RARE Daily

Bluebird bio Reports Positive Long-Term Data for CALD Gene Therapy

March 15, 2021

Rare Daily Staff

Bluebird Bio reported positive new data from the clinical development program for its experimental gene therapy in patients with cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that is estimated to affect one in 21,000 male newborns worldwide. ALD is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein (ALDP) and subsequently cause toxic accumulation of very long-chain fatty acids (VLCFAs) primarily in the adrenal cortex and white matter of the brain and spinal cord.

Approximately 40 percent of boys with adrenoleukodystrophy will develop CALD, the most severe form of ALD, which is progressive and neurodegenerative, involving the breakdown of the nerve cells in the brain that are responsible for thinking and muscle control. CALD is associated with six major functional disabilities (MFDs), which severely compromise a patient’s ability to function independently: loss of communication, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement. CALD usually occurs in early childhood and progresses rapidly, if untreated, leading to severe loss of neurologic function, and eventual death, in most patients.

Updated results from the pivotal phase 2/3 Starbeam study (ALD-102) and the long-term follow-up study LTF-304, as well as safety outcomes from the phase 3 ALD-104 study were presented in an oral session during the Presidential Symposium at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation.

The results showed that 90 percent of evaluable patients (27/30) were alive and free of major functional disabilities (MFDs) at two year follow-up in the phase 2/3 Starbeam study. Patients in the long-term follow-up study continue to remain alive and MFD-free up to nearly seven years of follow-up, suggesting Bluebird’s eli-cel gene therapy stabilized the progression of the disease. Importantly, there have been no reports of graft failure, rejection, graft-versus host disease, replication competent lentivirus or insertional oncogenesis in the 51 patients treated with eli-cel in the two studies.

“As we continue the long-term follow-up of these patients, we are encouraged that there are now 14 boys who have reached at least their Year five follow-up visit and continue to be living without MFDs, demonstrating the potential for a prolonged treatment effect,” said Richard Colvin, head of severe genetic diseases clinical research and development, Bluebird Bio. “There is a great need for alternative treatment options that reduce the risk of the serious immune complications associated with allogeneic stem cell transplantation, the current standard of care for CALD.”

Early diagnosis of CALD is important, and newborn screening for ALD is currently part of active in 19 states and the District of Columbia, accounting for greater than 60 percent of U.S. newborns. Outside the U.S., the Netherlands has approved the addition of ALD to their newborn screening program. Even though ALD newborn screening has not been implemented in most EU countries, efforts to begin pilot programs are slowly progressing.

Bluebird’s eli-cel is a one-time experimental gene therapy designed to add functional copies of the ABCD1 gene into a patient’s own hematopoietic (blood) stem cells (HSCs) that have been transduced ex vivo with the Lenti-D lentiviral vector (LVV). The addition of the functional ABCD1 gene allows patients to produce the adrenoleukodystrophy protein (ALDP), which is thought to activate the breakdown of VLCFAs. The goal of treatment with eli-cel is to stabilize the progression of CALD and consequently preserve as much neurological function as possible. Importantly, with eli-cel, there is no need for donor HSCs from another person.

In October 2020, the European Medicines Agency (EMA) accepted Bluebird Bio’s marketing authorization application for its investigational eli-cel gene therapy for the treatment of patients with CALD. The EMA accepted eli-cel gene therapy for the treatment of CALD into its Priorities Medicines scheme (PRIME) in July 2018, and previously granted Orphan Medicinal Product designation to eli-cel.

The U.S. Food and Drug Administration granted eli-cel 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 (BLA) in the U.S. in mid-2021.

Bluebird Bio is currently enrolling patients for a Phase 3 study (ALD-104) designed to assess the efficacy and safety of eli-cel after myeloablative conditioning using busulfan and fludarabine in patients with CALD.

Photo: Richard Colvin, head of severe genetic diseases clinical research and development, Bluebird Bio

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