Rare Daily Staff

Bluebird bio reported positive, long-term results from the clinical development program for its investigational gene therapy in patients with cerebral adrenoleukodystrophy (CALD), which showed that 88 percent of treated patients were free of major functional disabilities at two years, and continued to remain free of these disabilities at up to five years of follow-up.

The updated results were presented at the 13th European Pediatric Neurology Society Congress in Athens, Greece.

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 35 to 40 percent of boys with ALD will develop cerebral ALD, or 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, and if untreated, lead to severe loss of neurologic function, and eventual death in most patients.

Currently, the only therapeutic option for patients with CALD is allogeneic hematopoietic stem cell transplant (allo-HSCT). Beneficial effects have been reported if allo-HSCT is performed early in the course of cerebral disease. Potential complications of allo-HSCT, which can be fatal, include graft failure and rejection, GvHD, and opportunistic infections, particularly in patients who do not have an HLA-matched sibling donor for transplant.

The phase 2/3 Starbeam study (ALD-102) is assessing the efficacy and safety of bluebird’s Lenti-D gene therapy in boys 17 years of age and under with CALD. Updated data from the ongoing observational study (ALD-103) of allogeneic hematopoietic stem cell transplant (allo-HSCT) in boys 17 years of age and under with CALD were also presented.

“With the longest follow-up from the phase 2/3 Starbeam study now up to five years, the data show that all boys with CALD who were treated with Lenti-D and were free of major functional disabilities (MFDs) at 24 months continued to be MFD-free. Importantly, there were no reports of graft failure or treatment-related mortality, and adverse events were generally consistent with myeloablative conditioning,” said David Davidson, chief medical officer of Bluebird Bio. “These results support the potential of Lenti-D as a treatment for CALD, which we hope may become an option for the boys and their families affected by this devastating disease.”

The phase 2/3 Starbeam study is completely enrolled with 32 patients with a median follow-up time of 21.2 months. Of the 32 patients who have received Lenti-D as of April 25, 2019, 15 have completed ALD-102 and enrolled in a long-term follow-up study, 14 are currently on-study, and three are no longer on-study.

The primary efficacy endpoint in the study is the proportion of patients who are alive and free of MFDs at 24 months. MFDs are six severe disabilities commonly attributed to CALD and thought to have the most profound impact on a patient’s ability to function independently, including loss of ability to communicate, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.

Of those patients who have or would have reached 24 months of follow-up and completed the study, 15 out of 17 patients, or 88 percent, continue to be alive and MFD-free in a long-term follow-up study. The 14 patients currently on study have less than 24 months of follow-up and have shown no evidence of MFDs. The longest follow-up of the additional 14 patients was 20.4 months. Three out of the 32 treated patients did not or will not meet the primary efficacy endpoint; two patients withdrew from the study at investigator discretion, and one experienced rapid disease progression early on-study resulting in MFDs and death. No patients experienced graft-versus-host disease by month 24, the primary safety endpoint.

“I see the impact CALD has on my young patients and their families in my practice and understand the urgent need for additional treatment options,” said Caroline Sevin, Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France, and an investigator in the Starbeam study. “These updated data from the Starbeam study are encouraging because there continues to be no report of graft-versus-host disease or graft failure post-Lenti-D treatment, and Lenti-D utilizes a child’s own cells, eliminating the need for a donor as well as complications that may be involved with donor cells.”

Bluebird also presented results from its ongoing observational study ALD-103 of allo-HSCT treatment in boys 17 years of age and younger with CALD. The study enrolled 47 patients who had undergone allo-HSCT. Updated results show that early treatment with allo-HSCT provides improved overall and MFD-free survival for patients with CALD irrespective of the stage of early disease. In the all early disease cohort at 24 months post-allo-HSCT, 77.2 percent of patients achieved MFD-free survival and 89.1 percent achieved overall survival compared to 35.0 percent and 52.5 percent, respectively, in the advanced disease cohort at 24 months post-allo-HSCT.

The risk associated with allo-HSCT varied by donor source. While there were no substantial differences observed between the groups in ALD-103, more patients who were treated with umbilical cord stem cells from an unrelated donor (38.9 percent) experienced engraftment failure by 24 months compared to patients who received bone marrow or umbilical cord cells from a matched sibling donor or bone marrow cells from an unrelated donor (zero percent in both groups).

About 25 percent of patients experienced acute and chronic GvHD. One-year transplant-related mortality was 12.1 percent (4 out of 33 evaluable patients). The overall rate of engraftment failure by 24 months was 21.6 percent occurring in eight of 37 evaluable patients.

These data suggest that, while allo-HSCT appears to halt disease progression, it can be associated with serious safety risks and most transplant-related risks vary by donor source and conditioning regimen.

Bluebird Bio is currently enrolling patients for a phase 3 study (ALD-104) designed to assess the efficacy and safety of Lenti-D gene therapy after myeloablative conditioning using busulfan and fludarabine in patients with CALD. Bluebird is also conducting a long-term safety and efficacy follow-up study for patients who have participated in the earlier gene therapy studies.

Bluebird’s Lenti-D gene therapy was approved for marketing by the European Medicines Agency in July 2018. It has Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation in the United States for the treatment of CALD.

Photo: David Davidson, chief medical officer of Bluebird Bio

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