated patients.1

For the CALD community, having access to an alternative therapy that can be deployed quickly provides hope to young boys born with this devastating disease.


  1. Rowlands J. Bluebird bio receives FDA accelerated approval for SKYSONA® gene therapy for early, active cerebral adrenoleukodystrophy (CALD). Published September 12, 2022. Accessed October 26, 2022.
  2. Rare Disease Database. X-linked adrenoleukiodystrophy. National Organization for Rare Diseases. Published 2019. Accessed October 26, 2022.
  3. Rowlands J. FDA advisory committee unanimously endorses Eli-CEL gene therapy for cerebral Adrenoleukodystrophy. Published June 9, 2022. Accessed October 26, 2022.
  4. FDA halts trial of gene therapy for rare neurological disease due to cancer risk. Healio. Published August 12, 2021. Accessed October 26, 2022.
  5. Highlights of prescribing information dosing of SKYSONA is based on the ... Published September 2022. Accessed October 26, 2022.
  6. A $3M gene therapy: Bluebird bio breaks its own pricing record with FDA approval of Skysona. Fierce Pharma. Published September 19, 2022. Accessed October 28, 2022.
Related Videos
Whole psilocybin mushroom in a clear medication capsule | Image credit: Zim -
Atopic dermatitis on a patient's hand -- Image credit: Ольга Тернавская |
Image credit: New Africa |
biosimilar word or concept represented by wooden letter tiles on a wooden table with glasses and a book | Image Credit: lexiconimages -
Image credit: alicja neumiler |
Laboratory test tubes and solution with stethoscope background | Image Credit: Shutter2U -
Pharmacist holding medicine box and capsule pack in pharmacy drugstore. -- Image credit: I Viewfinder |
Image credit: Goffkein |
Image credit: Wild Awake |
© 2024 MJH Life Sciences

All rights reserved.