FDA approved bluebird bio’s SKYSONA gene therapy for early, active CALD

Another gene therapy product has been added to the FDA-approved list: SKYSONA, a one-time gene therapy aimed to treat early, active cerebral adrenoleukodystrophy (CALD).

CALD is a rare, genetic, progressive neurodegenerative disease caused by a mutation in the ABCD1 gene on the X-chromosome. ABCD1 gene makes the adrenoleukodystrophy protein (ALD) that localizes to the peroxisome membrane and is involved in transporting very long-chain fatty acids (VLCFAs) for its breakdown. However, in CALD, the defective ALD proteins disrupt this degradation process resulting in the accumulation of VLCFAs, predominantly in the white matter of the brain and spinal cord. As the ABCD1 gene is located on the X-chromosome, CALD is mainly seen in young boys and exhibits significant motor, audial, visual, and cognitive disabilities. Additionally, nearly 50% of patients without treatment die within five years of symptom onset.

The current effective treatment option, hematopoietic stem cell (HSC) transplant, offers significant improvements when diagnosed and performed at the early stages of the disease. Despite its benefits, HSC transplants have serious complications, such as the progression of further cerebral damage that significantly deteriorates the quality of life.

SKYSONA (elivaldogene autotemcel) is a novel gene therapy developed by bluebird bio, Inc. that aims to replace the mutated ABCD1 gene with a functional copy. The treatment includes:

1. Collecting the patient’s hematopoietic stem cells (HSCs).
2. Delivering the functional ABCD1 gene to the HSCs using an ex vivo lentiviral-based (Lenti-D) transduction method.
3. Infusing the cells back into the patient.

This allows patients to produce normal ALD that can degrade the VLCFAs and possibly prevent further neuronal damage.

“Children with CALD and their families have been at the heart of bluebird’s mission since the company was founded more than a decade ago,” said Andrew Obenshain, chief executive officer, bluebird bio, in a statement. “For the ALD community, this long-awaited approval represents significant hope and offers families a new option where, for many, there had been none. We are grateful to every individual who was involved in the development of SKYSONA and is committed to working with providers and payers to make this important treatment option available to patients and their families.”

FDA has approved SKYSONA based on two clinical trials, ALD-102 (NCT01896102) and ALD-104 (NCT03852498); which are open-label, single-arm studies to evaluate the efficacy and safety of SKYSONA in patients with early, active CALD. The key inclusive criteria were elevated VLCFAs and significant white matter damage (Loes score, MRI/gadolinium enhancement). The primary outcome measures were the percentage of patients with none of the six major functional disabilities (MFDs) – loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement – at month 24.

The key results showed that SKYSONA-treated patients had significantly stabilized lesion progression and a 72% probability of MFD-free survival compared to 43% in the untreated patients at 24 months. Also, the safety data was in line with the expected outcome. Thus, based on the 24-month data, SKYSONA received FDA accelerated approval and is expected to be available by the end of 2022.