FDA Grants Breakthrough Therapy Designation to Gene Therapy for Cerebral Adrenoleukodystrophy


The FDA has granted a Breakthrough Therapy designation to bluebird bio, Inc’s Lenti-D, a gene therapy for patients with cerebral adrenoleukodystrophy, an X-linked genetic disorder caused by a defect in the gene ABCD1.

The FDA has granted a Breakthrough Therapy designation to bluebird bio, Inc’s Lenti-D, a gene therapy for patients with cerebral adrenoleukodystrophy (CALD), an X-linked genetic disorder caused by a defect in the gene ABCD1. This mutation results in the abnormal breakdown of very-long-chain fatty acids and adversely affects adrenal and nervous system tissues in male children. The inflammatory cerebral phenotype of adrenoleukodystrophy can be fatal. Currently, the only therapeutic option for patients with CALD is allogenic hematopoietic stem cell transplant, which must be undertaken early in the course of the disease.

According to a statement made by David Davidson, MD, CMO of bluebird bio, “The founding of bluebird was inspired by the potential to develop a one-time gene therapy for boys suffering from this potentially fatal form of adrenoleukodystrophy. With Lenti-D, we hope the modified, autologous hematopoietic stem cells will keep these boys alive and free from major functional disabilities while avoiding many of the safety risks of the current standard of care, allogeneic hematopoietic stem cell transplant.”

The Breakthrough designation for the drug was supported by preliminary data from the ongoing phase 2 and 3 STARBEAM study, early results of which were published in the New England Journal of Medicine in October 2017. STARBEAM enrolled boys with early CALD in a single-group, open-label safety and efficacy study. The primary endpoint was remaining alive and having no major functional disability at 24 months following infusion of autologous CD34+ cells that were transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector.

In total, 17 patients aged 17 years or younger received the study treatment between October 2013 and July 2015. At the time of the data cut-off for the interim analysis, the median follow-up was 29.4 months (range, 21.6-42.0). No toxic effects related to the infusion of the study drug were reported. Most adverse events occurred during the conditioning phase or the first 2 weeks after infusion, and were generally consistent with the adverse events associated with myeloablative chemotherapy.

At the time of the interim analysis, 15 of the 17 patients (88%) were alive, free of major functional disabilities. Two patients had neurologic disease progression; one withdrew from the study and later died from complications of allogenic transplantation, and the other developed a major functional disability by month 9 and later died from a viral infection.

The researchers reported that, at the time of the data cutoff, therapy with Lenti-D was effective in 15 of the 17 patients treated, but a longer follow-up and larger sample size will be needed to confirm the safety and efficacy of the treatment.


Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2017;377:1630-1638. doi: 10.1056/NEJMoa1700554.

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