BlueBird Provides Positive Results from Experimental CALD Gene Therapy

Rare Daily Staff

Bluebird Bio reported encouraging results for its experimental gene therapy eli-cel for people with cerebral adrenoleukodystrophy, a fatal neurodegenerative disease.

Researchers presented long-term results from the phase 2/3 Starbeam study (ALD-102/LTF-304) and data from the phase 3 ALD-104 study at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation, which is being held virtually.

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 and subsequently cause toxic accumulation of very long-chain fatty acids 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. CALD is a progressive neurodegenerative disease that involves breakdown of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. Symptoms of CALD usually occur in early childhood and progress rapidly, if untreated, leading to severe loss of neurologic function, and eventual death, in most patients. Nearly half of boys with CALD who do not receive treatment will die within five years of symptom onset.

Eli-cel is a one-time investigational gene therapy designed to address the underlying genetic cause of CALD by adding functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells that have been transduced ex vivo with the Lenti-D lentiviral vector. The addition of a functional gene allows patients to produce the adrenoleukodystrophy protein, which is thought to break down the toxic accumulation of very long-chain fatty acids in the brain. There is no need for donor hematopoietic stem cells from another person, as is required for allogenic transplantation.

Long-term results from the phase 2/3 Starbeam study (ALD-102/LTF-304) suggest durability of response post eli-cel with all 20 patients, who were free of major functional disabilities at two years (out of 23 evaluable patients), remained free of major functional disabilities through last available follow-up, including all 10 patients who reached at least year five follow-up visit.

“Eighty-seven percent of patients in our phase 2/3 Starbeam study of eli-cel are alive and free of major functional disabilities (MFDs) at 24 months or more of follow-up. Importantly, there were no reports of graft failure, graft rejection, or GVHD,” said David Davidson, chief medical officer. “It is gratifying to see the consistent outcomes with eli-cel and the durability of the treatment effect demonstrated in the children participating in our long-term follow-up study – including 10 boys who have now reached at least their year five follow-up visit.”

Some 31 out of 32 patients in ALD-102 had stable Neurologic Function Scores following treatment with eli-cel, including 24 patients with a score of zero as of the last available visit.

“Patients with CALD experience a rapid decrease in neurologic function after the initial onset of clinical symptoms, so early diagnosis and treatment is critical in order to stop the disease progression and preserve their neurological function,” said Jörn-Sven Kühl of the Department of Pediatric Oncology, Hematology, and Hemostaseology at the Center for Women’s and Children’s Medicine, University Hospital Leipzig. “In the phase 2/3 Starbeam study, 31 of 32 patients had a stable neurologic function score, suggesting that disease progression had stabilized, and minimal neurological function was lost, following eli-cel infusion.”

In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency granted an accelerated assessment to eli-cel gene therapy for CALD. Bluebird Bio is currently on track to submit the marketing authorization application in the European Union for eli-cel for CALD by the end of 2020, and a biologics license application in the United States in mid-2021.

The European Medicines Agency (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.   

Photo: David Davidson, chief medical officer