The Food and Drug Administration (FDA) has granted accelerated approval to Skysona® (elivaldogene autotemcel) to slow the progression of neurologic dysfunction in boys 4 to 17 years of age with early, active cerebral adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is a rare, X-linked metabolic disorder caused by mutations in the ABCD1 gene, which affects the production of adrenoleukodystrophy protein (ALDP). Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score [NFS] ≤1) boys who have gadolinium enhancement on brain magnetic resonance imaging and Loes scores of 0.5 to 9.

Skysona is a one-time gene therapy designed to add functional copies of the ABCD1 cDNA into a patient’s own hematopoietic stem cells, resulting in the production of functional ALDP. Treatment with Skysona does not prevent the development of or treat adrenal insufficiency due to adrenoleukodystrophy. Skysona has also not been studied in patients with CALD secondary to head trauma.

The accelerated approval was based on data from the phase 2/3 Starbeam study (ClinicalTrials.gov Identifier: NCT01896102) and phase 3 ALD-104 study (ClinicalTrials.gov Identifier: NCT03852498), which evaluated the efficacy and safety of elivaldogene autotemcel in a total of 67 patients with early, active CALD. All patients (N=67) had elevated very long chain fatty acid levels and confirmed mutations in the ABCD1 gene.

The time from onset of symptoms (NFS ≥1) to time to first major functional disability (MFD) or death (MFD-free survival) was compared in elivaldogene autotemcel-treated and natural history patients in a post-hoc enrichment analysis. Findings showed a slower progression to MFD or death from time of symptom onset (first NFS ≥1) for early, active CALD patients treated with elivaldogene autotemcel compared with a similar natural history of disease. Patients treated with elivaldogene autotemcel had an estimated 72% (95% CI, 35-90) likelihood of MFD-free survival at month 24 from time of first NFS 1 or greater vs the natural history population who had an estimated 43% (95% CI, 10-73) likelihood of MFD-free survival.

As a condition of accelerated approval, bluebird bio has agreed to provide confirmatory long-term clinical data to the FDA that includes data from an ongoing long-term follow-up study (LTF-304; ClinicalTrials.gov Identifier: NCT02698579) and from commercially treated patients.

Skysona carries a Boxed Warning associated with hematologic malignancy, including life-threatening cases of myelodysplastic syndrome, which appear to be the result of the Skysona lentiviral vector, Lenti-D, integration in proto-oncogenes. Given the risk of hematologic malignancy and unclear long-term durability of Skysona and human ALDP expression, careful consideration should be given to the timing of treatment for each boy and treatment of boys with isolated pyramidal tract disease as clinical manifestations do not usually occur until adulthood.

The most common adverse reactions reported with treatment were mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, and rash. The most common grade 3 or 4 laboratory abnormalities were leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, and hypokalemia.

Skysona is supplied in 1 or 2 infusion bags containing a frozen suspension of genetically modified autologous cells, enriched for CD34+ cells. A single dose of Skysona for intravenous infusion contains a minimum of 5.0 × 106 CD34+ cells/kg of body weight, suspended in a solution containing 5% dimethyl sulfoxide. 

Skysona will be available by the end of 2022 through a limited number of qualified treatment centers in the US, including Boston Children’s Hospital and Children’s Hospital of Philadelphia.

References

  1. bluebird bio receives FDA accelerated approval for Skysona® gene therapy for early, active cerebral adrenoleukodystrophy (CALD). News release. bluebird bio. September 16, 2022. Accessed September 19, 2022. https://www.businesswire.com/news/home/20220916005595/en/bluebird-bio-Receives-FDA-Accelerated-Approval-for-SKYSONA%C2%AE-Gene-Therapy-for-Early-Active-Cerebral-Adrenoleukodystrophy-CALD
  2. Skysona. Package insert. bluebird bio; 2022. Accessed September 19, 2022. https://www.businesswire.com/news/home/20220916005595/en/bluebird-bio-Receives-FDA-Accelerated-Approval-for-SKYSONA%C2%AE-Gene-Therapy-for-Early-Active-Cerebral-Adrenoleukodystrophy-CALD