Rare Disease Report

NEJM Publishes Interim Data from Study of Gene Therapy in Lorenzo

OCTOBER 05, 2017
Mathew Shanley
Yesterday, the New England Journal of Medicine (NEJM) published interim data from an initial cohort of 17 patients in bluebird bio’s ongoing Phase 2/3 Starbeam Study (ALD-102).1

The global, multi-center study is assessing the safety and efficacy of the Lenti-D investigational gene therapy in boys up to 17 years of age with cerebral adrenoleukodystrophy (CALD), or Lorenzo’s Oil disease.

CALD is the cerebral form of ALD, which affects approximately 21,000 male births worldwide. The disease can cause permanent damage to the nerve cells in the brain due to breakdown of the myelin sheath.

In CALD, severe clinical symptoms can lead to irreversible impairments which jeopardizes a patient’s ability to function. Children generally are symptom-free for the first few years of life, however, between the ages of 2 and 10, the disease begins present more severely. Early symptoms commonly include mild dementia, hyperactivity, poor coordination, but patients are subject to rapid progression, and will most likely be in a vegetative state within a few years.

At present, the only effective treatment option for patients with CALD is allogeneic hematopietic stem cell transplant (HSCT), however, there are many potential complications of such a procedure, including graft failure, graft versus host disease (GVHD) and opportunistic infections. The goal of Lenti-D  gene therapy is to halt progression of the disease.

The interim data published in the NEJM was updated as of April 25, 2017, and at that time, 16 of the 17 patients enrolled in the study had completed the primary analysis period (24 months or discontinuation). Additionally, 15 infused with Lenti-D gene therapy had met the primary endpoint of the trial, as they remained alive and free of major functional disabilities (MFDs).

As it pertains to the 2 remaining patients, 1 withdrew from the study and later died from complications of allogeneic transplantation. The second patient showed rapid deterioration of neurologic function soon after treatment and died approximately 22 months after the infusion due to a viral infection complicated by rhabdomyolysis and acute kidney and liver failure. Cause of death was not directly related to the investigational therapy. 

The preliminary results imply that treatment of CALD with Lenti-D gene therapy is safe and has led to clinical stabilization and stable neurological function in a large proportion of patients in the study. Additionally, many patients with CALD who had been administered Lenti-D therapy experienced limited progression of the disease in comparison to the known rates of progression among untreated boys.
In July, when bluebird bio announced the clinical data from the Starbeam Study, David Davidson, M.D., the company’s chief medical officer stressed the importance of the trial.2

“The hope that Lenti-D may benefit boys facing such a devastating disease inspires all of us at bluebird,” Davidson said in a press release. “Having this proportion of the initial cohort of patients meet the primary endpoint is truly gratifying, bringing us one step closer to our goal of making Lenti-D available for patients with CALD. The two patients who did not meet the primary endpoint underscore the devastating nature of CALD, the importance of early diagnosis through newborn screening, and the challenges of the current standard of care with allogeneic hematopoietic stem cell transplant.”

In their discussion of the study, the authors noted that concerns of mutagenesis pertinent to viral integration after a gene is added to hematopoietic stem cells were not observed That is likely due to the use of a lentiviral vector in lieu of the gamma-retroviral vector used in other studies in which mutagenesis was observed, leading to the development of leukemia and myelodysplastic syndrome in some patients receiving gene therapy.

While vectors of Lenti-D appear to reduce the risk of mutagenesis, a longer follow-up and larger sample size are still required to confirm the duration of response, and long-term clinical efficacy and safety of the gene therapy in CALD.

  1. Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Gene Therapy for Cerebral Adrenoleukodystrophy. New England Journal of Medicine. 2017. doi: 10.1056/NEJMoa1700554.
  2. bluebird bio Announces [news release]. Cambridge, MA: bluebird bio, Inc.; October 4, 2017. businesswire.com/news/home/20171004006203/en/bluebird-bio-Announces-Publication-Interim-Data-Starbeam. Accessed October 5, 2017.

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