brain x-ray image

x-ray image of the brain

Bluebird Bio gene therapy is now the first treatment approved by the FDA for a neurodegenerative disorder that causes progressive and irreversible functional decline that usually leads to death within five years.

Friday’s late approval of the therapy, elivaldogene autotemcel (commonly abbreviated to eli-cel), covers boys ages 4 to 17 who have an early form of the disease, cerebral adrenoleukodystrophy (CALD). As the first FDA-approved therapy for CALD, the therapy, which will be marketed under the name Skysona, carries a premium price of $3 million. Approval comes with some qualifications. Although Bluebird gene therapy is a one-time treatment, it is not a cure for a disease. The approval covers its use to slow the progressive loss of neurological function in CALD. Skysona’s label also carries a black box warning that alerts patients and doctors to the risk of blood cancer associated with the therapy.

“We are confident that the risks of Skysona will be carefully weighed against the risks of other treatment approaches and of CALD itself as families and clinicians make these complex and deeply personal treatment decisions,” Bluebird CEO Andrew Obenschein said during conference call on Monday.

Adrenoleukodystrophy results from genetic mutations that lead to a buildup of very long-chain fatty acids in the brain that damage myelin, the protective covering of nerve cells. This impairment leads to a number of problems, such as loss of the ability to walk, communicate, see and control muscle movements, among other complications. CALD is the most severe form of childhood-onset adrenoleukodystrophy. The X-linked disorder occurs predominantly in boys. Bluebird estimates that about 40 boys in the US develop CALD annually. Stem cell transplantation offers a treatment option that can slow the progression of the disease. However, this procedure can lead to dangerous complications, especially in patients who do not have a suitable donor.

Bluebird makes Skysona from a patient’s own hematopoietic, or immature, stem cells. Once these cells are collected, they are engineered in a laboratory. A lentiviral vector is used to insert a functional copy of a key gene into the patient’s stem cells. These cells are then infused back into the patient, where they are taken up in the bone marrow to differentiate into different types of cells that are capable of producing the protein needed to break down very long-chain fatty acids. Bluebird evaluated this gene therapy in a Phase 2/3 study and a Phase 3 clinical trial, both open-label studies, that treated a total of 67 patients with early and active CALD. The FDA’s regulatory decision was based on results showing 24 months of improvement according to a test that assesses six basic functions, such as communication and wheelchair dependence.

Despite the positive results of the clinical trials, the studies had a setback. Bluebird reported that three boys were treated with Skysona advanced myelodysplastic syndrome thought to be caused by gene therapy. This bone marrow cancer can develop when a lentivirus-based gene therapy delivers its genetic cargo into or near a gene that causes cancer cells to grow. Those cancer cases in the Skysona trials prompted the FDA to place the CALD therapy on clinical hold last year. In June of this year, an FDA advisory committee unanimously voted in favor I recommend approval of the therapy, concluding that its benefits outweigh the risks. Bluebird said the FDA lifted the clinical hold on Sept. 15, just ahead of Skysona’s approval. But the cancer risk is at the heart of the black box warning on Skysona’s label.

The positive decision for Skysona is the second regulatory nod for Bluebird in a month. In August, the agency approved the Bluebird Zynteglo gene therapy to treat the rare blood disorder beta thalassemia. This therapy carries a price tag of $2.8 million and is offered under an outcome-based agreement that ties reimbursement to how well the therapy works for a patient. Skysona will not have a similar reimbursement program because the extremely rare nature of CALD makes it too difficult to offer one, Obenschein said.

The European Commission granted Skysona standard approval last year to treat CALD. The FDA’s decision on the gene therapy is an accelerated approval, which means the biotech will have to provide the FDA with additional data to confirm the treatment’s safety and efficacy. Obenshain said the accelerated approval pathway was chosen over standard approval after an advisory committee and discussions with the FDA concluded it was the fastest way to get the therapy to patients. He added that the company expects to be able to meet accelerated approval requirements by using data from patients enrolled in a long-term follow-up study that will follow clinical trial participants for 15 years, as well as data from those treated with commercially available Skysona.

Skysona will be manufactured in the same facility where Zynteglo is manufactured. Bluebird expects to launch Skysona by the end of this year, available through a limited number of qualified treatment centers, which include Boston Children’s Hospital and Children’s Hospital of Philadelphia. The successful commercialization of the two gene therapies is critical to correcting Bluebird’s course, which implemented corporate restructuring earlier this year to save money and focus on its two most advanced gene therapies.

The approvals of both Zynteglo and Skysona came with the award of rare pediatric priority review vouchers. Such vouchers can be applied to the FDA’s expedited review of a prospective drug for a rare pediatric disease. However, these vouchers have become commodities and many companies choose to sell them to raise money. Obenshain said Bluebird hired a bank to sell the vouchers; the company expects each of these to sell for about $110 million, which will bring the company additional non-dilutive capital.

In a note sent to investors on Monday, William Blair analyst Raju Prasad said CALD is already included in US newborn screening, currently covering about 75% of babies born. He added that the launch of Bluebird’s two gene therapies could be a lead, showing how a small biotech can pull off a commercial launch of its gene therapies. Prasad said Skysona’s approval is a positive sign for Rocket Pharmaceuticals, a lentiviral gene therapy developer on track for two regulatory filings with its lead therapeutic candidate.

Photo: Jolygon, Getty Images

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