Data Point to Promise of Stem Cell Therapies for CALD Patients, Bluebird Bio Reports

Data Point to Promise of Stem Cell Therapies for CALD Patients, Bluebird Bio Reports

Bluebird Bio presented recent data from clinical trials in which two of its lead investigational therapies for cerebral adrenoleukodystrophy (CALD) were tested — a gene therapy that uses patient-derived stem cells called Lenti-D, and an allogeneic (donor-derived) stem cell transplant called ALD-103.

The data, particularly promising in patients treated with Lenti-D and those given ALD-103 using stem cells from a sibling donor, were presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018 Symposium in Athens.


Lenti-D is based on the patients’ own (autologous) hematopoietic (blood)-forming stem cells, which are harvested and modified via gene transfer, using an inactive lentivirus to deliver the ABCD-1 gene. This gene carries the instructions to produce a functional adrenoleukodystrophy protein (ALDP) that is critical for the breakdown of very long chain fatty acids (VLCFAs), but is defective in CALD patients. Lenti-D is delivered in a single blood infusion.

In CALD, the build-up of VLCFAs in the brain causes the destruction of the protective myelin sheath around nerve cells, impairing the nerve cell’s ability to communicate with the brain.

The ongoing, open-label Phase 2/3 Starbeam study (NCT01896102) testing Lenti-D has completed patient enrollment, with a total of 31 boys under age 18 diagnosed with CALD.

The trial’s main goal is to assess the effectiveness and safety of Lenti-D. Efficacy is measured by the number of participants who are alive and free of major functional disabilities after two years of follow-up. Such disabilities include loss of ability to communicate, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.

Additional (secondary) efficacy endpoint disabilities include brain lesions, detected by magnetic resonance imaging (MRI) performed every six months, and Neurologic Function Scores (NFS).

As of April 25, 29 of the 31 patients had received the Lenti-D gene therapy. Out of the 17 patients who completed the two-year follow-up period (median follow-up of 41.4 months), 88 percent of them (15 patients) were alive and free of major functional disabilities. One of these 17 withdrew from the study, and another died after quickly developing major disabilities post-treatment.

Fourteen of these 15 patients were negative for new brain lesions, compared to their previous MRI scans. Eleven did have intermittent re-emergence of brain lesions at various follow-up assessments, but the intensity of these lesions was significantly lower and not related to clinical outcomes.

After 24 months, 14 of the 15 patients had a NFS below or equal to 1 at their most recent follow-up — the lower the NFS score, the lower the degree of neurological dysfunction. One patient had an increase in NFS from 1 to 2, because of impaired vision and non-febrile seizures. Another, whose disease progressed rapidly and led to several major functional disabilities, had an NFS of 17 at the last follow-up.

Safety, based on the number of patients who develop graft-versus-host-disease (GVHD), which occurs when the body’s immune system reacts to and rejects the transplant, seemed promising. No case of acute or chronic GvHD was reported 24 months after Lenti-D treatment, and researchers reported no case of transplant failure.

Treatment with Lenti-D was linked to three potential adverse events: bladder inflammation, tachycardia, and vomiting.

The update on the Starbeam’s results was presented by Paul Gissen, PhD, consultant at the Pediatric Metabolic Diseases at Great Ormond Street Hospital, London, United Kingdom, in a SSIEM presentation titled, “Lenti-D hematopoietic stem cell gene therapy for cerebral adrenoleukodystrophy: safety and efficacy outcomes from an ongoing Ph 2/3 trial.”

“As a physician who treats boys with CALD, I see its devastating effects on young children and families,” Gissen said in a press release.

“Data from the Phase 2/3 Starbeam study suggest that Lenti-D, which utilizes a child’s own cells and does not require a matched donor, may be a potential treatment for CALD,” Gissen added.


ALD-103, Bluebird’s allogeneic (donor-derived) hematopoietic stem cell transplant (HSCT) is being tested in an ongoing observational study. Currently recruiting patients at sites in the U.S., Europe and Canada, the study (NCT02204904) is evaluating the therapy’s efficacy and safety in young (under 18) CALD patients.

As of April 25, 41 patients received treatment with ALD-103 – in 31 patients, the cells came from unrelated donors. The other 10 received cells from a family donor.

Early cerebral disease was found in 25 patients, as shown by positive MRI lesions, or a score of 0.5 or higher (but below 9) in the Loes scale (a measure of the location and extension of myelin loss), or a NFS score up to 1.

Estimates for two-year outcomes in these patients predict that 78 percent of those with early disease will be free of major functional disabilities, as will 71 percent of all patients (41 in total).

Six patients (14.6 percent) who received the transplant from an unrelated donor died within a year, and the transplant failed in another five of them (12 percent), requiring a second transplant.

Out of the 41 who received ALD-103, 34 percent (14 patients) experienced acute or chronic GvHD.

Overall, the findings suggest that while ALD-103 may help treat CALD, using donor-derived stem cells may lead to immune-related complications, especially in patients whose transplant cells come from non-family matched donors.

The data were presented by Robert Chiesa, MD, at the Pediatric Bone Marrow Transplantation at Great Ormond Street Hospital, London, at SSIEM in a presentation titled, “An observational study of patients with cerebral adrenoleukodystrophy (CALD) treated with allogeneic hematopoietic stem cell transplant.”


“The data we presented from our Phase 2/3 Starbeam study are consistent with the results we have observed with Lenti-D to date, with the additional follow-up showing durable lack of progression to major functional disabilities (MFD) in boys who were MFD-free at 24 months post-treatment,” said David Davidson, MD, chief medical officer of Bluebird Bio.

“The data from the ALD-103 study highlight the increased risks of mortality and morbidity in boys without a matched sibling donor who undergo allogeneic HSCT,” he added.

Bluebird Bio also announced that it has reached an agreement with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on the clinical development of Lenti-D as a therapy for CALD, in order to support future marketing applications.

“We look forward to working with the FDA and EMA to advance our goal of delivering a gene therapy for patients with this terrible disease,” Davidson concluded.