Bluebird Bio gene therapy becomes first FDA-approved drug for ultra-rare neurological disorders
A Bluebird Bio gene therapy is now the first FDA-approved treatment for a neurodegenerative disorder that causes progressive and irreversible functional decline that typically results in death within five years.
Friday night’s approval of the therapy, elivaldogene autotemcel (commonly shortened to eli-cel), covers boys aged 4 to 17 who have an early form of this condition, cerebral adrenoleukodystrophy (CALD). As the first FDA-approved therapy for CALD, the therapy, which will be marketed as Skysona, commands a premium price tag of $3 million. The approval is subject to certain reservations. Although Bluebird gene therapy is a one-time treatment, it is not a cure for the 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 warns patients and doctors about the blood cancer risk 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,” said the Bluebird CEO Andrew Obenshain in a conference call on Monday. .
Adrenoleukodystrophy results from genetic mutations that lead to the accumulation of very long chain fatty acids in the brain that damage myelin, the protective covering of nerve cells. This damage leads to a series of problems, such as loss of the ability to walk, communicate, see and control muscle movement, among other complications. CALD is the most severe form of adrenoleukodystrophy, with onset in childhood. The X-linked disease mainly affects boys. Bluebird, based in Somerville, Massachusetts, estimates that about 40 boys in the United States develop CALD each year. A stem cell transplant offers a treatment option that can slow the progression of the disease. However, this procedure can introduce dangerous complications, especially in patients who do not have a matched donor.
Bluebird manufactures 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 injected back into the patient, where they are taken up into the bone marrow to differentiate into different types of cells capable of producing the protein needed to break down very long chain fatty acids. Bluebird has evaluated this gene therapy in a Phase 2/3 study and a Phase 3 clinical trial, two open-label studies that treated a total of 67 patients with early and active CALD. The FDA’s regulatory decision is based on results showing 24 months of improvement in a test that assesses six major functions, such as communication and wheelchair dependency.
Despite the positive results of clinical trials, the studies suffered a setback. Bluebird reported that three boys treated with Skysona developed myelodysplastic syndrome believed to be caused by gene therapy. This bone marrow cancer can develop when a lentivirus-based gene therapy delivers its genetic payload into or near a gene that causes cancer cells to grow. These cancer cases in the Skysona studies led the FDA to place CALD therapy on clinical hold last year. In June of this year, an FDA advisory committee voted unanimously to recommend approval of the therapy, concluding that its benefits outweigh its risks. Bluebird said the FDA lifted the clinical hold on Sept. 15, just before Skysona’s approval. But the risk of cancer is the basis of the black box warning on Skysona’s label.
The affirmative decision for Skysona is the second regulatory nod for Bluebird in the space of a month. In August, the agency approved gene therapy Bluebird Zynteglo for the treatment of beta-thalassemia, a rare blood disorder. This therapy costs $2.8 million and is offered under an outcome-based agreement that ties reimbursement to how well the therapy works in a patient. Skysona will not have a similar refund program because the ultra-rare nature of CALD makes it too difficult to offer, Obenshain said.
The European Commission last year granted Skysona standard approval for the treatment of CALD. The FDA’s decision for the gene therapy is an expedited 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 the 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 the accelerated approval requirements by using data from patients enrolled in a long-term follow-up study, which will follow clinical trial participants for 15 years, as well as ‘with the data of those treated with commercially available Skysona.
Skysona will be manufactured in the same factory that produces Zynteglo. Bluebird expects Skysona to launch by the end of this year, available at a limited number of qualified treatment centers, including Boston Children’s Hospital and Children’s Hospital of Philadelphia. The successful commercialization of the two gene therapies is crucial to raising the bar for Bluebird, which implemented a corporate restructuring earlier this year to save money and focus on its two most advanced gene therapies.
Approvals of Zynteglo and Skysona were accompanied by the award of a rare pediatric priority review voucher. These vouchers can be applied to the FDA’s rapid review of a future drug for a rare pediatric disease. However, these vouchers have become commodities and many companies choose to sell them to raise funds. Obenshain said Bluebird hired a bank to sell the vouchers; the company expects each to sell for approximately $110 million, providing the company with additional non-dilutive capital.
In a note sent to investors on Monday, William Blair analyst Raju Prasad said CALD is already included in newborn screening in the United States, currently covering around 75% of infants born. He added that the launch of the two Bluebird gene therapies could be an indicator of how a small biotech can execute a commercial launch of its gene therapies. Prasad said Skysona’s approval is a positive sign for Rocket Pharmaceuticals, a developer of lentiviral gene therapies that is on track for two regulatory filings with its lead therapeutic candidate.
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