Gene therapy available for cerebral adrenoleukodystrophy

In September 2022, bluebird bio received Food and Drug Administration (FDA) approval for Skysona^® (elivaldogene autotemcel), a gene therapy treatment for early, active cerebral adrenoleukodystrophy in young boys. bluebird anticipates that commercial product will be available by the end of 2022 through a limited number of Qualified Treatment Centers (QTCs) in the United States.

Drug name:                  Skysona (elivaldogene autotemcel)

Manufacturer:             bluebird bio
Condition:                    Early, active cerebral adrenoleukodystrophy

Condition overview^1-9

Adrenoleukodystrophy (ALD) is a rare genetic disorder that affects the nerve fibers of the nervous system and the adrenal cortex. It is caused by a mutation in the ABCD1 gene.

ALD can lead to the progressive damage to nerve fibers in the nervous system and degradation of the adrenal glands. The nerve fibers relay nerve impulses from one cell to another. With ALD, the signals between nerve cells cannot be transmitted properly, resulting in neurological symptoms. The adrenal glands sit atop the kidneys and produce hormones that are vital to proper health and development including cortisol and the sex hormones. Many of those affected experience serious neurological problems either during childhood or during adulthood with different forms of disabilities.

Early, active cerebral adrenoleukodystrophy (CALD) primarily affects young boys. It causes irreversible, devastating neurologic decline, including major functional disabilities such as loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement.

It is estimated that approximately 35-40% of the 1:20,000 males affected with ALD have CALD. Boys typically present CALD between 4 and 12 years of age. Cases are rare before two years of age or after 15 years of age. Brain lesions are typically visible on MRI before symptom onset and once detected, diagnosis is typically confirmed through serum VLCFA testing. Initial symptoms present as learning difficulties and behavioral problems and progresses into cortical blindness, central deafness, and the development of weakness in all four limbs. The rate of disease progression can be variable, but nearly half of patients who do not receive treatment die within five years of symptom onset.

Current treatment

Stem cell transplantation is the standard of care in CALD. Approximately 30% of patients have an HLA-matched unaffected sibling, which is the preferred donor. Transplants are typically performed when patients have early active disease with no or minimal neurologic dysfunction. If the graft takes, stabilization usually occurs within 12-24 months. HSCT has a five-year survival rate of 50-70%, depending on donor type, with percentages reflecting death from both disease progression and transplant-related causes.

Studies have shown that a stem cell transplant stops the progression of neurological disease in ALD, although it does not improve adrenal insufficiency. It is also being studied as a treatment for CALD affected adults with significant disability.

Because of the significant morbidity and mortality associated with stem cell transplants in patients without matched sibling donors, Skysona was developed with the intention of generating a safer treatment.

Skysona overview

Skysona is FDA approved to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active CALD.  Skysona is a genetically modified autologous cell-enriched formulation, designed to provide a normal copy of the mutated gene. Skysona is supplied frozen in cryopreservation solution for one-time IV infusion.

The goal of treatment is to stop the progression of ccALD to preserve as much neurological function as possible. In ALD-102, 90.6% (29/32) of patients met the primary endpoint of major functional disabilities (MFD)-free survival at 24 months. The median duration of follow-up is 3.5 years. Cost is $3 million per patient for the one-time administration.

Date approved:          September 16, 2022
Benefit:                        Medical benefit

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References

1. Bluebird bio announces FDA priority review of biologics license application for eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD) in patients without a match sibling donor. Accessed in June 2022 at: https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-priority-review-biologics-license-0
2. Advisory committee Elivaldogene autotemcel briefing document. BLA 125755. Accessed in June 2022 at: https://www.fda.gov/media/159010/download
3. Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017;377(17):1630-1638. https://www.nejm.org/doi/full/10.1056/NEJMoa1700554
4. Helman G, Venkateswaran S, Vanderver A. Chapter 43: The spectrum of adult-onset heritable white-matter disorders. In: Geschwind DH, Paulson HL, Klein C, eds. Handbook of Clinical Neurology. Elsevier; 2018: 669-692.
5. Raymond GV, Moser AB, Fatemi A. X-Linked Adrenoleukodystrophy. 1999 Mar 26 [Updated 2018 Feb 15]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.
6. Zhu J, Eichler F, Biffi A, Duncan CN, Williams DA, Majzoub JA. The Changing Face of Adrenoleukodystrophy. Endocr Rev. 2020;41(4):577-593. https://pubmed.ncbi.nlm.nih.gov/32364223/
7. bluebird bio Receives FDA Accelerated Approval for SKYSONA® Gene Therapy for Early, Active Cerebral Adrenoleukodystrophy (CALD). Sept. 16, 2022. Bluebird bio. Accessed at: https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-receives-fda-accelerated-approval-skysonar-gene
8. X-Linked Adrenoleukodystrophy, Copyright ©2021 NORD – National Organization for Rare Disorders, Inc. Accessed at: https://rarediseases.org/rare-diseases/adrenoleukodystrophy/
9. FDA Advisory Committee Unanimously Endorses eli-cel Gene Therapy for Cerebral Adrenoleukodystrophy. June 9, 2022. Bluebird bio. Accessed at: https://investor.bluebirdbio.com/news-releases/news-release-details/fda-advisory-committee-unanimously-endorses-eli-cel-gene-therapy