Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy

Abstract

Background: Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy.

Methods: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score.

Results: A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up.

Conclusions: At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

Figure 1.. Kaplan–Meier Analyses of Overall Survival and Survival Free of Major Functional Disabilities.

Survival free of major functional disabilities (MFDs) was defined as survival without receipt of allogeneic hematopoietic stem-cell transplantation and free of the following six MFDs: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement. Data from patients who withdrew from the study and whose final outcome was unknown were censored at the time they withdrew from the study. Twenty-six patients are MFD-free and remain in long-term follow-up. One patient died of transplantation-related causes after withdrawal from the study after undergoing allogeneic hematopoietic stem-cell transplantation, which had been performed owing to disease progression detected by radiography; this death is included in the Kaplan–Meier estimate. I bars indicate 95% confidence intervals; the widths of the confidence intervals have not been adjusted for multiplicity and should not be used for hypothesis testing.

Figure 2.. Individual Patient Results for Gadolinium Enhancement Status and Neurologic Function Score Over Time (Secondary End Points).

The neurologic function score ranges from 0 to 25, with higher scores indicating more severe deficits.