RARE Daily

FDA Approves Bluebird Bio’s Gene Therapy for CALD

September 19, 2022

The U.S. Food and Drug Administration approved Bluebird Bio’s Skysona, its gene therapy to treat the progressive neurodegenerative condition early, active cerebral adrenoleukodystrophy.

Photo: Andrew Obenshain, CEO of Bluebird Bio

The approval was made under the agency’s accelerated approval pathway. Skysona will have a wholesale price of $3 million. It follows the agency’s approval last month of Bluebird’s Zynteglo, the first gene therapy for beta thalassemia.

Cerebra adrenoleukodystrophy (CALD) primarily affects young boys and 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. Nearly half of patients who do not receive treatment die within five years of symptom onset. Prior to the approval of Skysona, effective options were limited to allogeneic hematopoietic stem cell transplant, which is associated with the risk of serious potential complications including death, which can increase dramatically in patients without a human leukocyte antigen matched donor.

Skysona is a one-time gene therapy custom-designed to treat the underlying cause of 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 cells. The addition of the functional ABCD1 gene allows patients to produce the ALD protein, which can then participate in the local degradation of very long-chain fatty acids. This degradation of VLCFAs is believed to slow or possibly prevent further inflammation and demyelination.

“For the ALD community, this long-awaited approval represents significant hope and offers families a new option where, for many, there had been none,” said Andrew Obenshain, CEO of Bluebird Bio. He said the company will work with providers and payers to make the gene therapy available to patients and their families.

As a condition of the Skysona accelerated approval, bluebird has agreed to provide confirmatory long-term clinical data to the FDA. Bluebird anticipates that this will include data from the ongoing long-term follow-up study (LTF-304), which follows patients treated in clinical trials for 15 years, and from commercially treated patients.

Bluebird anticipates that commercial product will be available by the end of 2022 through a limited number of Qualified Treatment Centers in the United States, including Boston Children’s Hospital and Children’s Hospital of Philadelphia.

Bluebird received a rare pediatric priority review voucher upon the approval of Skysona. The agency previously granted the gene therapy Orphan Drug designation, Rare Pediatric Disease designation, and Breakthrough Therapy designation.

The approval of Skysona is based on data from Bluebird Bio’s phase 2/3 study ALD-102 (Starbeam) and phase 3 ALD-104 study. Both open-label, single-arm studies enrolled patients with early, active CALD who had elevated very long chain fatty acid values, a Loes score between 0.5 and 9 (inclusive), and gadolinium enhancement on magnetic resonance imaging of demyelinating lesions. Additionally, patients were required to have a neurologic function score of ≤ 1, indicating limited changes in neurologic function. The efficacy of Skysona was compared to a natural history population.

Per protocol, patients treated with Skysona were assessed using the neurologic function score and monitored for the emergence of six Major Functional Disabilities associated with CALD progression including loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement.

The Accelerated Approval of Skysona is based on 24-month Major Functional Disabilities-free survival. A post-hoc enrichment analysis in symptomatic patients assessed MFD-free survival from onset of symptoms (NFS ≥ 1) in Skysona treated (N=11) and untreated patients (N=7). Skysona treated patients had an estimated 72 percent likelihood of MFD-free survival at 24 months from time of first NFS ≥ 1, compared to untreated patients who had only an estimated 43 percent likelihood of MFD-free survival.

The most common non-laboratory adverse reactions (incidence ≥ 20 percent) are mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥40 percent) include leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, and hypokalemia.

“The agony of watching your child slip away is something no parent should have to bear,” said Elisa Seeger, co-founder, ALD Alliance. “We have made significant strides in providing children diagnosed with CALD the best chance at life with early identification of ALD through expanded newborn screening. Yet with limited treatment options, early diagnosis is still cause for despair instead of hope for many families. Today, parents whose boys receive a CALD diagnosis can have renewed hope for the future.”

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