Rare Daily Staff

Bluebird Bio said interim results from an initial cohort of 17 patients in the ongoing phase 2/3 study Lenti-D, its experimental gene therapy in boys with cerebral adrenoleukodystrophy, or CALD, a potentially fatal disease that causes a breakdown in the protective sheath of nerve cells in the brain responsible for thinking and muscle control.

Currently, the only effective treatment option for patients with CALD is allogeneic hematopoietic stem cell transplant. However, such transplants carry potential fatal complications and opportunistic infections.

“Currently, allogeneic hematopoietic stem cell transplant is the only available therapy–but one that presents challenges for patients without a matched sibling donor,” said David Williams, principal investigator of the study. “These data suggest that Lenti-D may also be a viable option for patients, and one that, being autologous, could potentially overcome some of the challenges associated with allogeneic stem cell transplantation.”

The primary efficacy endpoint for the study is the proportion of patients who are alive and have no major functional disabilities at 24 months post drug product infusion. Major functional disabilities are the six severe disabilities commonly attributed to CALD that, if present, would have a profound negative impact on patients’ lives: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence and complete loss of voluntary movement.

The primary safety endpoint is the proportion of patients who experience grade 2+ acute graft vs. host disease or chronic graft vs. host disease at 24 months post-treatment. Secondary and exploratory assessments include Neurologic Function Score (NFS; a scoring system of 15 symptoms/signs across multiple domains used to evaluate the severity of gross neurologic dysfunction), gadolinium enhancement on MRI (an indicator of neuroinflammation), MRI Loes score (a method for quantifying brain lesions in patients with CALD using brain MRI), and additional safety assessments.

As of the April 25, 2017 data cut-off, 15 of the 17 the patients infused with Lenti-D drug product remain alive and free of major functional disabilities, the primary efficacy endpoint of the trial. Median follow-up at the time of data analysis was 29.4 months. This exceeds the pre-defined efficacy success benchmark for the study of 76 percent major functional disability-free survival at 24 months for this initial subset of patients.

Most adverse events occurred during the two weeks post-transplant and most were associated with myeloablative chemotherapy. One possibly drug-related serious adverse event occurred (viral cystitis) and resolved with standard measures. There was no engraftment failure, graft versus host disease, or life-threatening infections. There was no evidence of insertional oncogenesis.

Two patients did not meet the primary efficacy endpoint. One patient had not experienced an MFD, but withdrew from the study due to radiographic progression of disease and underwent allogeneic hematopoietic stem cell transplantation. He subsequently died from complications of the allogeneic transplantation.

A second patient, as previously reported in April 2016, had rapid disease progression beginning early in his participation in the study, resulting in multiple MFDs and an NFS of 15. The rapidity of his disease progression suggests it would have been difficult to alter his early neurological decline given that Lenti-D treatment takes months to exert a therapeutic effect in CALD.

The results were published in the New England Journal of Medicine.

October 5, 2017

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