Rare Daily Staff

The European Commission has granted marketing authorization to Bluebird Bio’s Skysona, a one-time gene therapy for the treatment of the rare and progressive neurodegenerative disease early cerebral adrenoleukodystrophy in patients less than 18 years of age.

The approval is for patients with an ABCD1 genetic mutation, and for whom a human leukocyte antigen-matched sibling hematopoietic stem cell donor is not available.

Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that primarily affects males; worldwide, an estimated one in 21,000 male newborns are diagnosed with ALD. The disorder is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein and subsequently causes toxic accumulation of very long-chain fatty acids, primarily in the adrenal gland and white matter of the brain and spinal cord. Approximately 40 percent of boys with ALD will develop cerebral adrenoleukodystrophy (CALD), the most severe form of ALD.

CALD is an irreversible condition that involves the breakdown of myelin, the protective sheath that nerve cells need to function effectively, especially for thinking and muscle control. The onset of symptoms of CALD typically occurs in childhood (median age 7). Early diagnosis of CALD is essential as the outcome of treatment varies with the clinical stage of the disease. Therefore, treatment must be administered before the disease progresses too far.

Skysona is a one-time gene therapy custom-designed to treat the underlying cause of the neurologic condition CALD. Skysona uses ex vivo transduction with the Lenti-D lentiviral vector to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cell. The addition of the functional ABCD1 gene allows patients to produce the ALD protein, which is thought to facilitate the breakdown of very long-chain fatty acids. The expression of ALDP and effect of Skysona is expected to be life-long. The goal of treatment with Skysona is to stop the progression of CALD and, consequently, preserve as much neurological function as possible, including the preservation of motor function and communication ability. Importantly, with Skysona, there is no need for donor HSCs from another person.

Previously, the only therapeutic option available to CALD patients was transplantation of stem cells from a donor, called allogeneic hematopoietic stem cell transplant, which is associated with severe potential complications and mortality that increase in patients without a matched sibling donor. It is estimated that more than 80 percent of patients diagnosed with CALD do not have a matched sibling donor.

“Bluebird Bio was founded with the mission of developing a therapy to recode CALD on the genetic level, and today’s announcement represents over twenty years of research and development that has laid the groundwork for future gene therapies to be possible,” said Andrew Obenshain, president, severe genetic diseases for Bluebird Bio.

Skysona was reviewed as part of the European Medicines Agency’s Priority Medicines scheme (PRIME) and was previously granted Orphan Medicinal Product status. The marketing authorization is valid in all 27 member states of the EU, as well as Norway, Liechtenstein, and Iceland.

The marketing authorization of Skysona is supported by efficacy and safety data from the phase 2/3 Starbeam study ALD-102. Additionally, the phase 3 ALD-104 study is ongoing. All patients who completed ALD-102, as well as those who will complete ALD-104, will be asked to participate in a long-term follow-up study LTF-304.

The primary efficacy endpoint of the pivotal ALD-102 study was Major Functional Disabilities (MFD)-free survival, measuring the proportion of patients who did not have any of the six MFDs, were alive, did not receive a second allogeneic hematopoietic stem cell transplant or rescue cell administration, and had not withdrawn or been lost to follow-up at Month 24.

In ALD-102, 32 patients have been treated with Skysona and, as of October 2020, 30 of 32 patients were evaluable for follow-up at Month 24. As of the data cutoff date, 90 percent of the patients met the Month 24 MFD-free survival endpoint. As previously reported, two patients withdrew from the study at investigator discretion, and one experienced rapid disease progression early in the study, resulting in MFDs and subsequent death.

In ALD-102, 26 of 28 evaluable patients maintained a neurologic function score (NFS) less than or equal to 1 through Month 24, and 24 of those patients had no change in their NFS, which showed maintenance of neurological function in the majority of patients. All patients who completed ALD-102 enrolled for long-term follow-up in the LTF-304 study.

Skysona showed a durable effect on MFD-free survival, with most patients (96.3 percent) who enrolled in LTF-304 remaining alive and maintaining their MFD-free status through their last follow-up on study. The median duration of follow-up was 3.2 years and 14 patients reached at least their Year 5 follow-up visit. One patient enrolled in LTF-304 but refused further follow-up later.

Adverse reactions attributed to Skysona observed in clinical trials include cystitis viral, pancytopenia, and vomiting.

There have been no reports of graft-versus-host-disease, graft failure or rejection, transplant-related mortality, or replication competent lentivirus in the 51 patients treated with Skysona in clinical studies. Clonal expansion resulting in clonal predominance has been detected in some patients treated with Skysona. While there have been no reports of lentiviral vector-mediated oncogenesis, including myelodysplasia, leukemia, or lymphoma, associated with Skysona, there is a potential risk of malignancy after treatment with Skysona.

The U.S. Food and Drug Administration (FDA) granted Skysona Orphan Drug status, Rare Pediatric Disease designation and Breakthrough Therapy designation for the treatment of CALD. Bluebird Bio is currently on track to submit the Biologics License Application in the United States this year.

Photo: Andrew Obenshain, president, severe genetic diseases for Bluebird Bio

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